Mullerian Aplasia and Hyperandrogenism

Mendelian MONDO:0008019 Pathograph 18 Show in embeddings browser Müllerian duct anomaly 46,XX disorder of sex development

Mullerian aplasia and hyperandrogenism (WNT4 deficiency) is a very rare 46,XX difference of sex development caused by heterozygous loss-of-function missense variants in WNT4, the secreted signal that is required to form the Mullerian ducts and that represses androgen synthesis in the developing and adult ovary. Affected women present in adolescence with primary amenorrhea and an absent or hypoplastic uterus, as in Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, but in addition show clinical hyperandrogenism (acne, hirsutism) with raised serum testosterone of ovarian origin. Unilateral renal agenesis was present in the index case and ovarian follicle depletion in one later case. Functional studies of the reported variants show loss of WNT4 signalling, dominant-negative behaviour for at least some alleles, and derepression of the steroidogenic enzymes CYP17A1 and HSD3B2 in ovarian cells. The phenotype closely mirrors that of female Wnt4-null mice, which lack Mullerian ducts and ectopically synthesize testosterone in the ovary. It is distinct from SERKAL syndrome, the recessive WNT4 disorder of biallelic loss with 46,XX sex reversal and kidney, adrenal and lung dysgenesis, and from classic MRKH syndrome, in which WNT4 variants are not found.

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Mappings

MONDO

MONDO:0008019 mullerian aplasia and hyperandrogenism

Primary MONDO identifier for the disease.

NCIT

NCIT:C120376 Mullerian Aplasia and Hyperandrogenism

MONDO records NCIT C120376 as an equivalent of MONDO:0008019, and the NCIT label names the same entity.

NCIT

NCIT:C120376 Mullerian Aplasia and Hyperandrogenism

MONDO records NCIT C120376 as an equivalent of MONDO:0008019, and the NCIT label names the same entity.

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Inheritance

Autosomal dominant HP:0000006

All reported patients carry a single heterozygous WNT4 missense variant, and at least some of these alleles behave as dominant negatives in functional assays. Familial transmission has not been documented in the published abstracts, so the dominant mode rests on heterozygosity of the disease alleles rather than on pedigree segregation.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:40992710 SUPPORT BACKGROUND Human Clinical

"Autosomal dominant WNT4 missense variants have been shown to cause Mullerian aplasia and hyperandrogenism (MIM# 158330)."

States the dominant mode of inheritance for this disease, named by its OMIM number, in the background of a SERKAL syndrome study.

PMID:18987495 SUPPORT REVIEW SYNTHESIS Human Clinical

"The recent demonstration of heterozygous WNT4 defects in patients with Mullerian agenesis and signs of ovarian hyperandrogenism added WNT4 to the growing list of genes"

A review by the group that reported the first cases summarizes that the causal WNT4 defects are heterozygous.

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Pathophysiology

Heterozygous WNT4 Loss of Function

Heterozygous missense variants reduce WNT4 signalling. The four reported alleles (E226G, R83C, L12P, A233T) were each shown to be functionally defective, and R83C acts as a dominant negative, which would explain how a single allele produces a phenotype when heterozygous Wnt4 loss is silent in the mouse. The degree of loss differs between alleles: A233T only partly loses the ability to repress ovarian steroidogenic enzymes.

WNT4 hgnc:12783

Wnt signaling pathway GO:0016055 ↓ DECREASED

frizzled binding GO:0005109 ↓ DECREASED

Downstream

Failed Mullerian Duct Formation WNT4 is required for the formation and elongation of the Mullerian duct, so loss of WNT4 signalling prevents the duct and its derivatives from forming.

Derepressed Ovarian Androgen Biosynthesis WNT4 normally represses steroidogenic enzyme expression in the ovary; the mutant proteins fail to do so.

Impaired Nephron Tubulogenesis Wnt4 is required in the metanephric mesenchyme for the mesenchyme-to-epithelium conversion that forms nephrons. This edge rests on homozygous null mouse data; whether a single human dominant allele disturbs kidney development by this route is not established.

Show evidence (3 references)

PMID:15317892 SUPPORT Human Clinical

"A genetic evaluation revealed a loss-of-function mutation in the WNT4 gene."

The index case carries a loss-of-function WNT4 variant.

PMID:16959810 SUPPORT Human Clinical

"This patient carried the novel R83C loss-of-function dominant negative mutation in her WNT4"

The second case carries an allele characterized as a dominant-negative loss of function; the functional characterization was done in human ovarian (OVCAR3) cells, as the same abstract states.

PMID:40992710 SUPPORT BACKGROUND In Vitro

"Functional studies suggest that at least a subset of these WNT4 missense variants act in a dominant negative fashion"

Summarizes the functional work on the dominant alleles: a subset, not all, have been shown to be dominant negative.

Failed Mullerian Duct Formation

The Mullerian (paramesonephric) duct is the anlage of the Fallopian tubes, uterus and upper vagina. WNT4 is needed for the migration of the cells that initiate the duct and for its posterior elongation; without it the duct fails to form, and its derivatives are absent or hypoplastic. In the reported patients the uterus was absent or hypoplastic while ovaries were present.

paramesonephric duct development GO:0061205 ↓ DECREASED

Animal models

Wnt4-null mouse Mouse recapitulates Complete absence of the Mullerian duct in female null embryos.

Wnt4 mCherry hypomorphic mouse Mouse partially recapitulates Incompletely penetrant failure of Mullerian duct formation with reduced WNT4 dosage.

Amhr2-Cre Wnt4 and Wnt5a double conditional knockout mouse Mouse partially recapitulates Partial Mullerian agenesis after combined mesenchymal loss of Wnt4 and Wnt5a.

Downstream

Aplasia of the Uterus The uterus is a Mullerian duct derivative, so failure of duct formation leaves it absent.

Hypoplasia of the Uterus A hypomorphic allele may allow partial duct development, leaving a small uterus rather than none.

Aplasia of the Vagina The upper vagina is a Mullerian duct derivative, so failure of duct formation can leave the vagina absent.

Primary Amenorrhea Without a functional uterus there is no menstruation, so failure of Mullerian duct formation presents as primary amenorrhea despite ovarian tissue.

Show evidence (2 references)

PMID:26721931 SUPPORT Model Organism

"Moreover, Wnt4 is required for the initiation of MD-forming cell migration."

Mouse lineage tracing and antibody-blocking work places the WNT4 requirement at the initiation and extension of the duct.

PMID:9989404 SUPPORT Model Organism

"Wnt-4-mutant females are masculinized-the Mullerian duct is absent while the Wolffian duct continues to develop."

Female Wnt-4-null mice have no Mullerian duct.

Derepressed Ovarian Androgen Biosynthesis

In the ovary WNT4 represses the steroidogenic enzymes of the androgen pathway (CYP17A1, HSD3B2, and in the mouse also Cyp11a1 and Hsd17b enzymes) and, in the fetal mouse gonad, keeps adrenal-type steroidogenic precursor cells from migrating in. Loss of WNT4 releases this repression and the ovary synthesizes testosterone. In mice the excess androgen maintains the Wolffian ducts; in women it produces acne, hirsutism and raised serum testosterone.

negative regulation of androgen biosynthetic process GO:2000180 ↓ DECREASED androgen biosynthetic process GO:0006702 ↑ INCREASED

Animal models

Wnt4-null mouse Mouse recapitulates Null ovaries express testosterone biosynthetic enzymes and secrete testosterone into the embryonic circulation.

Downstream

Increased Serum Testosterone Ovarian testosterone synthesis raises circulating testosterone.

Hirsutism Hirsutism is the androgen-dependent hair response to the raised circulating testosterone.

Acne Acne is a cutaneous sign of the androgen excess.

Show evidence (3 references)

PMID:15932923 SUPPORT Model Organism

"We demonstrate here that testosterone is produced by the ovary of Wnt-4-deficient female embryos and is also detected in the embryonic plasma."

Direct demonstration in the mouse that loss of Wnt-4 makes the ovary synthesize testosterone.

PMID:12835383 SUPPORT Model Organism

"We show that WNT4 represses mesonephric endothelial and steroidogenic cell migration in the XX gonad, preventing the formation of a male-specific coelomic blood vessel and the production of steroids."

Identifies a cellular route for the repression in the fetal XX gonad: WNT4 keeps steroidogenic cells out.

PMID:21377155 SUPPORT In Vitro

"Interestingly, this mutant partially lacks the capability to repress ovarian steroidogenic enzymes, with abnormal expression of 17α- hydroxylase."

In human ovarian cells a disease allele fails to repress 17alpha-hydroxylase (CYP17A1).

Impaired Nephron Tubulogenesis

In the developing kidney Wnt4 acts as an autoinducer of the conversion of metanephric mesenchyme into the epithelial tubules that become nephrons. Wnt4-null mice fail at this step. In this disease only the index patient had a renal anomaly (unilateral renal agenesis), so the kidney arm is poorly characterized in humans and the mechanism is extrapolated from the mouse.

mesenchymal to epithelial transition involved in metanephros morphogenesis GO:0003337 ↓ DECREASED

Animal models

Wnt4-null mouse Mouse recapitulates Null metanephric mesenchyme fails to form pretubular aggregates.

Downstream

Unilateral Renal Agenesis Proposed link between disturbed WNT4-dependent kidney development and the renal agenesis of the index patient. Renal agenesis normally reflects failure of the ureteric bud rather than of nephron induction, and mouse Wnt4 loss leaves ureteric development intact, so the intermediate steps are unknown.

Show evidence (1 reference)

PMID:7990960 SUPPORT Model Organism

"Thus, Wnt-4 appears to act as an autoinducer of the mesenchyme to epithelial transition that underlies nephron development."

Defines the renal function of Wnt-4 from the knockout mouse.

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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

Endocrine 1

Increased Serum Testosterone Increased serum testosterone level HP:0030088

Show evidence (3 references)

PMID:16959810 SUPPORT Human Clinical

"biochemical (repeatedly high levels of testosterone) signs of androgen excess"

Raised testosterone on repeated measurement in the R83C patient.

PMID:18182450 SUPPORT Human Clinical

"plasma testosterone: 1.8 vs. 1.2 nmol/liter in controls"

Raised plasma testosterone in the L12P patient.

PMID:24641817 SUPPORT BACKGROUND Human Clinical

"While nearly all cases of WNT4 mutations reported in the literature to date had clinical and biochemical signs of androgen excess as pathognomonic signs"

Summarizes the WNT4 case literature: biochemical androgen excess was present in nearly all reported carriers.

Genitourinary 5

Aplasia of the Uterus HP:0000151

Show evidence (2 references)

PMID:16959810 SUPPORT Human Clinical

"the absence of a uterus (and not other Müllerian abnormalities) and the androgen excess are the pathognomonic signs of WNT4 defects"

Names uterine absence as one of the two defining signs.

PMID:15317892 SUPPORT Human Clinical

"An 18-year-old woman presented with primary amenorrhea and an absence of müllerian-derived structures"

The index case lacks Mullerian-derived structures, including the uterus.

Hypoplasia of the Uterus HP:0000013

Show evidence (1 reference)

PMID:18182450 SUPPORT Human Clinical

"She also presented with uterine hypoplasia and follicle depletion."

Reports uterine hypoplasia in a WNT4 L12P carrier.

Aplasia of the Vagina HP:0003250

Show evidence (1 reference)

PMID:24641817 SUPPORT BACKGROUND Human Clinical

"the absence of the vagina and uterus and excess androgen levels are the pathognomonic signs of WNT4 defects"

A later MRKH cohort study summarizes the WNT4 case literature as showing absence of both vagina and uterus.

Primary Amenorrhea HP:0000786

Show evidence (2 references)

PMID:15317892 SUPPORT Human Clinical

"An 18-year-old woman presented with primary amenorrhea and an absence of müllerian-derived structures"

Primary amenorrhea was the presenting complaint of the index case.

PMID:18182450 SUPPORT Human Clinical

"the adolescent carrying the mutation was referred to our clinic for primary amenorrhea and hyperandrogenism"

Primary amenorrhea was also the presenting complaint of the L12P carrier.

Unilateral Renal Agenesis HP:0000122

Show evidence (1 reference)

PMID:15317892 SUPPORT Human Clinical

"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"

Unilateral renal agenesis in the index case.

Immune 1

Acne HP:0001061

Show evidence (2 references)

PMID:16959810 SUPPORT Human Clinical

"clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess"

Acne is reported in the R83C patient.

PMID:18182450 SUPPORT Human Clinical

"hyperandrogenism (severe acne and plasma testosterone: 1.8 vs. 1.2 nmol/liter in controls)"

Severe acne is reported in the L12P patient.

Integument 1

Hirsutism HP:0001007

Show evidence (1 reference)

PMID:16959810 SUPPORT Human Clinical

"clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess"

Hirsutism is reported in the R83C patient.

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Genetic Associations

WNT4 (Heterozygous loss-of-function missense variants)

Gene: WNT4 hgnc:12783 gene page relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:15317892 SUPPORT Human Clinical

"A genetic evaluation revealed a loss-of-function mutation in the WNT4 gene."

The founding gene-disease report.

PMID:16959810 SUPPORT Human Clinical

"This patient carried the novel R83C loss-of-function dominant negative mutation in her WNT4, confirming the role of WNT4 in the development and maintenance of the female phenotype in women."

A second unrelated patient with the same phenotype and a different WNT4 allele.

PMID:18182450 SUPPORT Human Clinical

"This amino acid substitution is unlikely to be a polymorphism because it was not found in 100 DNAs from control subjects."

A third allele, L12P, absent from controls.

+ 1 more reference

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Medical Actions

Progressive Vaginal Dilation

Action: progressive vaginal self-dilation Ontology label: Vaginal Dilation Therapy NCIT:C93165

Platform: Behavioral / lifestyle

Non-surgical creation of a functional vagina by progressive dilation is the first-line approach in Mullerian agenesis, with surgical vaginoplasty reserved for failure or patient preference. No treatment study is specific to WNT4 deficiency; the recommendation is carried over from Mullerian agenesis in general, which shares the vaginal defect.

Mechanism Target:

RESTORES Aplasia of the Vagina — Creates a functional vaginal canal by stretching the residual vaginal dimple, without correcting the developmental defect.

Show evidence (2 references)

PMID:29266078 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Nonsurgical vaginal elongation by dilation should be the first-line approach."

Guideline recommendation for Mullerian agenesis, applied here because this disorder is a genetically defined form of Mullerian agenesis.

PMID:28434104 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Several non-surgical and surgical procedures have been reported for the creation of a functional neovagina; in general, non-surgical treatment should be the first initially pursued."

A review of MRKH syndrome management reaching the same first-line recommendation.

In Vitro Fertilization with a Gestational Carrier

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

Platform: Other

IVF with the patient's own oocytes and transfer to a gestational carrier is the established route to genetic parenthood in Mullerian agenesis, and uterus transplantation is an emerging alternative. In WNT4 deficiency the route depends on ovarian reserve, which may be reduced: follicle depletion was reported in one patient. No fertility outcomes specific to this disorder are published.

Mechanism Target:

BYPASSES Aplasia of the Uterus — Bypasses the absent uterus by gestating the patient's genetic embryo in a carrier.

Show evidence (1 reference)

PMID:29266078 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

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

Efficacy in Mullerian agenesis generally; not studied in WNT4 deficiency specifically.

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Diagnosis

WNT4 sequencing in Mullerian anomaly with hyperandrogenism

WNT4 analysis is indicated in an adolescent with primary amenorrhea, an absent or hypoplastic uterus and clinical or biochemical hyperandrogenism. WNT4 screening of unselected Mullerian aplasia without androgen excess has a very low yield.

Show evidence (2 references)

PMID:18182450 SUPPORT Human Clinical

"We suggest that in adolescent girls with primary amenorrhea, müllerian duct abnormalities, and hyperandrogenism, a WNT4 mutation should be sought."

States the clinical triad that should prompt WNT4 testing.

PMID:22503279 SUPPORT Human Clinical

"The results suggest that WNT4 might not contribute to the aetiology of Müllerian duct abnormalities in Chinese women."

An unselected Mullerian anomaly cohort without hyperandrogenism yielded no WNT4 cases.

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Prevalence

Worldwide

Cases In Literature Not yet documented

No population estimate exists. Four distinct pathogenic WNT4 alleles had been reported by 2011 (E226G, R83C, L12P and A233T), each in a single patient. Screening of Mullerian anomaly cohorts in China (189 women) and India (32 women) found no causal WNT4 variants, so the disorder accounts for a very small fraction of Mullerian aplasia.

Show evidence (3 references)

PMID:21377155 SUPPORT Human Clinical

"This fourth new WNT4 mutation confirms that this signaling molecule is involved in mullerian development and androgen biosynthesis repression in the ovary."

Identifies the A233T allele as the fourth reported WNT4 mutation, which is the size of the published case series at that point.

PMID:22503279 SUPPORT Human Clinical

"This study screened WNT4 for mutation in 189 Chinese women with Müllerian duct abnormalities (10 Mayer-Rokitansky-Küster-Hauser syndrome, five Müllerian aplasia and 174 incomplete Müllerian fusion) and detected no perturbation that would indicate a major role for WNT4."

A negative cohort screen that bounds how often WNT4 explains Mullerian anomalies.

PMID:36738897 SUPPORT Human Clinical

"In conclusion, we could not find any indication about WNT4 involvement in the disease condition."

A second negative screen, in 32 Indian 46,XX patients with Mullerian agenesis or gonadal dysgenesis, consistent with the disorder being rare.

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Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Mullerian Aplasia and Hyperandrogenism:

Mayer-Rokitansky-Kuster-Hauser syndrome MONDO:0017771

Overlapping Features The closest mimic: congenital absence of the uterus and upper vagina in a 46,XX woman with normal ovarian function, presenting as primary amenorrhea. Classic MRKH syndrome does not show clinical virilization, and WNT4 variants are not found in MRKH cohorts. Biochemical hyperandrogenemia alone does not separate the two, because raised androgen indices without clinical signs are common in MRKH syndrome. Acne or hirsutism with Mullerian aplasia should prompt WNT4 analysis.

Show evidence (5 references)

PMID:38699388 SUPPORT REVIEW SYNTHESIS Human Clinical

"MD agenesis caused by WNT4 variants is associated with clinical and biochemical hyperandrogenism, representing a phenotype distinct from MRKH syndrome in general"

A 2024 review of MRKH genetics separates WNT4 Mullerian agenesis from MRKH syndrome on the basis of hyperandrogenism.

PMID:16959810 SUPPORT Human Clinical

"suggesting that this might be a clinical entity distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome"

The original argument for treating WNT4 deficiency as a separate entity.

PMID:24641817 SUPPORT Human Clinical

"As many as 42/69 (60.1%) showed hyperandrogenemia without other clinical signs of virilization"

A second MRKH cohort with frequent, clinically silent hyperandrogenemia, reinforcing that biochemistry alone does not separate the two disorders.

+ 2 more references

MURCS association Not Yet Curated MONDO:0010989

Overlapping Features Mullerian duct aplasia with renal anomalies and cervicothoracic somite dysplasia (MRKH syndrome type 2). It shares Mullerian aplasia and renal agenesis with this disorder and can coexist with clinical hyperandrogenism, but the vertebral and other skeletal anomalies distinguish it, and WNT4 is not mutated.

Show evidence (1 reference)

PMID:24356390 SUPPORT Human Clinical

"We report an adolescent girl with the cardinal features of MURCS association, obesity, and clinical findings of hyperandrogenism who did not show any exonic mutation of the WNT4 gene."

A MURCS patient with hyperandrogenism, the closest phenocopy, had no WNT4 variant.

SERKAL syndrome Not Yet Curated MONDO:0012734

Overlapping Features The allelic recessive WNT4 disorder. Homozygous loss-of-function WNT4 variants cause 46,XX female-to-male sex reversal with dysgenesis of the kidneys, adrenals and lungs and other developmental defects, typically lethal in fetal life. It differs from this disorder in inheritance (biallelic versus a single dominant allele), in gonadal sex (testicular differentiation versus ovaries) and in the extent of organ involvement.

Show evidence (1 reference)

PMID:18179883 SUPPORT Human Clinical

"We report a novel autosomal-recessive syndrome that consists of female to male sex reversal and renal, adrenal, and lung dysgenesis and is associated with additional developmental defects."

Defines SERKAL syndrome, the distinct recessive WNT4 phenotype.

Polycystic ovary syndrome MONDO:0008487

Overlapping Features Shares ovarian hyperandrogenism with acne and hirsutism, and can present with amenorrhea, but the uterus is present and the amenorrhea is anovulatory. WNT4 coding variants were not found in a PCOS series, so WNT4 is not a cause of typical PCOS.

Show evidence (2 references)

PMID:17071531 SUPPORT Human Clinical

"Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women of childbearing age and is characterized by chronic anovulation with either oligomenorrhea or amenorrhea and hyperandrogenism."

States the features PCOS shares with this disorder.

PMID:17071531 SUPPORT Human Clinical

"This study demonstrates that, at least in the population studied, mutations of the open reading frame of WNT-4 gene or its intron/exon junctions are not the cause of PCOS."

WNT4 coding variants were absent in 25 women with PCOS.

🐁

Animal Models

Wnt4-null mouse

Female Wnt4-null mice lack Mullerian ducts, retain Wolffian ducts and ectopically synthesize testosterone in the ovary, which is the combination seen in the human disease. Males are normal at birth. The knockout also fails to form nephrons and dies shortly after birth, so the adult reproductive phenotype cannot be studied in it.

Species

Mouse

Genotype

Wnt4 homozygous null (knockout)

Publication

PMID:9989404

Pathograph links

Failed Mullerian Duct Formation recapitulates fidelity: moderate observes: tissue Complete absence of the Mullerian duct in female null embryos.

Limitations: The mouse is homozygous null whereas patients are heterozygous for missense alleles, some dominant negative; heterozygous mice are not reported to share the phenotype, so the model shows the requirement for WNT4 rather than the human dosage sensitivity.

Show evidence (1 reference)

PMID:9989404 SUPPORT Model Organism

"Wnt-4-mutant females are masculinized-the Mullerian duct is absent while the Wolffian duct continues to develop."

Reports the absent Mullerian duct in null females.

Derepressed Ovarian Androgen Biosynthesis recapitulates fidelity: moderate observes: organism Null ovaries express testosterone biosynthetic enzymes and secrete testosterone into the embryonic circulation.

Limitations: Androgen excess in the mouse is fetal and is read out as Wolffian duct maintenance; the human phenotype is adolescent clinical hyperandrogenism, which the perinatal-lethal knockout cannot show.

Show evidence (1 reference)

PMID:15932923 SUPPORT Model Organism

"Consistent with this, the expression of several genes encoding enzymes in the pathway leading to the synthesis of testosterone in the mouse is induced in the Wnt-4-deficient ovary, including Cyp11a, Cyp17, Hsd3b1, Hsd17b1, and Hsd17b3."

Measures the derepressed steroidogenic enzymes in the null ovary.

Impaired Nephron Tubulogenesis recapitulates fidelity: low observes: tissue Null metanephric mesenchyme fails to form pretubular aggregates.

Limitations: The null mouse has a severe bilateral nephrogenesis defect, while the human disease shows at most unilateral renal agenesis in a single case; the model establishes the renal role of WNT4 but not that heterozygous human alleles act through it.

Show evidence (1 reference)

PMID:7990960 SUPPORT Model Organism

"Mice lacking Wnt-4 activity fail to form pretubular cell aggregates; however, other aspects of mesenchymal and ureteric development are unaffected."

Reports the tubulogenesis defect in the knockout kidney.

Show evidence (1 reference)

PMID:9989404 SUPPORT Model Organism

"Wnt-4 is initially required in both sexes for formation of the Mullerian duct, then Wnt-4 in the developing ovary appears to suppress the development of Leydig cells; consequently, Wnt-4-mutant females ectopically activate testosterone biosynthesis."

Summarizes the two arms of the null phenotype that correspond to the human disease.

Wnt4 mCherry hypomorphic mouse

A hypomorphic Wnt4 allele allows some animals to survive to adulthood. The Mullerian duct forms in only about 45 percent of cases, and the resulting reproductive tract shows a poorly coiled oviduct, no endometrial glands and an undifferentiated myometrium. The model shows that reduced rather than absent WNT4 activity can still prevent or distort Mullerian development, which bears on the partial-loss human alleles.

Species

Mouse

Genotype

Wnt4 mCh/mCh (hypomorphic allele)

Publication

PMID:26721931

Pathograph links

Failed Mullerian Duct Formation partially recapitulates fidelity: moderate observes: tissue Incompletely penetrant failure of Mullerian duct formation with reduced WNT4 dosage.

Limitations: The allele is a reporter fusion hypomorph in a homozygous state, not a heterozygous human missense variant, and ovarian androgen production was not reported.

Show evidence (1 reference)

PMID:26721931 SUPPORT Model Organism

"In contrast to the Wnt4 null embryos, some Wnt4(monomeric cherry/monomeric cherry) (Wnt4(mCh/mCh)) hypomorphic mice survived to adulthood and formed MD in ∼45% of cases."

Reduced Wnt4 dosage leaves Mullerian duct formation incompletely penetrant.

Show evidence (1 reference)

PMID:26721931 SUPPORT Model Organism

"Examination of the reproductive tract of the Wnt4(mCh/mCh) females indicated a poorly coiled oviduct, absence of the endometrial glands and an undifferentiated myometrium, and these mice were prone to develop a hydro-uterus."

Describes the adult reproductive tract of the hypomorph.

Amhr2-Cre Wnt4 and Wnt5a double conditional knockout mouse

Deleting Wnt4 together with Wnt5a in Mullerian duct mesenchyme causes partial agenesis of Mullerian derivatives in a third of females, with normal ovaries. It shows that WNT4 acts partly redundantly with WNT5A in the mesenchyme after the duct has formed.

Species

Mouse

Genotype

Wnt4 flox/flox; Wnt5a flox/flox; Amhr2-Cre

Publication

PMID:30010727

Pathograph links

Failed Mullerian Duct Formation partially recapitulates fidelity: low observes: tissue Partial Mullerian agenesis after combined mesenchymal loss of Wnt4 and Wnt5a.

Limitations: Requires loss of a second Wnt gene and acts after duct initiation, so it models a later and partly redundant WNT4 function rather than the single-gene human defect; the ovaries are normal, so the androgen arm is not modelled.

Show evidence (1 reference)

PMID:30010727 SUPPORT Model Organism

"Furthermore, a third of Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+ females had a partial agenesis of Müllerian duct-derived structures, but with normal oviducts and ovaries."

Reports partial Mullerian agenesis in the double conditional knockout.

Show evidence (1 reference)

PMID:30010727 SUPPORT Model Organism

"Together, our results suggest that Wnt4 and Wnt5a play redundant roles in the development of the female reproductive tract, and may provide insight into the etiology of certain cases of Müllerian agenesis in women."

States the redundancy conclusion and its relevance to human Mullerian agenesis.

{ }

Source YAML

click to show

name: Mullerian Aplasia and Hyperandrogenism
creation_date: "2026-10-08T13:31:10Z"
category: Mendelian
description: >-
  Mullerian aplasia and hyperandrogenism (WNT4 deficiency) is a very rare 46,XX
  difference of sex development caused by heterozygous loss-of-function
  missense variants in WNT4, the secreted signal that is required to form the
  Mullerian ducts and that represses androgen synthesis in the developing and
  adult ovary. Affected women present in adolescence with primary amenorrhea
  and an absent or hypoplastic uterus, as in Mayer-Rokitansky-Kuster-Hauser
  (MRKH) syndrome, but in addition show clinical hyperandrogenism (acne,
  hirsutism) with raised serum testosterone of ovarian origin. Unilateral
  renal agenesis was present in the index case and ovarian follicle depletion
  in one later case. Functional studies of the reported variants show loss of
  WNT4 signalling, dominant-negative behaviour for at least some alleles, and
  derepression of the steroidogenic enzymes CYP17A1 and HSD3B2 in ovarian
  cells. The phenotype closely mirrors that of female Wnt4-null mice, which
  lack Mullerian ducts and ectopically synthesize testosterone in the ovary.
  It is distinct from SERKAL syndrome, the recessive WNT4 disorder of
  biallelic loss with 46,XX sex reversal and kidney, adrenal and lung
  dysgenesis, and from classic MRKH syndrome, in which WNT4 variants are not
  found.
disease_term:
  preferred_term: Mullerian aplasia and hyperandrogenism
  term:
    id: MONDO:0008019
    label: mullerian aplasia and hyperandrogenism
synonyms:
- WNT4 deficiency
- Mullerian duct failure and hyperandrogenism
- Müllerian duct failure and hyperandrogenism
- Müllerian aplasia and hyperandrogenism
- Atypical Mayer-Rokitansky-Kuster-Hauser syndrome with hyperandrogenism
parents:
- Müllerian duct anomaly
- 46,XX disorder of sex development
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008019
      label: mullerian aplasia and hyperandrogenism
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO identifier for the disease.
  ncit_mappings:
  - term:
      id: NCIT:C120376
      label: Mullerian Aplasia and Hyperandrogenism
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO records NCIT C120376 as an equivalent of MONDO:0008019, and the NCIT
      label names the same entity.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    All reported patients carry a single heterozygous WNT4 missense variant,
    and at least some of these alleles behave as dominant negatives in
    functional assays. Familial transmission has not been documented in the
    published abstracts, so the dominant mode rests on heterozygosity of the
    disease alleles rather than on pedigree segregation.
  evidence:
  - reference: PMID:40992710
    reference_title: "WNT4 deficiency impacts heart, diaphragm, and palate development: Insights from human genetics, machine learning, and mouse models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Autosomal dominant WNT4 missense variants have been shown to cause Mullerian aplasia and hyperandrogenism (MIM# 158330)."
    explanation: >-
      States the dominant mode of inheritance for this disease, named by its
      OMIM number, in the background of a SERKAL syndrome study.
  - reference: PMID:18987495
    reference_title: WNT4 and sex development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The recent demonstration of heterozygous WNT4 defects in patients with Mullerian agenesis and signs of ovarian hyperandrogenism added WNT4 to the growing list of genes"
    explanation: >-
      A review by the group that reported the first cases summarizes that the
      causal WNT4 defects are heterozygous.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population estimate exists. Four distinct pathogenic WNT4 alleles had
    been reported by 2011 (E226G, R83C, L12P and A233T), each in a single
    patient. Screening of Mullerian anomaly cohorts in China (189 women) and
    India (32 women) found no causal WNT4 variants, so the disorder accounts
    for a very small fraction of Mullerian aplasia.
  evidence:
  - reference: PMID:21377155
    reference_title: Molecular analysis of WNT4 gene in four adolescent girls with mullerian duct abnormality and hyperandrogenism (atypical Mayer-Rokitansky-Küster-Hauser syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This fourth new WNT4 mutation confirms that this signaling molecule is involved in mullerian development and androgen biosynthesis repression in the ovary."
    explanation: >-
      Identifies the A233T allele as the fourth reported WNT4 mutation, which
      is the size of the published case series at that point.
  - reference: PMID:22503279
    reference_title: Mutations in WNT4 are not responsible for Müllerian duct abnormalities in Chinese women.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study screened WNT4 for mutation in 189 Chinese women with Müllerian duct abnormalities (10 Mayer-Rokitansky-Küster-Hauser syndrome, five Müllerian aplasia and 174 incomplete Müllerian fusion) and detected no perturbation that would indicate a major role for WNT4."
    explanation: >-
      A negative cohort screen that bounds how often WNT4 explains Mullerian
      anomalies.
  - reference: PMID:36738897
    reference_title: "Mutation analysis of WNT4 gene in SRY negative 46,XX DSD patients with Mullerian agenesis and/or gonadal dysgenesis- An Indian study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, we could not find any indication about WNT4 involvement in the disease condition."
    explanation: >-
      A second negative screen, in 32 Indian 46,XX patients with Mullerian
      agenesis or gonadal dysgenesis, consistent with the disorder being rare.
pathophysiology:
- name: Heterozygous WNT4 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Heterozygous missense variants reduce WNT4 signalling. The four reported
    alleles (E226G, R83C, L12P, A233T) were each shown to be functionally
    defective, and R83C acts as a dominant negative, which would explain how a
    single allele produces a phenotype when heterozygous Wnt4 loss is silent in
    the mouse. The degree of loss differs between alleles: A233T only partly
    loses the ability to repress ovarian steroidogenic enzymes.
  genes:
  - preferred_term: WNT4
    term:
      id: hgnc:12783
      label: WNT4
  molecular_functions:
  - preferred_term: frizzled binding
    modifier: DECREASED
    term:
      id: GO:0005109
      label: frizzled binding
  biological_processes:
  - preferred_term: Wnt signaling pathway
    modifier: DECREASED
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  evidence:
  - 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: "A genetic evaluation revealed a loss-of-function mutation in the WNT4 gene."
    explanation: >-
      The index case carries a loss-of-function WNT4 variant.
  - reference: PMID:16959810
    reference_title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This patient carried the novel R83C loss-of-function dominant negative mutation in her WNT4"
    explanation: >-
      The second case carries an allele characterized as a dominant-negative
      loss of function; the functional characterization was done in human
      ovarian (OVCAR3) cells, as the same abstract states.
  - reference: PMID:40992710
    reference_title: "WNT4 deficiency impacts heart, diaphragm, and palate development: Insights from human genetics, machine learning, and mouse models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Functional studies suggest that at least a subset of these WNT4 missense variants act in a dominant negative fashion"
    explanation: >-
      Summarizes the functional work on the dominant alleles: a subset, not
      all, have been shown to be dominant negative.
  downstream:
  - target: Failed Mullerian Duct Formation
    causal_link_type: DIRECT
    description: >-
      WNT4 is required for the formation and elongation of the Mullerian duct,
      so loss of WNT4 signalling prevents the duct and its derivatives from
      forming.
    evidence:
    - 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: "WNT4 appears to be important in the development and maintenance of the female phenotype in women, by means of the regulation of müllerian-duct formation and control of ovarian steroidogenesis."
      explanation: >-
        The authors attribute the patient's absent Mullerian structures to loss
        of WNT4 regulation of Mullerian duct formation.
    - reference: PMID:9989404
      reference_title: Female development in mammals is regulated by Wnt-4 signalling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Wnt-4 is initially required in both sexes for formation of the Mullerian duct"
      explanation: >-
        In the mouse, absence of Wnt-4 is sufficient to prevent Mullerian duct
        formation.
  - target: Derepressed Ovarian Androgen Biosynthesis
    causal_link_type: DIRECT
    description: >-
      WNT4 normally represses steroidogenic enzyme expression in the ovary;
      the mutant proteins fail to do so.
    evidence:
    - reference: PMID:18182450
      reference_title: "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional analysis revealed that the mutation induces significantly increased expression of the enzymes involved in androgen biosynthesis (3beta-hydroxysteroid dehydrogenase and 17alpha-hydroxylase)."
      explanation: >-
        The L12P allele, expressed in vitro, raises expression of the androgen
        biosynthetic enzymes that wild-type WNT4 represses.
    - reference: PMID:21377155
      reference_title: Molecular analysis of WNT4 gene in four adolescent girls with mullerian duct abnormality and hyperandrogenism (atypical Mayer-Rokitansky-Küster-Hauser syndrome).
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional studies revealed partial repression of steroidogenic enzymes (normal repression of HSD3B2) contrasting with the abnormal reexpression of CYP17A1 enzyme in the OVCAR3 cell line."
      explanation: >-
        The A233T allele fails to repress CYP17A1 in ovarian cells, a partial
        version of the same defect.
  - target: Impaired Nephron Tubulogenesis
    causal_link_type: DIRECT
    description: >-
      Wnt4 is required in the metanephric mesenchyme for the
      mesenchyme-to-epithelium conversion that forms nephrons. This edge rests
      on homozygous null mouse data; whether a single human dominant allele
      disturbs kidney development by this route is not established.
    evidence:
    - reference: PMID:7990960
      reference_title: Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice lacking Wnt-4 activity fail to form pretubular cell aggregates; however, other aspects of mesenchymal and ureteric development are unaffected."
      explanation: >-
        Loss of Wnt-4 in the mouse blocks the first step of nephron formation.
- name: Failed Mullerian Duct Formation
  biological_scale: TISSUE
  description: >-
    The Mullerian (paramesonephric) duct is the anlage of the Fallopian tubes,
    uterus and upper vagina. WNT4 is needed for the migration of the cells that
    initiate the duct and for its posterior elongation; without it the duct
    fails to form, and its derivatives are absent or hypoplastic. In the
    reported patients the uterus was absent or hypoplastic while ovaries were
    present.
  biological_processes:
  - preferred_term: paramesonephric duct development
    modifier: DECREASED
    term:
      id: GO:0061205
      label: paramesonephric duct development
  evidence:
  - reference: PMID:26721931
    reference_title: Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, Wnt4 is required for the initiation of MD-forming cell migration."
    explanation: >-
      Mouse lineage tracing and antibody-blocking work places the WNT4
      requirement at the initiation and extension of the duct.
  - reference: PMID:9989404
    reference_title: Female development in mammals is regulated by Wnt-4 signalling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Wnt-4-mutant females are masculinized-the Mullerian duct is absent while the Wolffian duct continues to develop."
    explanation: >-
      Female Wnt-4-null mice have no Mullerian duct.
  downstream:
  - target: Aplasia of the Uterus
    causal_link_type: DIRECT
    description: >-
      The uterus is a Mullerian duct derivative, so failure of duct formation
      leaves it absent.
    evidence:
    - reference: PMID:16959810
      reference_title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This 19-year-old woman was affected by primary amenorrhoea, absence of Müllerian ducts derivatives, clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess."
      explanation: >-
        The R83C patient lacks Mullerian duct derivatives, the uterus among
        them.
  - target: Hypoplasia of the Uterus
    causal_link_type: DIRECT
    description: >-
      A hypomorphic allele may allow partial duct development, leaving a small
      uterus rather than none.
    evidence:
    - reference: PMID:18182450
      reference_title: "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Moreover, our data confirm that WNT4 is involved in the regulation of müllerian duct development and ovarian androgen biosynthesis."
      explanation: >-
        The study reporting the L12P patient with uterine hypoplasia attributes
        the Mullerian abnormality to WNT4's role in duct development; that the
        hypoplasia reflects partial rather than absent duct formation is an
        inference.
  - target: Aplasia of the Vagina
    causal_link_type: DIRECT
    description: >-
      The upper vagina is a Mullerian duct derivative, so failure of duct
      formation can leave the vagina absent.
    evidence:
    - reference: PMID:24641817
      reference_title: "Acne and PCOS are less frequent in women with Mayer-Rokitansky-Küster-Hauser syndrome despite a high rate of hyperandrogenemia: a cross-sectional study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "the absence of the vagina and uterus and excess androgen levels are the pathognomonic signs of WNT4 defects"
      explanation: >-
        Attributes absence of the vagina, alongside the uterus, to WNT4
        defects.
  - target: Primary Amenorrhea
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Without a functional uterus there is no menstruation, so failure of
      Mullerian duct formation presents as primary amenorrhea despite ovarian
      tissue.
    evidence:
    - 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"
      explanation: >-
        Primary amenorrhea is reported together with the absent Mullerian
        structures that account for it.
- name: Derepressed Ovarian Androgen Biosynthesis
  biological_scale: CELLULAR
  description: >-
    In the ovary WNT4 represses the steroidogenic enzymes of the androgen
    pathway (CYP17A1, HSD3B2, and in the mouse also Cyp11a1 and Hsd17b
    enzymes) and, in the fetal mouse gonad, keeps adrenal-type steroidogenic
    precursor cells from migrating in. Loss of WNT4 releases this repression
    and the ovary synthesizes testosterone. In mice the excess androgen
    maintains the Wolffian ducts; in women it produces acne, hirsutism and
    raised serum testosterone.
  biological_processes:
  - preferred_term: negative regulation of androgen biosynthetic process
    modifier: DECREASED
    term:
      id: GO:2000180
      label: negative regulation of androgen biosynthetic process
  - preferred_term: androgen biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0006702
      label: androgen biosynthetic process
  evidence:
  - reference: PMID:15932923
    reference_title: "The partial female to male sex reversal in Wnt-4-deficient females involves induced expression of testosterone biosynthetic genes and testosterone production, and depends on androgen action."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We demonstrate here that testosterone is produced by the ovary of Wnt-4-deficient female embryos and is also detected in the embryonic plasma."
    explanation: >-
      Direct demonstration in the mouse that loss of Wnt-4 makes the ovary
      synthesize testosterone.
  - reference: PMID:12835383
    reference_title: Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that WNT4 represses mesonephric endothelial and steroidogenic cell migration in the XX gonad, preventing the formation of a male-specific coelomic blood vessel and the production of steroids."
    explanation: >-
      Identifies a cellular route for the repression in the fetal XX gonad:
      WNT4 keeps steroidogenic cells out.
  - reference: PMID:21377155
    reference_title: Molecular analysis of WNT4 gene in four adolescent girls with mullerian duct abnormality and hyperandrogenism (atypical Mayer-Rokitansky-Küster-Hauser syndrome).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Interestingly, this mutant partially lacks the capability to repress ovarian steroidogenic enzymes, with abnormal expression of 17α- hydroxylase."
    explanation: >-
      In human ovarian cells a disease allele fails to repress 17alpha-hydroxylase
      (CYP17A1).
  downstream:
  - target: Increased Serum Testosterone
    causal_link_type: DIRECT
    description: >-
      Ovarian testosterone synthesis raises circulating testosterone.
    evidence:
    - reference: PMID:15932923
      reference_title: "The partial female to male sex reversal in Wnt-4-deficient females involves induced expression of testosterone biosynthetic genes and testosterone production, and depends on androgen action."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These data imply that Wnt-4 signaling normally acts to suppress testosterone biosynthesis in the female, and that testosterone is the putative mediator of the masculinization phenotype in Wnt-4-deficient females."
      explanation: >-
        Places testosterone production downstream of Wnt-4 loss in the mouse
        ovary.
    - reference: PMID:18182450
      reference_title: "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is interesting to note that the adolescent carrying the mutation was referred to our clinic for primary amenorrhea and hyperandrogenism (severe acne and plasma testosterone: 1.8 vs. 1.2 nmol/liter in controls)."
      explanation: >-
        The patient whose allele derepressed androgen enzymes in vitro had
        raised plasma testosterone.
  - target: Hirsutism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Hirsutism is the androgen-dependent hair response to the raised
      circulating testosterone.
    evidence:
    - reference: PMID:16959810
      reference_title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess"
      explanation: >-
        The R83C patient's hirsutism is reported as a sign of her androgen
        excess.
  - target: Acne
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Acne is a cutaneous sign of the androgen excess.
    evidence:
    - reference: PMID:16959810
      reference_title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess"
      explanation: >-
        Acne is reported as a clinical sign of the androgen excess.
- name: Impaired Nephron Tubulogenesis
  biological_scale: TISSUE
  description: >-
    In the developing kidney Wnt4 acts as an autoinducer of the conversion of
    metanephric mesenchyme into the epithelial tubules that become nephrons.
    Wnt4-null mice fail at this step. In this disease only the index patient
    had a renal anomaly (unilateral renal agenesis), so the kidney arm is
    poorly characterized in humans and the mechanism is extrapolated from the
    mouse.
  biological_processes:
  - preferred_term: mesenchymal to epithelial transition involved in metanephros morphogenesis
    modifier: DECREASED
    term:
      id: GO:0003337
      label: mesenchymal to epithelial transition involved in metanephros morphogenesis
  evidence:
  - reference: PMID:7990960
    reference_title: Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, Wnt-4 appears to act as an autoinducer of the mesenchyme to epithelial transition that underlies nephron development."
    explanation: >-
      Defines the renal function of Wnt-4 from the knockout mouse.
  downstream:
  - target: Unilateral Renal Agenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed link between disturbed WNT4-dependent kidney development and the
      renal agenesis of the index patient. Renal agenesis normally reflects
      failure of the ureteric bud rather than of nephron induction, and mouse
      Wnt4 loss leaves ureteric development intact, so the intermediate steps
      are unknown.
    evidence:
    - 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
      directness: INDIRECT
      snippet: "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 authors relate the patient's combined phenotype, renal agenesis
        included, to the Wnt4-knockout mouse; the specific renal mechanism is
        not tested.
phenotypes:
- category: Genitourinary
  name: Aplasia of the Uterus
  description: >-
    Absence of the uterus with a 46,XX karyotype. The reporting group
    considers absence of the uterus, rather than other Mullerian anomalies,
    together with androgen excess, to be the pathognomonic combination for
    WNT4 deficiency.
  phenotype_term:
    preferred_term: Absent uterus
    term:
      id: HP:0000151
      label: Aplasia of the uterus
  evidence:
  - reference: PMID:16959810
    reference_title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the absence of a uterus (and not other Müllerian abnormalities) and the androgen excess are the pathognomonic signs of WNT4 defects"
    explanation: >-
      Names uterine absence as one of the two defining signs.
  - 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"
    explanation: >-
      The index case lacks Mullerian-derived structures, including the uterus.
- category: Genitourinary
  name: Hypoplasia of the Uterus
  description: >-
    A small uterus rather than complete absence, reported in the patient
    carrying the L12P allele.
  phenotype_term:
    preferred_term: Uterine hypoplasia
    term:
      id: HP:0000013
      label: Hypoplasia of the uterus
  evidence:
  - reference: PMID:18182450
    reference_title: "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also presented with uterine hypoplasia and follicle depletion."
    explanation: >-
      Reports uterine hypoplasia in a WNT4 L12P carrier.
- category: Genitourinary
  name: Aplasia of the Vagina
  description: >-
    Absence of the vagina, which in Mullerian aplasia means the upper,
    Mullerian-derived part. The primary case reports describe absent
    Mullerian derivatives without itemizing the vagina, and the R83C report
    stresses absence of the uterus rather than other Mullerian anomalies, so
    how consistently the vagina is involved is uncertain.
  phenotype_term:
    preferred_term: Vaginal aplasia
    term:
      id: HP:0003250
      label: Aplasia of the vagina
  evidence:
  - reference: PMID:24641817
    reference_title: "Acne and PCOS are less frequent in women with Mayer-Rokitansky-Küster-Hauser syndrome despite a high rate of hyperandrogenemia: a cross-sectional study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "the absence of the vagina and uterus and excess androgen levels are the pathognomonic signs of WNT4 defects"
    explanation: >-
      A later MRKH cohort study summarizes the WNT4 case literature as
      showing absence of both vagina and uterus.
- category: Genitourinary
  name: Primary Amenorrhea
  description: >-
    Absence of menarche, the usual reason for presentation in adolescence.
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  evidence:
  - 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"
    explanation: >-
      Primary amenorrhea was the presenting complaint of the index case.
  - reference: PMID:18182450
    reference_title: "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the adolescent carrying the mutation was referred to our clinic for primary amenorrhea and hyperandrogenism"
    explanation: >-
      Primary amenorrhea was also the presenting complaint of the L12P carrier.
- category: Endocrine
  name: Increased Serum Testosterone
  description: >-
    Repeatedly raised serum testosterone of ovarian origin. Hyperandrogenemia
    alone does not discriminate this disorder from classic MRKH syndrome,
    in which raised androgen indices are common and usually silent; it is the
    combination with clinical signs of androgen excess that points to WNT4.
  phenotype_term:
    preferred_term: Increased serum testosterone
    term:
      id: HP:0030088
      label: Increased serum testosterone level
  evidence:
  - reference: PMID:16959810
    reference_title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biochemical (repeatedly high levels of testosterone) signs of androgen excess"
    explanation: >-
      Raised testosterone on repeated measurement in the R83C patient.
  - reference: PMID:18182450
    reference_title: "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "plasma testosterone: 1.8 vs. 1.2 nmol/liter in controls"
    explanation: >-
      Raised plasma testosterone in the L12P patient.
  - reference: PMID:24641817
    reference_title: "Acne and PCOS are less frequent in women with Mayer-Rokitansky-Küster-Hauser syndrome despite a high rate of hyperandrogenemia: a cross-sectional study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "While nearly all cases of WNT4 mutations reported in the literature to date had clinical and biochemical signs of androgen excess as pathognomonic signs"
    explanation: >-
      Summarizes the WNT4 case literature: biochemical androgen excess was
      present in nearly all reported carriers.
- category: Dermatologic
  name: Hirsutism
  description: >-
    Excess terminal hair growth in an androgen-dependent pattern, a clinical
    sign of the ovarian androgen excess.
  phenotype_term:
    preferred_term: Hirsutism
    term:
      id: HP:0001007
      label: Hirsutism
  evidence:
  - reference: PMID:16959810
    reference_title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess"
    explanation: >-
      Hirsutism is reported in the R83C patient.
- category: Dermatologic
  name: Acne
  description: >-
    Acne, severe in at least one patient, as a clinical sign of androgen
    excess.
  phenotype_term:
    preferred_term: Acne
    term:
      id: HP:0001061
      label: Acne
  evidence:
  - reference: PMID:16959810
    reference_title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess"
    explanation: >-
      Acne is reported in the R83C patient.
  - reference: PMID:18182450
    reference_title: "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperandrogenism (severe acne and plasma testosterone: 1.8 vs. 1.2 nmol/liter in controls)"
    explanation: >-
      Severe acne is reported in the L12P patient.
- category: Renal
  name: Unilateral Renal Agenesis
  description: >-
    Absence of one kidney, reported in the index patient only. Later patients
    are not described with renal anomalies in the published abstracts, so its
    frequency in the disorder is unknown.
  phenotype_term:
    preferred_term: Unilateral renal agenesis
    term:
      id: HP:0000122
      label: Unilateral renal agenesis
  evidence:
  - 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"
    explanation: >-
      Unilateral renal agenesis in the index case.
genetic:
- name: WNT4
  gene_term:
    preferred_term: WNT4
    term:
      id: hgnc:12783
      label: WNT4
  relationship_type: CAUSATIVE
  association: Heterozygous loss-of-function missense variants
  notes: >-
    Reported pathogenic alleles are E226G (index case), R83C, L12P and A233T,
    each in a single 46,XX patient and each supported by functional assays in
    OVCAR3 or other cells. No ClinGen gene-disease validity curation exists for
    WNT4 in this disease (checked against the ClinGen gene-validity download),
    so no validity tier is recorded. Biallelic WNT4 loss causes a different
    disease, SERKAL syndrome. Common WNT4 locus variants associated with
    endometriosis, uterine fibroids and gynecologic cancers are not relevant to
    this entry.
  evidence:
  - 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: "A genetic evaluation revealed a loss-of-function mutation in the WNT4 gene."
    explanation: >-
      The founding gene-disease report.
  - reference: PMID:16959810
    reference_title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This patient carried the novel R83C loss-of-function dominant negative mutation in her WNT4, confirming the role of WNT4 in the development and maintenance of the female phenotype in women."
    explanation: >-
      A second unrelated patient with the same phenotype and a different WNT4
      allele.
  - reference: PMID:18182450
    reference_title: "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This amino acid substitution is unlikely to be a polymorphism because it was not found in 100 DNAs from control subjects."
    explanation: >-
      A third allele, L12P, absent from controls.
  - reference: PMID:21377155
    reference_title: Molecular analysis of WNT4 gene in four adolescent girls with mullerian duct abnormality and hyperandrogenism (atypical Mayer-Rokitansky-Küster-Hauser syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular analysis of the WNT4 gene permitted us to identify a new mutation (p.A233T)."
    explanation: >-
      A fourth allele, A233T, in a series of 46,XX girls with Mullerian
      anomaly and hyperandrogenism.
diagnosis:
- name: WNT4 sequencing in Mullerian anomaly with hyperandrogenism
  description: >-
    WNT4 analysis is indicated in an adolescent with primary amenorrhea, an
    absent or hypoplastic uterus and clinical or biochemical hyperandrogenism.
    WNT4 screening of unselected Mullerian aplasia without androgen excess has
    a very low yield.
  evidence:
  - reference: PMID:18182450
    reference_title: "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that in adolescent girls with primary amenorrhea, müllerian duct abnormalities, and hyperandrogenism, a WNT4 mutation should be sought."
    explanation: >-
      States the clinical triad that should prompt WNT4 testing.
  - reference: PMID:22503279
    reference_title: Mutations in WNT4 are not responsible for Müllerian duct abnormalities in Chinese women.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results suggest that WNT4 might not contribute to the aetiology of Müllerian duct abnormalities in Chinese women."
    explanation: >-
      An unselected Mullerian anomaly cohort without hyperandrogenism yielded
      no WNT4 cases.
treatments:
- name: Progressive Vaginal Dilation
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: progressive vaginal self-dilation
    term:
      id: NCIT:C93165
      label: Vaginal Dilation Therapy
  description: >-
    Non-surgical creation of a functional vagina by progressive dilation is
    the first-line approach in Mullerian agenesis, with surgical vaginoplasty
    reserved for failure or patient preference. No treatment study is
    specific to WNT4 deficiency; the recommendation is carried over from
    Mullerian agenesis in general, which shares the vaginal defect.
  target_mechanisms:
  - target: Aplasia of the Vagina
    treatment_effect: RESTORES
    description: >-
      Creates a functional vaginal canal by stretching the residual vaginal
      dimple, without correcting the developmental defect.
  evidence:
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Nonsurgical vaginal elongation by dilation should be the first-line approach."
    explanation: >-
      Guideline recommendation for Mullerian agenesis, applied here because
      this disorder is a genetically defined form of Mullerian agenesis.
  - reference: PMID:28434104
    reference_title: "Mullerian dysgenesis: a critical review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Several non-surgical and surgical procedures have been reported for the creation of a functional neovagina; in general, non-surgical treatment should be the first initially pursued."
    explanation: >-
      A review of MRKH syndrome management reaching the same first-line
      recommendation.
- 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 with the patient's own oocytes and transfer to a gestational carrier
    is the established route to genetic parenthood in Mullerian agenesis, and
    uterus transplantation is an emerging alternative. In WNT4 deficiency the
    route depends on ovarian reserve, which may be reduced: follicle depletion
    was reported in one patient. No fertility outcomes specific to this
    disorder are published.
  target_mechanisms:
  - target: Aplasia of the Uterus
    treatment_effect: BYPASSES
    description: >-
      Bypasses the absent uterus by gestating the patient's genetic embryo in
      a carrier.
  evidence:
  - reference: PMID:29266078
    reference_title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Assisted reproductive techniques with use of a gestational carrier (surrogate) have been shown to be successful for women with müllerian agenesis."
    explanation: >-
      Efficacy in Mullerian agenesis generally; not studied in WNT4
      deficiency specifically.
animal_models:
- name: Wnt4-null mouse
  species: Mouse
  genotype: Wnt4 homozygous null (knockout)
  publication: PMID:9989404
  description: >-
    Female Wnt4-null mice lack Mullerian ducts, retain Wolffian ducts and
    ectopically synthesize testosterone in the ovary, which is the
    combination seen in the human disease. Males are normal at birth. The
    knockout also fails to form nephrons and dies shortly after birth, so the
    adult reproductive phenotype cannot be studied in it.
  modeled_mechanisms:
  - target: Failed Mullerian Duct Formation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Complete absence of the Mullerian duct in female null embryos.
    limitations: >-
      The mouse is homozygous null whereas patients are heterozygous for
      missense alleles, some dominant negative; heterozygous mice are not
      reported to share the phenotype, so the model shows the requirement for
      WNT4 rather than the human dosage sensitivity.
    evidence:
    - reference: PMID:9989404
      reference_title: Female development in mammals is regulated by Wnt-4 signalling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Wnt-4-mutant females are masculinized-the Mullerian duct is absent while the Wolffian duct continues to develop."
      explanation: >-
        Reports the absent Mullerian duct in null females.
  - target: Derepressed Ovarian Androgen Biosynthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Null ovaries express testosterone biosynthetic enzymes and secrete
      testosterone into the embryonic circulation.
    limitations: >-
      Androgen excess in the mouse is fetal and is read out as Wolffian duct
      maintenance; the human phenotype is adolescent clinical
      hyperandrogenism, which the perinatal-lethal knockout cannot show.
    evidence:
    - reference: PMID:15932923
      reference_title: "The partial female to male sex reversal in Wnt-4-deficient females involves induced expression of testosterone biosynthetic genes and testosterone production, and depends on androgen action."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consistent with this, the expression of several genes encoding enzymes in the pathway leading to the synthesis of testosterone in the mouse is induced in the Wnt-4-deficient ovary, including Cyp11a, Cyp17, Hsd3b1, Hsd17b1, and Hsd17b3."
      explanation: >-
        Measures the derepressed steroidogenic enzymes in the null ovary.
  - target: Impaired Nephron Tubulogenesis
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Null metanephric mesenchyme fails to form pretubular aggregates.
    limitations: >-
      The null mouse has a severe bilateral nephrogenesis defect, while the
      human disease shows at most unilateral renal agenesis in a single case;
      the model establishes the renal role of WNT4 but not that heterozygous
      human alleles act through it.
    evidence:
    - reference: PMID:7990960
      reference_title: Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice lacking Wnt-4 activity fail to form pretubular cell aggregates; however, other aspects of mesenchymal and ureteric development are unaffected."
      explanation: >-
        Reports the tubulogenesis defect in the knockout kidney.
  evidence:
  - reference: PMID:9989404
    reference_title: Female development in mammals is regulated by Wnt-4 signalling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Wnt-4 is initially required in both sexes for formation of the Mullerian duct, then Wnt-4 in the developing ovary appears to suppress the development of Leydig cells; consequently, Wnt-4-mutant females ectopically activate testosterone biosynthesis."
    explanation: >-
      Summarizes the two arms of the null phenotype that correspond to the
      human disease.
- name: Wnt4 mCherry hypomorphic mouse
  species: Mouse
  genotype: Wnt4 mCh/mCh (hypomorphic allele)
  publication: PMID:26721931
  description: >-
    A hypomorphic Wnt4 allele allows some animals to survive to adulthood.
    The Mullerian duct forms in only about 45 percent of cases, and the
    resulting reproductive tract shows a poorly coiled oviduct, no
    endometrial glands and an undifferentiated myometrium. The model shows
    that reduced rather than absent WNT4 activity can still prevent or
    distort Mullerian development, which bears on the partial-loss human
    alleles.
  modeled_mechanisms:
  - target: Failed Mullerian Duct Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Incompletely penetrant failure of Mullerian duct formation with reduced
      WNT4 dosage.
    limitations: >-
      The allele is a reporter fusion hypomorph in a homozygous state, not a
      heterozygous human missense variant, and ovarian androgen production
      was not reported.
    evidence:
    - reference: PMID:26721931
      reference_title: Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast to the Wnt4 null embryos, some Wnt4(monomeric cherry/monomeric cherry) (Wnt4(mCh/mCh)) hypomorphic mice survived to adulthood and formed MD in ∼45% of cases."
      explanation: >-
        Reduced Wnt4 dosage leaves Mullerian duct formation incompletely
        penetrant.
  evidence:
  - reference: PMID:26721931
    reference_title: Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Examination of the reproductive tract of the Wnt4(mCh/mCh) females indicated a poorly coiled oviduct, absence of the endometrial glands and an undifferentiated myometrium, and these mice were prone to develop a hydro-uterus."
    explanation: >-
      Describes the adult reproductive tract of the hypomorph.
- name: Amhr2-Cre Wnt4 and Wnt5a double conditional knockout mouse
  species: Mouse
  genotype: Wnt4 flox/flox; Wnt5a flox/flox; Amhr2-Cre
  publication: PMID:30010727
  description: >-
    Deleting Wnt4 together with Wnt5a in Mullerian duct mesenchyme causes
    partial agenesis of Mullerian derivatives in a third of females, with
    normal ovaries. It shows that WNT4 acts partly redundantly with WNT5A in
    the mesenchyme after the duct has formed.
  modeled_mechanisms:
  - target: Failed Mullerian Duct Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Partial Mullerian agenesis after combined mesenchymal loss of Wnt4 and
      Wnt5a.
    limitations: >-
      Requires loss of a second Wnt gene and acts after duct initiation, so it
      models a later and partly redundant WNT4 function rather than the
      single-gene human defect; the ovaries are normal, so the androgen arm is
      not modelled.
    evidence:
    - reference: PMID:30010727
      reference_title: Targeted ablation of Wnt4 and Wnt5a in Müllerian duct mesenchyme impedes endometrial gland development and causes partial Müllerian agenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, a third of Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+ females had a partial agenesis of Müllerian duct-derived structures, but with normal oviducts and ovaries."
      explanation: >-
        Reports partial Mullerian agenesis in the double conditional knockout.
  evidence:
  - reference: PMID:30010727
    reference_title: Targeted ablation of Wnt4 and Wnt5a in Müllerian duct mesenchyme impedes endometrial gland development and causes partial Müllerian agenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Together, our results suggest that Wnt4 and Wnt5a play redundant roles in the development of the female reproductive tract, and may provide insight into the etiology of certain cases of Müllerian agenesis in women."
    explanation: >-
      States the redundancy conclusion and its relevance to human Mullerian
      agenesis.
differential_diagnoses:
- name: Mayer-Rokitansky-Kuster-Hauser syndrome
  disease_term:
    preferred_term: Mayer-Rokitansky-Kuster-Hauser syndrome
    term:
      id: MONDO:0017771
      label: Mayer-Rokitansky-Kuster-Hauser syndrome
  description: >-
    The closest mimic: congenital absence of the uterus and upper vagina in a
    46,XX woman with normal ovarian function, presenting as primary
    amenorrhea. Classic MRKH syndrome does not show clinical virilization, and
    WNT4 variants are not found in MRKH cohorts. Biochemical hyperandrogenemia
    alone does not separate the two, because raised androgen indices without
    clinical signs are common in MRKH syndrome. Acne or hirsutism with
    Mullerian aplasia should prompt WNT4 analysis.
  evidence:
  - reference: PMID:38699388
    reference_title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "MD agenesis caused by WNT4 variants is associated with clinical and biochemical hyperandrogenism, representing a phenotype distinct from MRKH syndrome in general"
    explanation: >-
      A 2024 review of MRKH genetics separates WNT4 Mullerian agenesis from
      MRKH syndrome on the basis of hyperandrogenism.
  - reference: PMID:16959810
    reference_title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting that this might be a clinical entity distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome"
    explanation: >-
      The original argument for treating WNT4 deficiency as a separate entity.
  - reference: PMID:24641817
    reference_title: "Acne and PCOS are less frequent in women with Mayer-Rokitansky-Küster-Hauser syndrome despite a high rate of hyperandrogenemia: a cross-sectional study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As many as 42/69 (60.1%) showed hyperandrogenemia without other clinical signs of virilization"
    explanation: >-
      A second MRKH cohort with frequent, clinically silent
      hyperandrogenemia, reinforcing that biochemistry alone does not
      separate the two disorders.
  - reference: PMID:28246310
    reference_title: Hyperandrogenemia and high prolactin in congenital utero-vaginal aplasia patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Taken together, this study shows that over 52% of MRKH patients have hyperandrogenemia without clinical presentation and 14% hyperprolactinemia"
    explanation: >-
      In 215 MRKH patients, raised androgen indices were common but
      clinically silent, so a laboratory value alone does not distinguish the
      two disorders.
  - reference: PMID:28246310
    reference_title: Hyperandrogenemia and high prolactin in congenital utero-vaginal aplasia patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sequencing of WNT4, WNT5A, WNT7A and WNT9B demonstrated no significant mutations correlating with hyperandrogenemia."
    explanation: >-
      WNT4 variants do not account for the hyperandrogenemia seen in MRKH
      syndrome.
- name: MURCS association
  disease_term:
    preferred_term: MURCS association
    term:
      id: MONDO:0010989
      label: Mayer-Rokitansky-Küster-Hauser syndrome type 2
  description: >-
    Mullerian duct aplasia with renal anomalies and cervicothoracic somite
    dysplasia (MRKH syndrome type 2). It shares Mullerian aplasia and renal
    agenesis with this disorder and can coexist with clinical
    hyperandrogenism, but the vertebral and other skeletal anomalies
    distinguish it, and WNT4 is not mutated.
  evidence:
  - reference: PMID:24356390
    reference_title: Absence of WNT4 gene mutation in a patient with MURCS association.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report an adolescent girl with the cardinal features of MURCS association, obesity, and clinical findings of hyperandrogenism who did not show any exonic mutation of the WNT4 gene."
    explanation: >-
      A MURCS patient with hyperandrogenism, the closest phenocopy, had no
      WNT4 variant.
- name: SERKAL syndrome
  disease_term:
    preferred_term: SERKAL syndrome
    term:
      id: MONDO:0012734
      label: SERKAL syndrome
  description: >-
    The allelic recessive WNT4 disorder. Homozygous loss-of-function WNT4
    variants cause 46,XX female-to-male sex reversal with dysgenesis of the
    kidneys, adrenals and lungs and other developmental defects, typically
    lethal in fetal life. It differs from this disorder in inheritance
    (biallelic versus a single dominant allele), in gonadal sex (testicular
    differentiation versus ovaries) and in the extent of organ involvement.
  evidence:
  - reference: PMID:18179883
    reference_title: "SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a novel autosomal-recessive syndrome that consists of female to male sex reversal and renal, adrenal, and lung dysgenesis and is associated with additional developmental defects."
    explanation: >-
      Defines SERKAL syndrome, the distinct recessive WNT4 phenotype.
- name: Polycystic ovary syndrome
  disease_term:
    preferred_term: polycystic ovary syndrome
    term:
      id: MONDO:0008487
      label: polycystic ovary syndrome
  description: >-
    Shares ovarian hyperandrogenism with acne and hirsutism, and can present
    with amenorrhea, but the uterus is present and the amenorrhea is
    anovulatory. WNT4 coding variants were not found in a PCOS series, so
    WNT4 is not a cause of typical PCOS.
  evidence:
  - reference: PMID:17071531
    reference_title: Mutation analysis of the WNT-4 gene in patients with polycystic ovary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women of childbearing age and is characterized by chronic anovulation with either oligomenorrhea or amenorrhea and hyperandrogenism."
    explanation: >-
      States the features PCOS shares with this disorder.
  - reference: PMID:17071531
    reference_title: Mutation analysis of the WNT-4 gene in patients with polycystic ovary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study demonstrates that, at least in the population studied, mutations of the open reading frame of WNT-4 gene or its intron/exon junctions are not the cause of PCOS."
    explanation: >-
      WNT4 coding variants were absent in 25 women with PCOS.
references:
- reference: PMID:15317892
  title: "A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman."
- reference: PMID:16959810
  title: "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report."
- reference: PMID:18182450
  title: "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study."
- reference: PMID:21377155
  title: Molecular analysis of WNT4 gene in four adolescent girls with mullerian duct abnormality and hyperandrogenism (atypical Mayer-Rokitansky-Küster-Hauser syndrome).
- reference: PMID:18987495
  title: WNT4 and sex development.
- reference: PMID:40992710
  title: "WNT4 deficiency impacts heart, diaphragm, and palate development: Insights from human genetics, machine learning, and mouse models."
- reference: PMID:38699388
  title: "Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications."
- reference: PMID:28246310
  title: Hyperandrogenemia and high prolactin in congenital utero-vaginal aplasia patients.
- reference: PMID:24641817
  title: "Acne and PCOS are less frequent in women with Mayer-Rokitansky-Küster-Hauser syndrome despite a high rate of hyperandrogenemia: a cross-sectional study."
- reference: PMID:24356390
  title: Absence of WNT4 gene mutation in a patient with MURCS association.
- reference: PMID:29266078
  title: "ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment."
- reference: PMID:28434104
  title: "Mullerian dysgenesis: a critical review of the literature."
- reference: PMID:22503279
  title: Mutations in WNT4 are not responsible for Müllerian duct abnormalities in Chinese women.
- reference: PMID:36738897
  title: "Mutation analysis of WNT4 gene in SRY negative 46,XX DSD patients with Mullerian agenesis and/or gonadal dysgenesis- An Indian study."
- reference: PMID:18179883
  title: "SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4."
- reference: PMID:17071531
  title: Mutation analysis of the WNT-4 gene in patients with polycystic ovary syndrome.
- reference: PMID:9989404
  title: Female development in mammals is regulated by Wnt-4 signalling.
- reference: PMID:15932923
  title: "The partial female to male sex reversal in Wnt-4-deficient females involves induced expression of testosterone biosynthetic genes and testosterone production, and depends on androgen action."
- reference: PMID:12835383
  title: Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad.
- reference: PMID:7990960
  title: Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4.
- reference: PMID:26721931
  title: Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract.
- reference: PMID:30010727
  title: Targeted ablation of Wnt4 and Wnt5a in Müllerian duct mesenchyme impedes endometrial gland development and causes partial Müllerian agenesis.
notes: >-
  OMIM 158330 and Orphanet ORPHA:247768 describe this disease; both are listed
  by MONDO as equivalents of MONDO:0008019. No GeneReviews chapter covers it.
  The published human evidence is four single-patient reports with functional
  assays, so phenotype frequencies are not given. Absence of the uterus is the
  defining Mullerian finding; vaginal involvement is recorded from a secondary
  summary of the case literature, because the primary abstracts describe
  absent Mullerian derivatives without itemizing the vagina. Treatment
  evidence is borrowed from Mullerian agenesis in general and no therapy has
  been studied in this disorder; management of the androgen excess is not
  described in any cited source.

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