46,XY complete gonadal dysgenesis
46,XY complete gonadal dysgenesis (Swyer syndrome) is a genetically heterogeneous disorder of testis development in which an individual with a nonmosaic 46,XY karyotype has typical female external genitalia, Müllerian structures, and bilateral streak or severely dysgenetic gonads because functional testes never differentiate. Loss of fetal Sertoli-cell and Leydig-cell function causes absent anti-Müllerian hormone and testicular androgen secretion; loss of pubertal gonadal hormone production causes hypergonadotropic hypogonadism, absent or incomplete breast development, delayed puberty, primary amenorrhea, uterine hypoplasia, infertility, and impaired bone accrual. Y-bearing dysgenetic gonadal tissue also confers a substantial, but imprecisely quantified, risk of gonadoblastoma and invasive germ-cell tumor.
Ask OpenScientist
Ask a research question about 46,XY complete gonadal dysgenesis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Submitting...
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
Mappings
MONDO
MONDO:0010765
46,XY complete gonadal dysgenesis
MONDO:0010765 is the exact disease anchor and carries the corresponding ORDO:242 and OMIMPS:400044 cross-references.
Definitions
1Classic nonsyndromic 46,XY complete gonadal dysgenesis case definition
The modeled disease requires a 46,XY karyotype, typical female external genitalia and Müllerian internal structures, absent functional testicular differentiation, and bilateral streak or severely dysgenetic gonads.
Show evidence (1 reference)
"Thirty-two patients with hypergonadotropic hypogonadism, streak gonads, internal and external female genitalia, and normal karyotype (46,XX or 46,XY)"
This clinical cohort supplies the defining gonadal, internal-genital, external-genital, endocrine, and karyotypic features; this entry selects its 46,XY complete-dysgenesis subset.
Inheritance
4
Autosomal dominant inheritance
HP:0000006
Sex-limited autosomal dominant inheritance applies to several molecular subtypes, including MAP3K1, NR5A1, DMRT1, SOX8, SOX9-regulatory, and DHX37, with gene-specific penetrance and expressivity.
Show evidence (2 references)
"Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals."
Directly supports sex-limited dominant inheritance for MAP3K1.
"incomplete penetrance may be observed in males (46,XY)."
Supports incomplete penetrance in DHX37-related 46,XY disease.
Autosomal recessive inheritance
HP:0000007
The nonsyndromic DHH-related form is caused by biallelic pathogenic variants.
Show evidence (1 reference)
"both harboring novel DHH compound heterozygous mutations"
Compound heterozygosity supports recessive inheritance.
X-linked inheritance
HP:0001417
Sex-limited X-linked NR0B1 dosage gain can cause complete disease in 46,XY relatives; this is a duplication mechanism, not NR0B1 loss of function.
Show evidence (1 reference)
"Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene."
Directly supports an Xp21.2 dosage-gain subtype in two sisters.
Y-linked inheritance
HP:0001450
SRY lies on the Y chromosome, but chromosomal location and inheritance mode should not be conflated with variant origin or recurrence risk; both are lesion-specific.
Show evidence (1 reference)
"Mutations of the SRY gene is associated with complete gonadal dysgenesis in females with 46,XY karyotype."
Supports the SRY-associated 46,XY branch; recurrence is lesion-specific.
Subtypes
10gene
SRY-related 46,XY complete gonadal dysgenesis
Pathogenic SRY variants can prevent initiation of the testis pathway. Variant origin and recurrence risk are lesion-specific.
Show evidence (1 reference)
"Mutations of the SRY gene is associated with complete gonadal dysgenesis in females with 46,XY karyotype."
Directly associates SRY variants with the complete phenotype.
NR0B1/DAX1-duplication 46,XY complete gonadal dysgenesis
Xp21 dosage gain containing NR0B1 (DAX1), rather than NR0B1 sequence loss, can antagonize testis determination and cause isolated complete gonadal dysgenesis.
Show evidence (1 reference)
"our data support DAX1 as a dosage sensitive gene responsible for gonadal dysgenesis and highlight the importance of considering DAX1 locus duplications in the evaluation of all cases of 46,XY gonadal dysgenesis."
Supports the dosage-gain mechanism and isolated phenotype.
NR5A1-related complete 46,XY gonadal dysgenesis
Heterozygous NR5A1 variants can cause the complete phenotype, with variable expressivity across families; the broader ontology subtype also includes partial 46,XY gonadal dysgenesis.
Show evidence (1 reference)
"46,XY complete gonadal dysgenesis (CGD) who had a non-communicating rudimentary uterus due to a c.132_134del (p.Asn44del) heterozygous in-frame-deletion in NR5A1"
Directly documents a heterozygous NR5A1 variant in complete disease.
DMRT1-related isolated 46,XY complete gonadal dysgenesis
Heterozygous DMRT1 sequence variants or focal 9p24.3 deletions can cause complete gonadal dysgenesis. Large syndromic 9p deletions are outside this nonsyndromic root.
Show evidence (1 reference)
"Deletions and, more recently, point mutations affecting human DMRT1 have demonstrated that its heterozygosity is associated with 46,XY complete gonadal dysgenesis."
Directly supports heterozygous DMRT1 defects in complete disease.
MAP3K1-related complete 46,XY gonadal dysgenesis
Sex-limited heterozygous gain-of-function MAP3K1 variants can cause complete or partial gonadal dysgenesis; only complete presentations are included here.
Show evidence (1 reference)
"Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis"
Establishes MAP3K1 as a cause across the partial-to-complete spectrum.
DHH-related nonsyndromic 46,XY complete gonadal dysgenesis
Biallelic pathogenic DHH variants causing reduced or absent DHH function can disrupt Sertoli-to-Leydig/peritubular signaling. The DHH-related form with motor-sensory neuropathy is a separate syndromic disorder rather than part of this root; only complete nonsyndromic presentations belong here.
Show evidence (1 reference)
"we describe two patients diagnosed with GD, both harboring novel DHH compound heterozygous mutations"
Supports biallelic DHH-associated gonadal dysgenesis across a broader spectrum; this entry selects only complete nonsyndromic presentations.
SOX8-related 46,XY complete gonadal dysgenesis
Rare heterozygous SOX8 sequence or structural variants can cause 46,XY disorders of testis development, including complete gonadal dysgenesis. Evidence remains limited and the published spectrum is broader than the complete phenotype.
Show evidence (1 reference)
"SOX8 mutations contribute to a spectrum of phenotypes including 46, XY DSD, male infertility and 46, XX POI."
Supports a causal 46,XY DSD spectrum; complete presentations are selected for this subtype.
SOX9-enhancer-deletion 46,XY complete gonadal dysgenesis
Deletion of testis-specific enhancers upstream of SOX9 can prevent adequate SOX9 induction and cause 46,XY sex reversal. Coding SOX9 loss with campomelic dysplasia is a syndromic differential.
Show evidence (1 reference)
"SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY sex reversal, respectively."
Directly associates upstream enhancer deletion with 46,XY sex reversal.
DHX37-related complete 46,XY gonadal dysgenesis
Heterozygous DHX37 variants show incomplete penetrance in 46,XY individuals and span testicular regression and gonadal dysgenesis. This subtype includes only complete-gonadal-dysgenesis presentations; its molecular mechanism remains unresolved.
Show evidence (1 reference)
"in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts, they have a high detection rate."
Supports association with gonadal dysgenesis while retaining spectrum uncertainty.
molecular
Molecularly unresolved 46,XY complete gonadal dysgenesis
Some individuals meeting the complete clinical case definition do not receive a molecular diagnosis after currently available copy-number and sequencing tests.
Show evidence (1 reference)
"Despite significant improvements in our understanding of the complex genetic pathways that underlie DSD, an accurate diagnosis still eludes many affected individuals."
Supports retention of a molecularly unresolved subtype.
Discussions and Knowledge Gaps
1In confirmed classic 46,XY complete gonadal dysgenesis with bilateral nonfunctional streak gonads, what disease-specific age-stratified tumor-risk estimate should be communicated, how promptly should bilateral gonadectomy follow diagnosis, do genotype or familial status modify risk, and is any imaging, marker, or biopsy surveillance strategy reliable enough to recommend if surgery is deferred?
Attached to
Published percentages mix familial and sporadic cases, mass-enriched referrals, pathology-selected series, ages, and complete, partial, mixed, CAIS, or other XY DSD diagnoses. These data establish clinically important risk and support current practice favoring timely gonadectomy but do not establish a precise population probability, an evidence-defined surgical interval, or a validated surveillance alternative.
Show evidence (3 references)
"complete GD (33 %)"
Supplies a multicenter adult cohort estimate with mixed ascertainment.
"Guidelines concerning the necessity of gonadectomy to avoid malignant transformation are still lacking."
Explicitly identifies the management-guideline gap.
"the risk of gonadal tumors could be increased in familial compared to sporadic cases (66.6% vs. 15-45%, respectively)."
Raises a possible familial modifier from a small literature review.
Pathophysiology
16SRY-SOX9-SOX8-DMRT1 transcriptional network failure
Loss or inadequate activation of the core pro-testis transcriptional network prevents stable supporting-cell commitment. This branch includes SRY defects, SOX9 enhancer deletion, rare SOX8 defects, and DMRT1 haploinsufficiency.
Downstream
Failure to activate or stabilize the pro-testis network prevents supporting cells from adopting the Sertoli-cell fate and organizing testis cords.
Show evidence (3 references)
"The SRY initiates cascade of gene expression that transforms the undifferentiated gonad, genital ridge into testis."
Places SRY at the start of the pro-testis network.
"All three enhancers showed synergistic activity and together drive SOX9 in the testis."
Supports the testis-specific SOX9 enhancer mechanism.
"DMRT1 is essential for male somatic and germ cell differentiation and maintenance of male somatic cell fate after differentiation."
Supports DMRT1 participation in pro-testis differentiation and maintenance.
MAP3K1 gain-of-function pro-ovarian signaling bias
Pathogenic MAP3K1 variants increase ERK1/2 and p38 signaling, interfere with testis determination, and permit a pro-ovarian signaling state.
Downstream
MAP3K1 gain of function shifts the bipotential gonad away from testis fate.
Show evidence (1 reference)
"The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination."
Defines the direction and downstream signaling effect of MAP3K1 variants.
NR5A1 gonadal transcription failure
Pathogenic NR5A1 variants impair transcriptional control of gonadal development and steroidogenic programs, with variable phenotypic severity.
Downstream
Severe NR5A1 dysfunction can prevent complete testicular differentiation.
Show evidence (1 reference)
"NR5A1, also known as steroidogenic factor 1, a crucial transcriptional factor regulating adrenal and gonadal development and function."
Supports NR5A1's gonadal-developmental transcriptional role.
DHH paracrine signaling failure
Biallelic DHH variants impair Sertoli-derived paracrine signaling needed for Leydig and peritubular-cell development. DHH is therefore modeled as a differentiation-signaling branch rather than as an SRY-equivalent trigger.
Downstream
Severe DHH signaling loss disrupts coordinated testicular differentiation.
Show evidence (2 references)
"In humans, mutations of Desert Hedgehog gene (DHH) have been described in patients with 46,XY gonadal dysgenesis (GD), associated or not with polyneuropathy."
Supports DHH as a gonadal-dysgenesis gene.
"p.(Asn337Lysfs*24) mutation resulted in a complete absence of auto-proteolysis."
Provides functional evidence that a patient variant disrupts DHH processing.
NR0B1 dosage gain
Duplication of an Xp21.2 interval containing NR0B1/DAX1 increases dosage of a sex-determination regulator and can antagonize testis development.
Downstream
NR0B1 dosage gain prevents normal testicular differentiation.
Show evidence (1 reference)
"Thus, our data support DAX1 as a dosage sensitive gene responsible for gonadal dysgenesis"
Directly supports the dosage-gain mechanism.
Failure of supporting-cell differentiation and testis-cord formation
Diverse lesions converge on failure of Sertoli/supporting-cell differentiation and testis-cord formation, so a functional testis and its dependent fetal hormone-producing compartments do not develop.
Downstream
Complete failure of testis differentiation leaves nonfunctional gonadal remnants.
Failure of fetal Sertoli-cell differentiation eliminates normal AMH secretion.
Failure of functional testis and Leydig-cell differentiation removes fetal testicular androgen output.
Show evidence (1 reference)
"46,XY karyotype and female phenotype with undeveloped streak gonads"
Supports the convergent failure of testicular gonadal differentiation.
Bilateral streak or dysgenetic gonads
Bilateral gonadal remnants consist predominantly of fibrous or severely dysgenetic tissue without useful steroidogenic or gametogenic function.
Downstream
The streak/dysgenetic gonad is the defining structural phenotype.
The complete developmental lesion commonly produces bilateral streak gonads.
Nonfunctional gonads cannot supply normal pubertal estrogen or inhibin.
Absence of functional gonadal gametes causes infertility.
Dysgenetic gonadal tissue containing Y-chromosome material creates a tumor-prone germ-cell environment.
Show evidence (1 reference)
"Gonadal histologic analysis revealed homogeneous fibrous tissue, and 46,XY complete gonadal dysgenesis was diagnosed"
Directly documents fibrous gonadal tissue in complete disease.
Absent fetal AMH secretion
Failed fetal Sertoli-cell function removes anti-Müllerian hormone signaling.
Downstream
Without fetal AMH, Müllerian derivatives including a uterus and tubes persist.
Show evidence (1 reference)
"the presence of Müllerian structures suggested a defect in fetal Sertoli cell differentiation and AMH secretion"
Supports the Sertoli/AMH branch and its anatomic consequence.
Müllerian-duct persistence
Müllerian structures are present, although prolonged hypoestrogenism can leave the uterus small or difficult to visualize before hormone treatment.
Downstream
A retained uterus remains hypoplastic without adequate pubertal estrogen.
Show evidence (1 reference)
"a vagina, a hypoplastic uterus with an undeniable rudimentary uterus"
Documents persistent but hypoplastic Müllerian structures.
Absent fetal testicular androgen secretion
Failure of functional fetal Leydig cells removes testicular testosterone and dihydrotestosterone exposure. Adult serum testosterone may remain detectable from adrenal or peripheral sources and should be interpreted against sex- and age-appropriate ranges rather than described as absolutely absent.
Downstream
Lack of fetal androgen-driven masculinization yields typical female external genitalia.
Show evidence (1 reference)
"there is an absence of testosterone that leads to lack of masculinization and the presence of female genitalia."
The paper's absolute wording is simplified, but the anatomy supports absent fetal testicular androgen effect rather than an inference from an adult serum concentration.
Female external genital development in a 46,XY individual
External genital development follows a typical female pattern despite the 46,XY chromosomal complement.
Downstream
This is the HPO-grounded external-genital phenotype.
Show evidence (1 reference)
"The cytogenetic analysis confirmed 46,XY sex reversal karyotype of a female."
Directly supports the chromosomal/anatomic discordance.
Absent pubertal gonadal hormone secretion
Nonfunctional streak gonads do not produce physiologic pubertal estradiol or inhibin, preventing spontaneous pubertal progression and normal uterine and skeletal estrogenization.
Downstream
Low estradiol and inhibin remove negative feedback on pituitary gonadotropin secretion.
Inadequate pubertal estrogen prevents normal breast development.
Absent pubertal gonadal hormone secretion prevents timely pubertal progression.
Absent spontaneous estrogenization and endometrial cycling prevent menarche.
Untreated hypoestrogenism impairs acquisition and maintenance of bone mass.
Show evidence (1 reference)
"elevated gonadotropin levels, oestrogen insufficiency, tall stature, delayed puberty, and primary amenorrhoea."
Directly supports the pubertal endocrine state and consequences.
Loss of gonadal negative feedback
Low gonadal estradiol and inhibin release the hypothalamic-pituitary axis from negative feedback, raising FSH and LH and producing hypergonadotropic hypogonadism.
Downstream
High FSH/LH with low estradiol is the characteristic endocrine phenotype.
Show evidence (1 reference)
"high luteinizing and follicle-stimulating hormone levels"
Directly documents elevated gonadotropins.
Dysgenetic Y-bearing germ-cell niche
Germ cells persisting in a poorly differentiated gonadal environment with Y-chromosome material can form gonadoblastoma or related precursor lesions.
Downstream
The dysgenetic niche permits precursor lesions and invasive germ-cell tumors.
Show evidence (1 reference)
"the presence of Y chromosomal material serves as a risk factor for malignant transformation"
Supports the Y-bearing dysgenetic gonadal substrate.
Gonadal germ-cell neoplasia risk
Complete gonadal dysgenesis carries clinically important risk of gonadoblastoma and invasive tumors, especially dysgerminoma. Published percentages vary substantially because cohorts are small, retrospective, referral-selected, pathology-selected, or combine multiple XY DSD diagnoses; no single percentage should be presented as population risk.
Downstream
Gonadoblastoma is a characteristic precursor neoplasm in dysgenetic gonads.
Show evidence (2 references)
"complete GD (33 %)"
Provides a multicenter adult cohort estimate, not a population-wide rate.
"The most commonly diagnosed tumors were dysgerminoma and gonadoblastoma."
Supports the tumor spectrum in a mass-enriched referral cohort.
Histopathology
2
Fibrous streak or severely dysgenetic gonadal tissue
Gonadectomy specimens can show homogeneous fibrous streak tissue or other severely dysgenetic gonadal remnants with little functional testicular architecture.
Show evidence (1 reference)
"Gonadal histologic analysis revealed homogeneous fibrous tissue, and 46,XY complete gonadal dysgenesis was diagnosed"
Directly supports the fibrous streak-gonad histology.
Gonadoblastoma and dysgerminoma in dysgenetic gonads
Complete examination of resected gonads may identify gonadoblastoma, dysgerminoma, or both. Limited biopsy is not a reliable exclusion test for focal neoplasia.
Show evidence (2 references)
"Histopathological examination revealed the presence of dysgerminoma in both dysgenetic gonads."
Directly documents bilateral dysgerminoma in Swyer syndrome.
"Tissue samples had been previously taken laparoscopically with benign histology."
A later seminoma in this mixed XY-DSD case illustrates sampling limitations of prior benign tissue samples.
Pathograph
Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Phenotypes
11Breast 1
Breast hypoplasia
Breast hypoplasia
HP:0003187
Show evidence (1 reference)
"lacked breast growth"
Directly supports absent breast development.
Endocrine 2
Delayed puberty
Delayed puberty
HP:0000823
Show evidence (1 reference)
"delayed puberty and primary amenorrhea."
Directly supports delayed puberty.
Hypergonadotropic hypogonadism
Hypergonadotropic hypogonadism
HP:0000815
Show evidence (1 reference)
"patients with hypergonadotropic hypogonadism, streak gonads"
Directly supports this endocrine phenotype in complete disease.
Genitourinary 4
Gonadal dysgenesis
Gonadal dysgenesis
HP:0000133
Show evidence (1 reference)
"Complete gonadal dysgenesis or Swyer syndrome"
Identifies gonadal dysgenesis as the defining lesion.
Female external genitalia in individual with 46,XY karyotype
Female external genitalia in individual with 46,XY karyotype
HP:0008730
Show evidence (1 reference)
"internal and external female genitalia"
Documents the defining anatomic phenotype in the cohort.
Primary amenorrhea
Primary amenorrhea
HP:0000786
Show evidence (1 reference)
"delayed puberty and primary amenorrhea."
Directly supports primary amenorrhea.
Female infertility
Female infertility
HP:0008222
Show evidence (1 reference)
"nonfunctional gonads resulting from complete gonadal dysgenesis."
Supports the gonadal basis of infertility.
Musculoskeletal 1
Reduced bone mineral density
Reduced bone mineral density
HP:0004349
Show evidence (1 reference)
"Bone density scan (DEXA scan) revealed osteoporosis at the lumbar spine (T score −2.7) and osteopenia at the hip (T score −1.5)."
This is direct evidence from severe estrogen deficiency in 46,XX gonadal dysgenesis and is used as a clearly labeled physiologic extrapolation.
Other 3
Streak gonad
Streak gonad
HP:0025733
Show evidence (1 reference)
"hypoplastic uterus with streak gonad"
Directly documents a streak gonad.
Hypoplasia of the uterus
Hypoplasia of the uterus
HP:0000013
Show evidence (1 reference)
"a vagina, a hypoplastic uterus with an undeniable rudimentary uterus"
Directly documents uterine hypoplasia in complete disease.
Gonadoblastoma
Gonadoblastoma
HP:0000150
Show evidence (1 reference)
"two siblings with Swyer syndrome in whom gonadoblastoma was found."
Directly documents gonadoblastoma in familial disease.
Genetic Associations
9
SRY
(Causal pathogenic SRY variant affecting testis determination)
Show evidence (2 references)
"The patient was confirmed with nucleotide substitution (c.226C>A; p.Arg76Ser) at in HMG box domain of SRY gene that causes 46,XY sex reversal female."
Directly associates an SRY variant with complete disease.
"Mutation prediction algorithms suggest that alteration might be disease causing mutation"
Separately classifies the in-silico pathogenicity support.
NR0B1
(Causal Xp21.2 copy-number gain containing NR0B1/DAX1)
Show evidence (1 reference)
"Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene."
Directly supports causal NR0B1-region duplication.
NR5A1
(Causal heterozygous pathogenic variant with variable expressivity)
Show evidence (1 reference)
"c.132_134del (p.Asn44del) heterozygous in-frame-deletion in NR5A1"
Directly documents a heterozygous NR5A1 variant in complete disease.
DMRT1
(Causal heterozygous sequence variant or focal deletion)
Show evidence (1 reference)
"its heterozygosity is associated with 46,XY complete gonadal dysgenesis."
Directly supports the DMRT1 association.
MAP3K1
(Causal heterozygous gain-of-function variant)
Show evidence (1 reference)
"Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis"
Directly includes complete disease in the MAP3K1 spectrum.
DHH
(Causal biallelic pathogenic variants causing reduced or absent DHH function)
Show evidence (2 references)
"both harboring novel DHH compound heterozygous mutations"
Supports biallelic DHH-associated gonadal dysgenesis across a broader phenotype spectrum; only complete nonsyndromic cases belong in this root.
"p.(Asn337Lysfs*24) mutation resulted in a complete absence of auto-proteolysis."
Functionally demonstrates absent processing for one allele; the companion p.Glu212Lys allele retains partial activity and the clinical report is not limited to classic complete disease.
SOX8
(Rare causal heterozygous sequence or structural variant in the 46,XY DSD spectrum)
Show evidence (2 references)
"two individuals with 46, XY disorders/differences in sex development (DSD) and chromosomal rearrangements encompassing the SOX8 locus and a third individual with 46, XY DSD and a missense mutation"
Supports human SOX8 lesions across the 46,XY DSD spectrum.
"In vitro functional assays indicate that this mutation alters the biological activity of the protein."
Provides functional support for the missense variant.
SOX9
(Causal deletion of upstream testis-specific enhancer sequence)
Show evidence (2 references)
"SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY sex reversal, respectively."
Directly supports the enhancer-deletion association.
"All three enhancers showed synergistic activity and together drive SOX9 in the testis."
Provides functional evidence for testis-specific enhancer activity.
DHX37
(Causal heterozygous variant with incomplete penetrance; molecular mechanism unresolved)
Show evidence (2 references)
"in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts, they have a high detection rate."
Supports the association while preserving phenotype-spectrum limits.
"the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear"
Explicitly records mechanistic uncertainty.
Medical Actions
6
Bilateral gonadectomy for nonfunctional dysgenetic gonads
Once classic complete 46,XY gonadal dysgenesis is confirmed, current expert practice favors arranging bilateral removal of nonfunctional streak/dysgenetic gonads without avoidable delay after informed, developmentally appropriate discussion. The gonads provide no useful pubertal function and retain clinically important tumor risk, but the literature does not define a precise post-diagnosis interval. Numerical risk estimates should be presented as cohort-dependent rather than as precise population probabilities.
Show evidence (2 references)
"The management of such patients is based on preventive excision of dysgenetic gonads and long-term hormonal replacement therapy."
Supports gonadectomy together with long-term hormone replacement.
"Early prophylactic gonadectomy could protect patients from developing tumors in dysgenetic gonads."
Supports early preventive gonadectomy as current expert practice; it does not establish an evidence-defined surgical interval.
Physiologic pubertal induction and maintenance hormone replacement
Hormone treatment proceeds in parallel with tumor-risk management; it is not contingent on waiting until after surgery. Near the expected age of puberty, use low-dose physiologic 17-beta-estradiol with gradual individualized escalation; later diagnosis can justify a faster individualized induction. If an endometrium-bearing uterine cavity is present, add progestogen to avoid unopposed estrogen; with patent outflow, cyclic progesterone is generally introduced after about two years of estrogen or first breakthrough bleeding. Obstructed or noncommunicating anatomy requires specialist management of the outflow and hormone regimen. Replacement usually continues through the expected age of natural menopause, followed by individualized reassessment. Treatment induces secondary sexual development and, when anatomy permits, scheduled withdrawal bleeding; it does not restore spontaneous menarche or ovulatory menstrual cycles. These regimen details derive from broader congenital gonadal-hormone-deficiency guidance and expert practice, not Swyer-specific comparative trials.
Show evidence (2 references)
"Puberty induction should be individualised but considered at 11 years in girls"
Supports individualized timely pubertal induction.
"long-term hormonal replacement therapy."
Supports long-term replacement in Swyer syndrome.
Endocrine, uterine, bone, and cardiometabolic monitoring
Provide individualized multidisciplinary follow-up during induction and maintenance, assessing pubertal and uterine response, adherence, and adverse effects. Bone and cardiometabolic assessment should reflect the duration and severity of hypoestrogenism, baseline findings, and individual risk. Exact tests and intervals are extrapolated from broader hypogonadism guidance rather than established by Swyer-specific outcome studies.
Show evidence (2 references)
"pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team."
Supports multidisciplinary follow-up during induction and maintenance.
"The improvement of bone mineral density was observed at the repeated DEXA scan at 18 months"
A broader gonadal-dysgenesis case shows that bone density can respond to hormone replacement; it does not establish a Swyer-specific DXA schedule.
Donor-oocyte or donor-embryo in vitro fertilization
Classic complete disease lacks usable gonadal gametes, but donor-oocyte or donor-embryo IVF can achieve pregnancy when estrogen treatment produces an adequate uterine response. Preconception uterine assessment and maternal-fetal-medicine counseling are appropriate; evidence consists mainly of case reports and small series.
Show evidence (1 reference)
"The IVF treatment using donor oocytes led to a successful pregnancy without complications."
Directly documents successful donor-oocyte IVF.
Gene-specific genetic counseling
Explain gene- and lesion-specific inheritance, penetrance, variant origin, and recurrence risk; offer parental or cascade testing when a cause is identified. Evaluate subtype-specific associated risks when relevant, such as adrenal disease in selected NR5A1 presentations or later neuropathy in biallelic DHH disease.
Show evidence (1 reference)
"importance of establishing a molecular diagnosis"
Supports molecular diagnosis as a basis for individualized lifelong care.
Psychosocial, disclosure, infertility, and sexual-health support
Provide staged, confidential, developmentally appropriate disclosure; psychological and peer support; infertility and reproductive counseling; sexual-health care; and support for autonomy and gender identity. Care should be coordinated by an experienced multidisciplinary DSD team.
Show evidence (2 references)
"Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders"
Directly supports psychosocial and fertility-focused support.
"long-term quality of life, sexual function, involvement with intimate partners, and optimizing fertility potential."
Supports lifelong quality-of-life, sexual, relationship, and fertility care.
Biochemical Markers
5
Follicle-stimulating hormone
(INCREASED)
Context: FSH is elevated after the expected onset of puberty because gonadal estradiol and inhibin feedback are deficient.
Pathograph Readouts
Readout Of
Loss of gonadal negative feedback
Positive
Diagnostic
Elevated FSH reports primary gonadal failure and loss of feedback.
Show evidence (1 reference)
"high luteinizing and follicle-stimulating hormone levels"
Elevated FSH directly reports loss of gonadal feedback.
Show evidence (1 reference)
"high luteinizing and follicle-stimulating hormone levels"
Directly documents elevated FSH and LH.
Luteinizing hormone
(INCREASED)
Context: LH is elevated after the expected onset of puberty as part of the hypergonadotropic pattern.
Pathograph Readouts
Readout Of
Loss of gonadal negative feedback
Positive
Diagnostic
Elevated LH reports loss of gonadal steroid feedback.
Show evidence (1 reference)
"high luteinizing and follicle-stimulating hormone levels"
Elevated LH directly reports loss of gonadal feedback.
Show evidence (1 reference)
"high luteinizing and follicle-stimulating hormone levels"
Directly documents elevated LH and FSH.
Estradiol
(DECREASED)
Context: Estradiol is low for pubertal age because streak gonads lack functional steroidogenic tissue.
Pathograph Readouts
Readout Of
Absent pubertal gonadal hormone secretion
Negative
Diagnostic
Low estradiol reports absent pubertal gonadal steroid secretion.
Show evidence (1 reference)
"low estradiol levels"
Low estradiol directly reports deficient pubertal gonadal secretion.
Show evidence (1 reference)
Testosterone relative to a 46,XY male reference range
(ABNORMAL)
Context: Testosterone generally reflects absent functional testicular production and is low relative to an age-matched 46,XY male reference range, but it can be detectable or slightly above a female reference range because adrenal and peripheral sources remain. Adult values do not reconstruct fetal exposure.
Show evidence (1 reference)
"slightly high testosterone levels"
The complete-disease case had detectable testosterone, supporting careful reference-range interpretation rather than an absolute-zero claim.
Anti-Müllerian hormone
(DECREASED)
Context: AMH is very low or undetectable because functional Sertoli cells are absent.
Pathograph Readouts
Readout Of
Failure of supporting-cell differentiation and testis-cord formation
Negative
Diagnostic
Undetectable AMH reports severe Sertoli-cell differentiation failure.
Show evidence (1 reference)
"anti-Müllerian hormone (AMH) levels below detection sensitivity."
Undetectable AMH reports severe Sertoli-cell differentiation failure.
Show evidence (1 reference)
"anti-Müllerian hormone (AMH) levels below detection sensitivity."
Directly documents undetectable AMH.
Differential Diagnoses
10Conditions with similar clinical presentations that must be differentiated from 46,XY complete gonadal dysgenesis:
Overlapping Features
CAIS also presents with a typical female external phenotype and 46,XY karyotype, but differentiated testes produce AMH, so the uterus is absent; testosterone is in the male range and breast development usually occurs through aromatization.
Show evidence (1 reference)
"We present 2 rare cases of 46, XY DSD, specifically XY pure gonadal dysgenesis and complete androgen insensitivity syndrome."
Supports the close clinical differential.
Overlapping Features
The endocrine and pubertal phenotype can be nearly identical, but formal karyotype distinguishes 46,XX from 46,XY disease and only the latter carries the Y-associated gonadal tumor substrate.
Show evidence (1 reference)
"normal karyotype (46,XX or 46,XY)"
Shows that complete gonadal dysgenesis occurs with either karyotype.
Turner syndrome
Overlapping Features
Turner syndrome can also cause streak gonads, hypergonadotropic hypogonadism, and absent puberty. Formal chromosome analysis and assessment for associated features distinguish it from nonmosaic 46,XY complete gonadal dysgenesis.
Show evidence (1 reference)
"There was no feature suggestive of Turner syndrome and no skeletal deformity was found."
Shows Turner syndrome being considered during a gonadal-dysgenesis differential; the evidence does not define the full Turner spectrum.
45,X/46,XY mixed gonadal dysgenesis
Overlapping Features
Sex-chromosome mosaic mixed gonadal dysgenesis is a separate chromosome-DSD diagnosis, often with asymmetric gonadal development rather than the nonmosaic 46,XY bilateral complete phenotype. Formal chromosome analysis distinguishes it from this root.
Show evidence (1 reference)
"sex chromosome DSD (Klinefelter or Turner Syndrome, chimerism), XX-DSD, and 46 XY-DSD"
Supports separation of sex-chromosome mosaic DSD from the 46,XY DSD category; the detailed asymmetric phenotype is clinical synthesis.
Partial or mixed 46,XY gonadal dysgenesis
Overlapping Features
Partial or mixed disease is a distinct tumor-prone category that does not meet the complete bilateral streak-gonad case definition; residual testicular differentiation and the full genital and gonadal phenotype must be assessed.
Show evidence (1 reference)
"gonadoblastoma, which is commonly observed in complete or partial dysgenesis"
Supports complete and partial dysgenesis as distinct tumor-prone categories.
Testicular regression syndrome
Overlapping Features
Testicular regression syndrome reflects loss of previously differentiated testicular tissue and spans absent or variable residual gonads and genital phenotypes. Evidence of prior fetal testicular function distinguishes it from complete failure of testis differentiation with bilateral streak gonads.
Show evidence (1 reference)
"in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts, they have a high detection rate."
Establishes testicular regression and gonadal dysgenesis as separately named DHX37-associated cohorts; detailed distinguishing features are clinical synthesis rather than a claim from this snippet.
Overlapping Features
MRKH causes primary amenorrhea with uterine and upper-vaginal aplasia or hypoplasia in a 46,XX individual who has functioning ovaries and spontaneous pubertal breast development; fallopian-tube anatomy can be variable.
Show evidence (1 reference)
"Patients with Mullerian agenesis lack all derivatives of the mullerian ducts (fallopian tubes, uterus, cervix, and upper vagina) but have ovaries and undergo puberty, with appropriately timed breast development"
Directly distinguishes ovarian function and uterine/upper-vaginal anatomy; its blanket statement about all duct derivatives is not universally applicable.
Central hypogonadism
Overlapping Features
Hypothalamic or pituitary gonadotropin deficiency can cause absent puberty and amenorrhea, but FSH and LH are low or inappropriately normal rather than elevated; it does not explain streak gonads with a 46,XY karyotype.
Show evidence (1 reference)
"high luteinizing and follicle-stimulating hormone levels"
The observed high-gonadotropin pattern argues against central hypogonadism.
46,XY androgen synthesis or action disorders
Overlapping Features
Steroidogenic defects, 5-alpha-reductase deficiency, and androgen receptor defects cause under-masculinization despite differentiated testicular tissue. AMH production and Müllerian regression, hormone profiles, and molecular testing distinguish them from complete testis-development failure.
Show evidence (1 reference)
"46 XY-DSD (disorders of testicular development and disorders of androgen synthesis or action)"
Supports the mechanistic distinction within 46,XY DSD.
Syndromic gonadal dysgenesis
Overlapping Features
Gonadal dysgenesis accompanied by neuropathy or other extra-gonadal features does not meet this nonsyndromic root and requires syndrome-specific evaluation. Biallelic DHH disease, for example, can occur with or without polyneuropathy.
Show evidence (1 reference)
"46,XY gonadal dysgenesis (GD), associated or not with polyneuropathy."
Supports separation of nonsyndromic and neuropathy-associated DHH disease.
Source YAML
click to showname: 46,XY complete gonadal dysgenesis
creation_date: "2026-04-14T12:00:00Z"
updated_date: "2026-07-15T15:55:01Z"
category: Mendelian
description: >-
46,XY complete gonadal dysgenesis (Swyer syndrome) is a genetically
heterogeneous disorder of testis development in which an individual with a
nonmosaic 46,XY karyotype has typical female external genitalia, Müllerian
structures, and bilateral streak or severely dysgenetic gonads because
functional testes never differentiate. Loss of fetal Sertoli-cell and
Leydig-cell function causes absent anti-Müllerian hormone and testicular
androgen secretion; loss of pubertal gonadal hormone production causes
hypergonadotropic hypogonadism, absent or incomplete breast development,
delayed puberty, primary amenorrhea, uterine hypoplasia, infertility, and
impaired bone accrual. Y-bearing dysgenetic gonadal tissue also confers a
substantial, but imprecisely quantified, risk of gonadoblastoma and invasive
germ-cell tumor.
disease_term:
preferred_term: 46,XY complete gonadal dysgenesis
term:
id: MONDO:0010765
label: 46,XY complete gonadal dysgenesis
synonyms:
- Swyer syndrome
- 46,XY CGD
- 46,XY pure gonadal dysgenesis
- 46,XY sex reversal
parents:
- Disorder of sex development
- Gonadal development disorder
definitions:
- name: Classic nonsyndromic 46,XY complete gonadal dysgenesis case definition
definition_type: CASE_DEFINITION
description: >-
The modeled disease requires a 46,XY karyotype, typical female external
genitalia and Müllerian internal structures, absent functional testicular
differentiation, and bilateral streak or severely dysgenetic gonads.
scope: >-
This entry models the classic nonsyndromic complete phenotype. Partial or
mixed 46,XY gonadal dysgenesis, complete androgen insensitivity, androgen
synthesis defects, testicular regression syndrome without the complete
phenotype, and syndromic gonadal dysgenesis are differential diagnoses or
separate disease entities. Gene-related subtype terms that span partial and
complete disease are included here only for their complete presentations.
evidence:
- reference: PMID:21982289
reference_title: "Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thirty-two patients with hypergonadotropic hypogonadism, streak gonads,
internal and external female genitalia, and normal karyotype (46,XX or
46,XY)
explanation: >-
This clinical cohort supplies the defining gonadal, internal-genital,
external-genital, endocrine, and karyotypic features; this entry selects
its 46,XY complete-dysgenesis subset.
mappings:
mondo_mappings:
- term:
id: MONDO:0010765
label: 46,XY complete gonadal dysgenesis
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
MONDO:0010765 is the exact disease anchor and carries the corresponding
ORDO:242 and OMIMPS:400044 cross-references.
tracked_issues:
- url: https://github.com/monarch-initiative/dismech/issues/6587
title: "Expert review: tumor-risk counseling and gonadectomy timing in 46,XY complete gonadal dysgenesis"
tracked_issue_role: curation_followup
tracked_issue_status: OPEN
notes: >-
Requests disease-specific age-stratified tumor-risk estimates, consensus on
surgical urgency and preoperative workup, evaluation of genotype or familial
modifiers, and evidence for any surveillance strategy when surgery is
deferred.
has_subtypes:
- name: SRY-related complete gonadal dysgenesis
display_name: SRY-related 46,XY complete gonadal dysgenesis
classification: gene
genes:
- preferred_term: SRY
term:
id: hgnc:11311
label: SRY
inheritance:
- name: Y-linked inheritance
inheritance_term:
preferred_term: Y-linked inheritance
term:
id: HP:0001450
label: Y-linked inheritance
evidence:
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations of the SRY gene is associated with complete gonadal dysgenesis
in females with 46,XY karyotype.
explanation: Supports the SRY-associated Y-chromosome branch.
description: >-
Pathogenic SRY variants can prevent initiation of the testis pathway.
Variant origin and recurrence risk are lesion-specific.
evidence:
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations of the SRY gene is associated with complete gonadal dysgenesis
in females with 46,XY karyotype.
explanation: Directly associates SRY variants with the complete phenotype.
- name: NR0B1-duplication complete gonadal dysgenesis
display_name: NR0B1/DAX1-duplication 46,XY complete gonadal dysgenesis
classification: gene
genes:
- preferred_term: NR0B1
term:
id: hgnc:7960
label: NR0B1
inheritance:
- name: X-linked inheritance
inheritance_term:
preferred_term: X-linked inheritance
term:
id: HP:0001417
label: X-linked inheritance
evidence:
- reference: PMID:17504899
reference_title: "Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2
interstitial duplication containing the DAX1 gene.
explanation: Supports an X-linked dosage-gain cause in two sisters.
description: >-
Xp21 dosage gain containing NR0B1 (DAX1), rather than NR0B1 sequence loss,
can antagonize testis determination and cause isolated complete gonadal
dysgenesis.
evidence:
- reference: PMID:17504899
reference_title: "Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
our data support DAX1 as a dosage sensitive gene responsible for gonadal
dysgenesis and highlight the importance of considering DAX1 locus
duplications in the evaluation of all cases of 46,XY gonadal dysgenesis.
explanation: Supports the dosage-gain mechanism and isolated phenotype.
- name: NR5A1-related complete gonadal dysgenesis
display_name: NR5A1-related complete 46,XY gonadal dysgenesis
classification: gene
genes:
- preferred_term: NR5A1
term:
id: hgnc:7983
label: NR5A1
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
c.132_134del (p.Asn44del) heterozygous in-frame-deletion in NR5A1
explanation: Supports a heterozygous NR5A1 cause.
description: >-
Heterozygous NR5A1 variants can cause the complete phenotype, with variable
expressivity across families; the broader ontology subtype also includes
partial 46,XY gonadal dysgenesis.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
46,XY complete gonadal dysgenesis (CGD) who had a non-communicating
rudimentary uterus due to a c.132_134del (p.Asn44del) heterozygous
in-frame-deletion in NR5A1
explanation: Directly documents a heterozygous NR5A1 variant in complete disease.
- name: DMRT1-related complete gonadal dysgenesis
display_name: DMRT1-related isolated 46,XY complete gonadal dysgenesis
classification: gene
genes:
- preferred_term: DMRT1
term:
id: hgnc:2934
label: DMRT1
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:34515237
reference_title: "DMRT1: An Ancient Sexual Regulator Required for Human Gonadogenesis."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
its heterozygosity is associated with 46,XY complete gonadal dysgenesis.
explanation: Supports dominant disease through DMRT1 heterozygosity.
description: >-
Heterozygous DMRT1 sequence variants or focal 9p24.3 deletions can cause
complete gonadal dysgenesis. Large syndromic 9p deletions are outside this
nonsyndromic root.
evidence:
- reference: PMID:34515237
reference_title: "DMRT1: An Ancient Sexual Regulator Required for Human Gonadogenesis."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Deletions and, more recently, point mutations affecting human DMRT1 have
demonstrated that its heterozygosity is associated with 46,XY complete
gonadal dysgenesis.
explanation: Directly supports heterozygous DMRT1 defects in complete disease.
- name: MAP3K1-related complete gonadal dysgenesis
display_name: MAP3K1-related complete 46,XY gonadal dysgenesis
classification: gene
genes:
- preferred_term: MAP3K1
term:
id: hgnc:6848
label: MAP3K1
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:35290982
reference_title: "Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Inheritance occurs in a sex-limited, autosomal dominant fashion
explanation: Directly supports the subtype inheritance mode.
description: >-
Sex-limited heterozygous gain-of-function MAP3K1 variants can cause complete
or partial gonadal dysgenesis; only complete presentations are included here.
evidence:
- reference: PMID:35290982
reference_title: "Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY
non-syndromic partial and complete gonadal dysgenesis
explanation: Establishes MAP3K1 as a cause across the partial-to-complete spectrum.
- name: DHH-related nonsyndromic complete gonadal dysgenesis
display_name: DHH-related nonsyndromic 46,XY complete gonadal dysgenesis
classification: gene
genes:
- preferred_term: DHH
term:
id: hgnc:2865
label: DHH
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:30298535
reference_title: "In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
both harboring novel DHH compound heterozygous mutations
explanation: Compound heterozygosity supports recessive inheritance.
description: >-
Biallelic pathogenic DHH variants causing reduced or absent DHH function can
disrupt Sertoli-to-Leydig/peritubular signaling. The DHH-related form with
motor-sensory neuropathy is a separate syndromic disorder rather than part
of this root; only complete nonsyndromic presentations belong here.
evidence:
- reference: PMID:30298535
reference_title: "In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
we describe two patients diagnosed with GD, both harboring novel DHH
compound heterozygous mutations
explanation: >-
Supports biallelic DHH-associated gonadal dysgenesis across a broader
spectrum; this entry selects only complete nonsyndromic presentations.
- name: SOX8-related complete gonadal dysgenesis
display_name: SOX8-related 46,XY complete gonadal dysgenesis
classification: gene
genes:
- preferred_term: SOX8
term:
id: hgnc:11203
label: SOX8
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:29373757
reference_title: "Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
a third individual with 46, XY DSD and a missense mutation in the
HMG-box of SOX8.
explanation: Supports a heterozygous SOX8-associated 46,XY DSD branch.
description: >-
Rare heterozygous SOX8 sequence or structural variants can cause 46,XY
disorders of testis development, including complete gonadal dysgenesis.
Evidence remains limited and the published spectrum is broader than the
complete phenotype.
evidence:
- reference: PMID:29373757
reference_title: "Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
SOX8 mutations contribute to a spectrum of phenotypes including 46, XY
DSD, male infertility and 46, XX POI.
explanation: >-
Supports a causal 46,XY DSD spectrum; complete presentations are selected
for this subtype.
- name: SOX9-regulatory deletion complete gonadal dysgenesis
display_name: SOX9-enhancer-deletion 46,XY complete gonadal dysgenesis
classification: gene
genes:
- preferred_term: SOX9
term:
id: hgnc:11204
label: SOX9
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:30552336
reference_title: "Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
SOX9 enhancers that, when duplicated or deleted, result in 46,XX or
46,XY sex reversal, respectively.
explanation: Supports a heterozygous regulatory-deletion mechanism.
description: >-
Deletion of testis-specific enhancers upstream of SOX9 can prevent adequate
SOX9 induction and cause 46,XY sex reversal. Coding SOX9 loss with
campomelic dysplasia is a syndromic differential.
evidence:
- reference: PMID:30552336
reference_title: "Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY
sex reversal, respectively.
explanation: Directly associates upstream enhancer deletion with 46,XY sex reversal.
- name: DHX37-related complete gonadal dysgenesis
display_name: DHX37-related complete 46,XY gonadal dysgenesis
classification: gene
genes:
- preferred_term: DHX37
term:
id: hgnc:17210
label: DHX37
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:40026690
reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
incomplete penetrance may be observed in males (46,XY).
explanation: Supports sex-limited incomplete penetrance for heterozygous DHX37 disease.
description: >-
Heterozygous DHX37 variants show incomplete penetrance in 46,XY individuals
and span testicular regression and gonadal dysgenesis. This subtype includes
only complete-gonadal-dysgenesis presentations; its molecular mechanism
remains unresolved.
evidence:
- reference: PMID:40026690
reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
supports: PARTIAL
evidence_source: OTHER
snippet: >-
in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts,
they have a high detection rate.
explanation: Supports association with gonadal dysgenesis while retaining spectrum uncertainty.
- name: Molecularly unresolved complete gonadal dysgenesis
display_name: Molecularly unresolved 46,XY complete gonadal dysgenesis
classification: molecular
description: >-
Some individuals meeting the complete clinical case definition do not
receive a molecular diagnosis after currently available copy-number and
sequencing tests.
evidence:
- reference: PMID:34781289
reference_title: "Establishing a Molecular Genetic Diagnosis in Children with Differences of Sex Development: A Clinical Approach."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Despite significant improvements in our understanding of the complex
genetic pathways that underlie DSD, an accurate diagnosis still eludes
many affected individuals.
explanation: Supports retention of a molecularly unresolved subtype.
prevalence:
- population: Worldwide
measure_type: UNKNOWN
prevalence_class: UNKNOWN
notes: >-
The disorder is rare, but no robust population-based prevalence estimate is
available. Referral series and broad 46,XY DSD denominators should not be
converted into a population prevalence.
evidence:
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Complete gonadal dysgenesis or Swyer syndrome is a rare genetic disorder
explanation: Supports qualitative rarity without asserting an unsupported rate.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Sex-limited autosomal dominant inheritance applies to several molecular
subtypes, including MAP3K1, NR5A1, DMRT1, SOX8, SOX9-regulatory, and DHX37,
with gene-specific penetrance and expressivity.
evidence:
- reference: PMID:35290982
reference_title: "Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Inheritance occurs in a sex-limited, autosomal dominant fashion with
virtually complete penetrance in 46,XY individuals.
explanation: Directly supports sex-limited dominant inheritance for MAP3K1.
- reference: PMID:40026690
reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
incomplete penetrance may be observed in males (46,XY).
explanation: Supports incomplete penetrance in DHX37-related 46,XY disease.
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
The nonsyndromic DHH-related form is caused by biallelic pathogenic variants.
evidence:
- reference: PMID:30298535
reference_title: "In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
both harboring novel DHH compound heterozygous mutations
explanation: Compound heterozygosity supports recessive inheritance.
- name: X-linked inheritance
inheritance_term:
preferred_term: X-linked inheritance
term:
id: HP:0001417
label: X-linked inheritance
description: >-
Sex-limited X-linked NR0B1 dosage gain can cause complete disease in 46,XY
relatives; this is a duplication mechanism, not NR0B1 loss of function.
evidence:
- reference: PMID:17504899
reference_title: "Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2
interstitial duplication containing the DAX1 gene.
explanation: Directly supports an Xp21.2 dosage-gain subtype in two sisters.
- name: Y-linked inheritance
inheritance_term:
preferred_term: Y-linked inheritance
term:
id: HP:0001450
label: Y-linked inheritance
description: >-
SRY lies on the Y chromosome, but chromosomal location and inheritance mode
should not be conflated with variant origin or recurrence risk; both are
lesion-specific.
evidence:
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations of the SRY gene is associated with complete gonadal dysgenesis
in females with 46,XY karyotype.
explanation: Supports the SRY-associated 46,XY branch; recurrence is lesion-specific.
progression:
- phase: Fetal gonadal-development phase
age_range: embryonic and fetal development
notes: >-
Failure of the pro-testis program prevents functional Sertoli-cell,
testis-cord, and Leydig-cell differentiation. Absent AMH permits Müllerian
persistence, while absent testicular androgen prevents masculinization.
evidence:
- reference: PMID:30552336
reference_title: "Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
SRY-mediated SOX9 upregulation in the early gonad is crucial for testis
development
explanation: Supports the early developmental timing of the core lesion.
- phase: Often clinically silent childhood phase
age_range: infancy through prepubertal childhood
notes: >-
Typical female external anatomy often permits the disorder to remain
unrecognized before puberty, although karyotype testing, a syndromic
feature, family history, or gonadal mass can lead to earlier diagnosis.
evidence:
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
2 patients (13.3%) were diagnosed at birth.
explanation: >-
The minority diagnosed at birth, contrasted with the cohort's adolescent
mean age, supports frequent prepubertal nonrecognition.
- phase: Pubertal-failure recognition phase
age_range: adolescence to young adulthood
notes: >-
Absent or incomplete spontaneous breast development, delayed puberty, and
primary amenorrhea usually trigger endocrine, chromosomal, and imaging
evaluation.
evidence:
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The condition usually manifests in teenage and young adults with delayed
puberty and primary amenorrhea.
explanation: Directly supports the usual recognition phase.
- phase: Untreated complication phase
age_range: adolescence and adulthood
notes: >-
Persistent hypoestrogenism impairs uterine maturation and bone accrual, and
retained dysgenetic Y-bearing gonads remain susceptible to precursor and
invasive germ-cell tumors. Infertility is intrinsic to absent functional
gonadal gametes.
evidence:
- reference: PMID:32905884
reference_title: "Risk of gonadal neoplasia in patients with disorders/differences of sex development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The highest risk (36 %) was observed in 46,XY patients with gonadal
dysgenesis (GD): complete GD (33 %) and partial GD (23 %)
explanation: Supports the major tumor complication while retaining mixed-cohort limitations.
- reference: PMID:31809259
reference_title: "Misdiagnosis of Mullerian agenesis in a patient with 46, XX gonadal dysgenesis: a missed opportunity for prevention of osteoporosis."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Delay in diagnosis and hormone substitution therapy causes secondary
osteoporosis.
explanation: >-
A 46,XX gonadal-dysgenesis case supports the broader hypoestrogenic bone
consequence; it is explicitly extrapolative rather than disease-specific.
pathophysiology:
- name: SRY-SOX9-SOX8-DMRT1 transcriptional network failure
role: trigger
description: >-
Loss or inadequate activation of the core pro-testis transcriptional network
prevents stable supporting-cell commitment. This branch includes SRY
defects, SOX9 enhancer deletion, rare SOX8 defects, and DMRT1
haploinsufficiency.
genes:
- preferred_term: SRY
term:
id: hgnc:11311
label: SRY
- preferred_term: SOX9
term:
id: hgnc:11204
label: SOX9
- preferred_term: SOX8
term:
id: hgnc:11203
label: SOX8
- preferred_term: DMRT1
term:
id: hgnc:2934
label: DMRT1
biological_processes:
- preferred_term: sex determination
term:
id: GO:0007530
label: sex determination
modifier: DECREASED
- preferred_term: male gonad development
term:
id: GO:0008584
label: male gonad development
modifier: DECREASED
evidence:
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The SRY initiates cascade of gene expression that transforms the
undifferentiated gonad, genital ridge into testis.
explanation: Places SRY at the start of the pro-testis network.
- reference: PMID:30552336
reference_title: "Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
All three enhancers showed synergistic activity and together drive SOX9
in the testis.
explanation: Supports the testis-specific SOX9 enhancer mechanism.
- reference: PMID:34515237
reference_title: "DMRT1: An Ancient Sexual Regulator Required for Human Gonadogenesis."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
DMRT1 is essential for male somatic and germ cell differentiation and
maintenance of male somatic cell fate after differentiation.
explanation: Supports DMRT1 participation in pro-testis differentiation and maintenance.
downstream:
- target: Failure of supporting-cell differentiation and testis-cord formation
causal_link_type: DIRECT
description: >-
Failure to activate or stabilize the pro-testis network prevents
supporting cells from adopting the Sertoli-cell fate and organizing
testis cords.
evidence:
- reference: PMID:30552336
reference_title: "Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
SRY-mediated SOX9 upregulation in the early gonad is crucial for testis
development
explanation: Directly supports this developmental transition.
- name: MAP3K1 gain-of-function pro-ovarian signaling bias
role: trigger
description: >-
Pathogenic MAP3K1 variants increase ERK1/2 and p38 signaling, interfere with
testis determination, and permit a pro-ovarian signaling state.
genes:
- preferred_term: MAP3K1
term:
id: hgnc:6848
label: MAP3K1
biological_processes:
- preferred_term: sex determination
term:
id: GO:0007530
label: sex determination
modifier: ABNORMAL
evidence:
- reference: PMID:35290982
reference_title: "Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The net effect of these variants is to increase phosphorylation of
downstream targets ERK1, ERK2, and p38, resulting in multiple
gain-of-function effects interfering with testis determination and
enabling ovarian determination.
explanation: Defines the direction and downstream signaling effect of MAP3K1 variants.
downstream:
- target: Failure of supporting-cell differentiation and testis-cord formation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- increased ERK1/2 and p38 phosphorylation
- reduced pro-testis pathway commitment
description: MAP3K1 gain of function shifts the bipotential gonad away from testis fate.
evidence:
- reference: PMID:35290982
reference_title: "Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
gain-of-function effects interfering with testis determination and
enabling ovarian determination.
explanation: Directly supports the fate-bias interpretation.
- name: NR5A1 gonadal transcription failure
role: trigger
description: >-
Pathogenic NR5A1 variants impair transcriptional control of gonadal
development and steroidogenic programs, with variable phenotypic severity.
genes:
- preferred_term: NR5A1
term:
id: hgnc:7983
label: NR5A1
biological_processes:
- preferred_term: male gonad development
term:
id: GO:0008584
label: male gonad development
modifier: DECREASED
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
NR5A1, also known as steroidogenic factor 1, a crucial transcriptional
factor regulating adrenal and gonadal development and function.
explanation: Supports NR5A1's gonadal-developmental transcriptional role.
downstream:
- target: Failure of supporting-cell differentiation and testis-cord formation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- impaired gonadal transcriptional activation
description: Severe NR5A1 dysfunction can prevent complete testicular differentiation.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
this case presented with CGD, a severe DSD phenotype
explanation: Links an NR5A1 variant to the complete developmental endpoint.
- name: DHH paracrine signaling failure
role: trigger
description: >-
Biallelic DHH variants impair Sertoli-derived paracrine signaling needed for
Leydig and peritubular-cell development. DHH is therefore modeled as a
differentiation-signaling branch rather than as an SRY-equivalent trigger.
genes:
- preferred_term: DHH
term:
id: hgnc:2865
label: DHH
cell_types:
- preferred_term: Sertoli cell
term:
id: CL:0000216
label: Sertoli cell
- preferred_term: Leydig cell
term:
id: CL:0000178
label: Leydig cell
evidence:
- reference: PMID:30298535
reference_title: "In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In humans, mutations of Desert Hedgehog gene (DHH) have been described in
patients with 46,XY gonadal dysgenesis (GD), associated or not with
polyneuropathy.
explanation: Supports DHH as a gonadal-dysgenesis gene.
- reference: PMID:30298535
reference_title: "In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
p.(Asn337Lysfs*24) mutation resulted in a complete absence of
auto-proteolysis.
explanation: Provides functional evidence that a patient variant disrupts DHH processing.
downstream:
- target: Failure of supporting-cell differentiation and testis-cord formation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- defective DHH autoprocessing
- impaired Sertoli-to-Leydig and peritubular signaling
description: Severe DHH signaling loss disrupts coordinated testicular differentiation.
evidence:
- reference: PMID:30298535
reference_title: "In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We propose a model that may explain the differences between Schwann and
Leydig cell development by autocrine versus paracrine DHh signaling.
explanation: Supports the paracrine Leydig-development branch.
- name: DHX37-related gonadal-development failure
role: trigger
description: >-
Heterozygous DHX37 variants are associated with 46,XY gonadal dysgenesis,
but whether ribosome synthesis, cell-cycle, NF-κB, Wnt, or another pathway
mediates the gonadal defect remains unresolved.
genes:
- preferred_term: DHX37
term:
id: hgnc:17210
label: DHX37
evidence:
- reference: PMID:40026690
reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Although the molecular mechanism of DHX37 mutation related 46,XY DSD is
unclear
explanation: Explicitly supports mechanistic uncertainty.
downstream:
- target: Failure of supporting-cell differentiation and testis-cord formation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
DHX37-associated complete disease converges on testis-development failure
through intermediates that are not yet established.
evidence:
- reference: PMID:40026690
reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
supports: PARTIAL
evidence_source: OTHER
snippet: >-
ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt
pathways may be affected.
explanation: Identifies candidate, but unproven, intermediates.
- name: NR0B1 dosage gain
role: trigger
description: >-
Duplication of an Xp21.2 interval containing NR0B1/DAX1 increases dosage of
a sex-determination regulator and can antagonize testis development.
genes:
- preferred_term: NR0B1
term:
id: hgnc:7960
label: NR0B1
evidence:
- reference: PMID:17504899
reference_title: "Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thus, our data support DAX1 as a dosage sensitive gene responsible for
gonadal dysgenesis
explanation: Directly supports the dosage-gain mechanism.
downstream:
- target: Failure of supporting-cell differentiation and testis-cord formation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- excess NR0B1 dosage
- antagonism of the pro-testis program
description: NR0B1 dosage gain prevents normal testicular differentiation.
evidence:
- reference: PMID:17504899
reference_title: "Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
two sisters with an apparent normal 46,XY karyotype and female external
genitalia due to gonadal dysgenesis
explanation: Links the dosage lesion to failed testis differentiation and phenotype.
- name: Failure of supporting-cell differentiation and testis-cord formation
role: central_effector
description: >-
Diverse lesions converge on failure of Sertoli/supporting-cell
differentiation and testis-cord formation, so a functional testis and its
dependent fetal hormone-producing compartments do not develop.
biological_processes:
- preferred_term: male gonad development
term:
id: GO:0008584
label: male gonad development
modifier: DECREASED
cell_types:
- preferred_term: Sertoli cell
term:
id: CL:0000216
label: Sertoli cell
evidence:
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
46,XY karyotype and female phenotype with undeveloped streak gonads
explanation: Supports the convergent failure of testicular gonadal differentiation.
downstream:
- target: Bilateral streak or dysgenetic gonads
causal_link_type: DIRECT
description: Complete failure of testis differentiation leaves nonfunctional gonadal remnants.
evidence:
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypoplastic uterus with streak gonad and underdeveloped secondary sexual
characters.
explanation: Documents streak gonads in molecularly confirmed complete disease.
- target: Absent fetal AMH secretion
causal_link_type: DIRECT
description: Failure of fetal Sertoli-cell differentiation eliminates normal AMH secretion.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
AMH levels below detection sensitivity.
explanation: Documents undetectable AMH in complete disease.
- target: Absent fetal testicular androgen secretion
causal_link_type: DIRECT
description: Failure of functional testis and Leydig-cell differentiation removes fetal testicular androgen output.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
fully female internal and external genitalia
explanation: >-
The complete anatomic phenotype supports loss of fetal testicular
hormone action; adult circulating testosterone need not be literally zero.
- name: Bilateral streak or dysgenetic gonads
role: central_effector
description: >-
Bilateral gonadal remnants consist predominantly of fibrous or severely
dysgenetic tissue without useful steroidogenic or gametogenic function.
biological_processes:
- preferred_term: steroid hormone biosynthetic process
term:
id: GO:0006694
label: steroid biosynthetic process
modifier: DECREASED
evidence:
- reference: PMID:19246354
reference_title: "Mutations in NR5A1 associated with ovarian insufficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Gonadal histologic analysis revealed homogeneous fibrous tissue, and
46,XY complete gonadal dysgenesis was diagnosed
explanation: Directly documents fibrous gonadal tissue in complete disease.
downstream:
- target: Gonadal dysgenesis
causal_link_type: DIRECT
description: The streak/dysgenetic gonad is the defining structural phenotype.
evidence:
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
undeveloped streak gonads
explanation: Supports the structural phenotype.
- target: Streak gonad
causal_link_type: DIRECT
description: The complete developmental lesion commonly produces bilateral streak gonads.
evidence:
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypoplastic uterus with streak gonad
explanation: Directly supports the streak-gonad phenotype.
- target: Absent pubertal gonadal hormone secretion
causal_link_type: DIRECT
description: Nonfunctional gonads cannot supply normal pubertal estrogen or inhibin.
evidence:
- reference: PMID:40097859
reference_title: "Infertility management in a patient with Swyer syndrome: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
nonfunctional gonads resulting from complete gonadal dysgenesis.
explanation: Supports loss of gonadal function in complete disease.
- target: Female infertility
causal_link_type: DIRECT
description: Absence of functional gonadal gametes causes infertility.
evidence:
- reference: PMID:40097859
reference_title: "Infertility management in a patient with Swyer syndrome: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
reproductive treatments for individuals with nonfunctional gonads
resulting from complete gonadal dysgenesis.
explanation: Supports infertility arising from nonfunctional gonads.
- target: Dysgenetic Y-bearing germ-cell niche
causal_link_type: DIRECT
description: Dysgenetic gonadal tissue containing Y-chromosome material creates a tumor-prone germ-cell environment.
evidence:
- reference: PMID:38337479
reference_title: "A Risk of Gonadoblastoma in Familial Swyer Syndrome-A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
intrabdominal dysgenetic gonads in the patient with genetic material of
a Y chromosome may conduce to the development of gonadal tumors
explanation: Directly supports the tumor-prone anatomic substrate.
- name: Absent fetal AMH secretion
role: central_effector
description: >-
Failed fetal Sertoli-cell function removes anti-Müllerian hormone signaling.
cell_types:
- preferred_term: Sertoli cell
term:
id: CL:0000216
label: Sertoli cell
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the presence of Müllerian structures suggested a defect in fetal Sertoli
cell differentiation and AMH secretion
explanation: Supports the Sertoli/AMH branch and its anatomic consequence.
downstream:
- target: Müllerian-duct persistence
causal_link_type: DIRECT
description: Without fetal AMH, Müllerian derivatives including a uterus and tubes persist.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the presence of Müllerian structures suggested a defect in fetal Sertoli
cell differentiation and AMH secretion
explanation: Directly supports Müllerian persistence after failed fetal AMH secretion.
- name: Müllerian-duct persistence
role: consequence
description: >-
Müllerian structures are present, although prolonged hypoestrogenism can
leave the uterus small or difficult to visualize before hormone treatment.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a vagina, a hypoplastic uterus with an undeniable rudimentary uterus
explanation: Documents persistent but hypoplastic Müllerian structures.
downstream:
- target: Hypoplasia of the uterus
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- persistent Müllerian-derived uterus
- absent pubertal estrogen-driven uterine growth
description: A retained uterus remains hypoplastic without adequate pubertal estrogen.
evidence:
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypoplastic uterus with streak gonad
explanation: Directly documents uterine hypoplasia in complete disease.
- name: Absent fetal testicular androgen secretion
role: central_effector
description: >-
Failure of functional fetal Leydig cells removes testicular testosterone and
dihydrotestosterone exposure. Adult serum testosterone may remain detectable
from adrenal or peripheral sources and should be interpreted against
sex- and age-appropriate ranges rather than described as absolutely absent.
cell_types:
- preferred_term: Leydig cell
term:
id: CL:0000178
label: Leydig cell
biological_processes:
- preferred_term: steroid hormone biosynthetic process
term:
id: GO:0006694
label: steroid biosynthetic process
modifier: DECREASED
evidence:
- reference: PMID:37994022
reference_title: "A rare case of Swyer syndrome from Pakistan in a young girl with primary amenorrhea and 46XY genotype."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
there is an absence of testosterone that leads to lack of masculinization
and the presence of female genitalia.
explanation: >-
The paper's absolute wording is simplified, but the anatomy supports absent
fetal testicular androgen effect rather than an inference from an adult
serum concentration.
downstream:
- target: Female external genital development in a 46,XY individual
causal_link_type: DIRECT
description: Lack of fetal androgen-driven masculinization yields typical female external genitalia.
evidence:
- reference: PMID:37994022
reference_title: "A rare case of Swyer syndrome from Pakistan in a young girl with primary amenorrhea and 46XY genotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
lack of masculinization and the presence of female genitalia.
explanation: Directly supports the external-genital consequence.
- name: Female external genital development in a 46,XY individual
role: consequence
description: >-
External genital development follows a typical female pattern despite the
46,XY chromosomal complement.
evidence:
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The cytogenetic analysis confirmed 46,XY sex reversal karyotype of a
female.
explanation: Directly supports the chromosomal/anatomic discordance.
downstream:
- target: Female external genitalia in individual with 46,XY karyotype
causal_link_type: DIRECT
description: This is the HPO-grounded external-genital phenotype.
evidence:
- reference: PMID:21982289
reference_title: "Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
internal and external female genitalia
explanation: Documents the phenotype in a complete-gonadal-dysgenesis cohort.
- name: Absent pubertal gonadal hormone secretion
role: central_effector
description: >-
Nonfunctional streak gonads do not produce physiologic pubertal estradiol or
inhibin, preventing spontaneous pubertal progression and normal uterine and
skeletal estrogenization.
biological_processes:
- preferred_term: steroid hormone biosynthetic process
term:
id: GO:0006694
label: steroid biosynthetic process
modifier: DECREASED
evidence:
- reference: PMID:40097859
reference_title: "Infertility management in a patient with Swyer syndrome: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
elevated gonadotropin levels, oestrogen insufficiency, tall stature,
delayed puberty, and primary amenorrhoea.
explanation: Directly supports the pubertal endocrine state and consequences.
downstream:
- target: Loss of gonadal negative feedback
causal_link_type: DIRECT
description: Low estradiol and inhibin remove negative feedback on pituitary gonadotropin secretion.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
high luteinizing and follicle-stimulating hormone levels
explanation: Supports loss of gonadal feedback.
- target: Breast hypoplasia
causal_link_type: DIRECT
description: Inadequate pubertal estrogen prevents normal breast development.
evidence:
- reference: PMID:37994022
reference_title: "A rare case of Swyer syndrome from Pakistan in a young girl with primary amenorrhea and 46XY genotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
lacked breast growth
explanation: Directly documents absent breast development.
- target: Delayed puberty
causal_link_type: DIRECT
description: Absent pubertal gonadal hormone secretion prevents timely pubertal progression.
evidence:
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
delayed puberty and primary amenorrhea.
explanation: Directly supports delayed puberty.
- target: Primary amenorrhea
causal_link_type: DIRECT
description: Absent spontaneous estrogenization and endometrial cycling prevent menarche.
evidence:
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
delayed puberty and primary amenorrhea.
explanation: Directly supports primary amenorrhea.
- target: Reduced bone mineral density
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- prolonged estrogen deficiency
- impaired pubertal bone accrual
description: Untreated hypoestrogenism impairs acquisition and maintenance of bone mass.
evidence:
- reference: PMID:37994022
reference_title: "A rare case of Swyer syndrome from Pakistan in a young girl with primary amenorrhea and 46XY genotype."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Hormone replacement therapy was started to induce pubertal development
and optimize bone mineral accumulation.
explanation: Supports bone mineral accrual as a management target in Swyer syndrome.
- name: Loss of gonadal negative feedback
role: consequence
description: >-
Low gonadal estradiol and inhibin release the hypothalamic-pituitary axis
from negative feedback, raising FSH and LH and producing
hypergonadotropic hypogonadism.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
high luteinizing and follicle-stimulating hormone levels
explanation: Directly documents elevated gonadotropins.
downstream:
- target: Hypergonadotropic hypogonadism
causal_link_type: DIRECT
description: High FSH/LH with low estradiol is the characteristic endocrine phenotype.
evidence:
- reference: PMID:40097859
reference_title: "Infertility management in a patient with Swyer syndrome: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
elevated gonadotropin levels, oestrogen insufficiency
explanation: Directly supports the endocrine phenotype.
- name: Dysgenetic Y-bearing germ-cell niche
role: central_effector
description: >-
Germ cells persisting in a poorly differentiated gonadal environment with
Y-chromosome material can form gonadoblastoma or related precursor lesions.
evidence:
- reference: PMID:34070473
reference_title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the presence of Y chromosomal material serves as a risk factor for
malignant transformation
explanation: Supports the Y-bearing dysgenetic gonadal substrate.
downstream:
- target: Gonadal germ-cell neoplasia risk
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- persistence of developmentally arrested germ cells
- aberrant germ-cell survival and maturation
description: The dysgenetic niche permits precursor lesions and invasive germ-cell tumors.
evidence:
- reference: PMID:34070473
reference_title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
pre-invasive tumors such as germ cell neoplasia in situ (GCNIS) or
gonadoblastoma, which is commonly observed in complete or partial
dysgenesis
explanation: Supports the precursor-to-invasive risk pathway.
- name: Gonadal germ-cell neoplasia risk
role: consequence
description: >-
Complete gonadal dysgenesis carries clinically important risk of
gonadoblastoma and invasive tumors, especially dysgerminoma. Published
percentages vary substantially because cohorts are small, retrospective,
referral-selected, pathology-selected, or combine multiple XY DSD
diagnoses; no single percentage should be presented as population risk.
evidence:
- reference: PMID:32905884
reference_title: "Risk of gonadal neoplasia in patients with disorders/differences of sex development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
complete GD (33 %)
explanation: Provides a multicenter adult cohort estimate, not a population-wide rate.
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
The most commonly diagnosed tumors were dysgerminoma and gonadoblastoma.
explanation: Supports the tumor spectrum in a mass-enriched referral cohort.
downstream:
- target: Gonadoblastoma
causal_link_type: DIRECT
description: Gonadoblastoma is a characteristic precursor neoplasm in dysgenetic gonads.
evidence:
- reference: PMID:38337479
reference_title: "A Risk of Gonadoblastoma in Familial Swyer Syndrome-A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
two siblings with Swyer syndrome in whom gonadoblastoma was found.
explanation: Directly documents gonadoblastoma in familial complete disease.
phenotypes:
- name: Gonadal dysgenesis
category: Reproductive
description: >-
Complete failure of testicular differentiation produces bilateral severely
dysgenetic gonads.
phenotype_term:
preferred_term: gonadal dysgenesis
term:
id: HP:0000133
label: Gonadal dysgenesis
evidence:
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Complete gonadal dysgenesis or Swyer syndrome
explanation: Identifies gonadal dysgenesis as the defining lesion.
- name: Streak gonad
category: Reproductive
description: >-
Gonads are commonly bilateral fibrous streaks or severely dysgenetic
remnants, not small ovaries.
phenotype_term:
preferred_term: Streak gonad
term:
id: HP:0025733
label: Streak gonad
evidence:
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypoplastic uterus with streak gonad
explanation: Directly documents a streak gonad.
- name: Female external genitalia in individual with 46,XY karyotype
category: Reproductive
description: >-
External genitalia are typically female because fetal testicular androgen
secretion is absent.
phenotype_term:
preferred_term: Female external genitalia in individual with 46,XY karyotype
term:
id: HP:0008730
label: Female external genitalia in individual with 46,XY karyotype
evidence:
- reference: PMID:21982289
reference_title: "Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
internal and external female genitalia
explanation: Documents the defining anatomic phenotype in the cohort.
- name: Delayed puberty
category: Reproductive
description: Puberty is delayed or absent without exogenous sex-steroid replacement.
phenotype_term:
preferred_term: delayed puberty
term:
id: HP:0000823
label: Delayed puberty
evidence:
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
delayed puberty and primary amenorrhea.
explanation: Directly supports delayed puberty.
- name: Breast hypoplasia
category: Reproductive
description: >-
Spontaneous breast development is absent or limited because pubertal
estradiol production is deficient. Pubic and axillary hair are not uniformly
sparse because adrenal androgen production may be preserved.
phenotype_term:
preferred_term: Breast hypoplasia
term:
id: HP:0003187
label: Breast hypoplasia
evidence:
- reference: PMID:37994022
reference_title: "A rare case of Swyer syndrome from Pakistan in a young girl with primary amenorrhea and 46XY genotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
lacked breast growth
explanation: Directly supports absent breast development.
- name: Primary amenorrhea
category: Reproductive
description: >-
Menarche does not occur spontaneously because the uterus is not exposed to
normal pubertal ovarian steroid production.
phenotype_term:
preferred_term: primary amenorrhea
term:
id: HP:0000786
label: Primary amenorrhea
evidence:
- reference: PMID:35720238
reference_title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
delayed puberty and primary amenorrhea.
explanation: Directly supports primary amenorrhea.
- name: Hypergonadotropic hypogonadism
category: Endocrine
description: >-
FSH and LH are elevated in the setting of deficient gonadal estradiol and
inhibin output.
phenotype_term:
preferred_term: hypergonadotropic hypogonadism
term:
id: HP:0000815
label: Hypergonadotropic hypogonadism
evidence:
- reference: PMID:21982289
reference_title: "Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
patients with hypergonadotropic hypogonadism, streak gonads
explanation: Directly supports this endocrine phenotype in complete disease.
- name: Hypoplasia of the uterus
category: Reproductive
description: >-
Müllerian structures persist, but the uterus is often small before adequate
estrogen exposure because pubertal uterine growth is hormone-dependent.
phenotype_term:
preferred_term: hypoplastic uterus
term:
id: HP:0000013
label: Hypoplasia of the uterus
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a vagina, a hypoplastic uterus with an undeniable rudimentary uterus
explanation: Directly documents uterine hypoplasia in complete disease.
- name: Female infertility
category: Reproductive
description: >-
Classic complete disease lacks functional gonadal gametes. A responsive
uterus may nevertheless support pregnancy using donated oocytes or embryos.
phenotype_term:
preferred_term: Female infertility
term:
id: HP:0008222
label: Female infertility
evidence:
- reference: PMID:40097859
reference_title: "Infertility management in a patient with Swyer syndrome: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
nonfunctional gonads resulting from complete gonadal dysgenesis.
explanation: Supports the gonadal basis of infertility.
- name: Reduced bone mineral density
category: Skeletal
description: >-
Prolonged untreated estrogen deficiency can impair pubertal bone accrual and
reduce bone mineral density.
phenotype_term:
preferred_term: Reduced bone mineral density
term:
id: HP:0004349
label: Reduced bone mineral density
evidence:
- reference: PMID:31809259
reference_title: "Misdiagnosis of Mullerian agenesis in a patient with 46, XX gonadal dysgenesis: a missed opportunity for prevention of osteoporosis."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Bone density scan (DEXA scan) revealed osteoporosis at the lumbar spine
(T score −2.7) and osteopenia at the hip (T score −1.5).
explanation: >-
This is direct evidence from severe estrogen deficiency in 46,XX gonadal
dysgenesis and is used as a clearly labeled physiologic extrapolation.
- name: Gonadoblastoma
category: Neoplasm
description: >-
Gonadoblastoma is a characteristic neoplasm arising in Y-bearing dysgenetic
gonads and may coexist with or progress to invasive dysgerminoma.
phenotype_term:
preferred_term: Gonadoblastoma
term:
id: HP:0000150
label: Gonadoblastoma
evidence:
- reference: PMID:38337479
reference_title: "A Risk of Gonadoblastoma in Familial Swyer Syndrome-A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
two siblings with Swyer syndrome in whom gonadoblastoma was found.
explanation: Directly documents gonadoblastoma in familial disease.
biochemical:
- name: Follicle-stimulating hormone
presence: INCREASED
context: >-
FSH is elevated after the expected onset of puberty because gonadal
estradiol and inhibin feedback are deficient.
biomarker_term:
preferred_term: Follicle stimulating hormone
term:
id: CHEBI:81569
label: Follicle stimulating hormone
readouts:
- target: Loss of gonadal negative feedback
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Elevated FSH reports primary gonadal failure and loss of feedback.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
high luteinizing and follicle-stimulating hormone levels
explanation: Elevated FSH directly reports loss of gonadal feedback.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
high luteinizing and follicle-stimulating hormone levels
explanation: Directly documents elevated FSH and LH.
- name: Luteinizing hormone
presence: INCREASED
context: >-
LH is elevated after the expected onset of puberty as part of the
hypergonadotropic pattern.
biomarker_term:
preferred_term: Luteinizing hormone
term:
id: CHEBI:81568
label: Luteinizing hormone
readouts:
- target: Loss of gonadal negative feedback
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Elevated LH reports loss of gonadal steroid feedback.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
high luteinizing and follicle-stimulating hormone levels
explanation: Elevated LH directly reports loss of gonadal feedback.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
high luteinizing and follicle-stimulating hormone levels
explanation: Directly documents elevated LH and FSH.
- name: Estradiol
presence: DECREASED
context: >-
Estradiol is low for pubertal age because streak gonads lack functional
steroidogenic tissue.
biomarker_term:
preferred_term: estradiol
term:
id: CHEBI:23965
label: estradiol
readouts:
- target: Absent pubertal gonadal hormone secretion
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Low estradiol reports absent pubertal gonadal steroid secretion.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
low estradiol levels
explanation: Low estradiol directly reports deficient pubertal gonadal secretion.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
low estradiol levels
explanation: Directly documents low estradiol.
- name: Testosterone relative to a 46,XY male reference range
presence: ABNORMAL
context: >-
Testosterone generally reflects absent functional testicular production and
is low relative to an age-matched 46,XY male reference range, but it can be
detectable or slightly above a female reference range because adrenal and
peripheral sources remain. Adult values do not reconstruct fetal exposure.
biomarker_term:
preferred_term: testosterone
term:
id: CHEBI:17347
label: testosterone
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
slightly high testosterone levels
explanation: >-
The complete-disease case had detectable testosterone, supporting careful
reference-range interpretation rather than an absolute-zero claim.
- name: Anti-Müllerian hormone
presence: DECREASED
context: >-
AMH is very low or undetectable because functional Sertoli cells are absent.
readouts:
- target: Failure of supporting-cell differentiation and testis-cord formation
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Undetectable AMH reports severe Sertoli-cell differentiation failure.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
anti-Müllerian hormone (AMH) levels below detection sensitivity.
explanation: Undetectable AMH reports severe Sertoli-cell differentiation failure.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
anti-Müllerian hormone (AMH) levels below detection sensitivity.
explanation: Directly documents undetectable AMH.
genetic:
- name: SRY
gene_term:
preferred_term: SRY
term:
id: hgnc:11311
label: SRY
association: Causal pathogenic SRY variant affecting testis determination
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient was confirmed with nucleotide substitution (c.226C>A;
p.Arg76Ser) at in HMG box domain of SRY gene that causes 46,XY sex
reversal female.
explanation: Directly associates an SRY variant with complete disease.
- reference: PMID:33570214
reference_title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
supports: PARTIAL
evidence_source: COMPUTATIONAL
snippet: >-
Mutation prediction algorithms suggest that alteration might be disease
causing mutation
explanation: Separately classifies the in-silico pathogenicity support.
- name: NR0B1
gene_term:
preferred_term: NR0B1
term:
id: hgnc:7960
label: NR0B1
association: Causal Xp21.2 copy-number gain containing NR0B1/DAX1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:17504899
reference_title: "Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2
interstitial duplication containing the DAX1 gene.
explanation: Directly supports causal NR0B1-region duplication.
- name: NR5A1
gene_term:
preferred_term: NR5A1
term:
id: hgnc:7983
label: NR5A1
association: Causal heterozygous pathogenic variant with variable expressivity
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
c.132_134del (p.Asn44del) heterozygous in-frame-deletion in NR5A1
explanation: Directly documents a heterozygous NR5A1 variant in complete disease.
- name: DMRT1
gene_term:
preferred_term: DMRT1
term:
id: hgnc:2934
label: DMRT1
association: Causal heterozygous sequence variant or focal deletion
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:34515237
reference_title: "DMRT1: An Ancient Sexual Regulator Required for Human Gonadogenesis."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
its heterozygosity is associated with 46,XY complete gonadal dysgenesis.
explanation: Directly supports the DMRT1 association.
- name: MAP3K1
gene_term:
preferred_term: MAP3K1
term:
id: hgnc:6848
label: MAP3K1
association: Causal heterozygous gain-of-function variant
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:35290982
reference_title: "Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY
non-syndromic partial and complete gonadal dysgenesis
explanation: Directly includes complete disease in the MAP3K1 spectrum.
- name: DHH
gene_term:
preferred_term: DHH
term:
id: hgnc:2865
label: DHH
association: Causal biallelic pathogenic variants causing reduced or absent DHH function
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:30298535
reference_title: "In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
both harboring novel DHH compound heterozygous mutations
explanation: >-
Supports biallelic DHH-associated gonadal dysgenesis across a broader
phenotype spectrum; only complete nonsyndromic cases belong in this root.
- reference: PMID:30298535
reference_title: "In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis."
supports: PARTIAL
evidence_source: IN_VITRO
snippet: >-
p.(Asn337Lysfs*24) mutation resulted in a complete absence of
auto-proteolysis.
explanation: >-
Functionally demonstrates absent processing for one allele; the companion
p.Glu212Lys allele retains partial activity and the clinical report is not
limited to classic complete disease.
- name: SOX8
gene_term:
preferred_term: SOX8
term:
id: hgnc:11203
label: SOX8
association: Rare causal heterozygous sequence or structural variant in the 46,XY DSD spectrum
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
Published evidence spans 46,XY DSD rather than only complete disease; this
record is restricted to complete presentations.
evidence:
- reference: PMID:29373757
reference_title: "Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
two individuals with 46, XY disorders/differences in sex development
(DSD) and chromosomal rearrangements encompassing the SOX8 locus and a
third individual with 46, XY DSD and a missense mutation
explanation: Supports human SOX8 lesions across the 46,XY DSD spectrum.
- reference: PMID:29373757
reference_title: "Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In vitro functional assays indicate that this mutation alters the
biological activity of the protein.
explanation: Provides functional support for the missense variant.
- name: SOX9
gene_term:
preferred_term: SOX9
term:
id: hgnc:11204
label: SOX9
association: Causal deletion of upstream testis-specific enhancer sequence
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: Coding SOX9 loss with campomelic dysplasia is outside the nonsyndromic root.
evidence:
- reference: PMID:30552336
reference_title: "Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY
sex reversal, respectively.
explanation: Directly supports the enhancer-deletion association.
- reference: PMID:30552336
reference_title: "Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
All three enhancers showed synergistic activity and together drive SOX9
in the testis.
explanation: Provides functional evidence for testis-specific enhancer activity.
- name: DHX37
gene_term:
preferred_term: DHX37
term:
id: hgnc:17210
label: DHX37
association: Causal heterozygous variant with incomplete penetrance; molecular mechanism unresolved
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
Include complete-gonadal-dysgenesis presentations only, not all
DHX37-associated testicular regression syndrome.
evidence:
- reference: PMID:40026690
reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
supports: PARTIAL
evidence_source: OTHER
snippet: >-
in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts,
they have a high detection rate.
explanation: Supports the association while preserving phenotype-spectrum limits.
- reference: PMID:40026690
reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear
explanation: Explicitly records mechanistic uncertainty.
environmental: []
histopathology:
- name: Fibrous streak or severely dysgenetic gonadal tissue
description: >-
Gonadectomy specimens can show homogeneous fibrous streak tissue or other
severely dysgenetic gonadal remnants with little functional testicular
architecture.
diagnostic: false
evidence:
- reference: PMID:19246354
reference_title: "Mutations in NR5A1 associated with ovarian insufficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Gonadal histologic analysis revealed homogeneous fibrous tissue, and
46,XY complete gonadal dysgenesis was diagnosed
explanation: Directly supports the fibrous streak-gonad histology.
- name: Gonadoblastoma and dysgerminoma in dysgenetic gonads
description: >-
Complete examination of resected gonads may identify gonadoblastoma,
dysgerminoma, or both. Limited biopsy is not a reliable exclusion test for
focal neoplasia.
diagnostic: false
evidence:
- reference: PMID:36767504
reference_title: "Late Diagnosis of Swyer Syndrome in a Patient with Bilateral Germ Cell Tumor Treated with a Contraceptive Due to Primary Amenorrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Histopathological examination revealed the presence of dysgerminoma in
both dysgenetic gonads.
explanation: Directly documents bilateral dysgerminoma in Swyer syndrome.
- reference: PMID:34070473
reference_title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Tissue samples had been previously taken laparoscopically with benign
histology.
explanation: >-
A later seminoma in this mixed XY-DSD case illustrates sampling limitations
of prior benign tissue samples.
imaging_findings:
- name: Persistent Müllerian structures with a hypoplastic uterus
modality: MRI
diagnostic: false
description: >-
Ultrasound or MRI usually demonstrates a uterus and vagina, often
hypoplastic before estrogen treatment. Very small Müllerian structures can
be difficult to visualize.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
pelvic magnetic resonance imaging (MRI) revealed a vagina, a hypoplastic
uterus with an undeniable rudimentary uterus
explanation: Directly supports the MRI finding.
- name: Streak, dysgenetic, or nonvisualized gonads
modality: OTHER
diagnostic: false
description: >-
Gonads may appear as small streak-like structures or may not be visualized;
the correct anatomic framing is dysgenetic gonads rather than small ovaries.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
no evidence of bilateral adnexa.
explanation: Documents nonvisualization of bilateral gonadal/adnexal structures.
- name: Imaging may be normal despite gonadal germ-cell tumor
modality: OTHER
diagnostic: false
description: >-
Normal imaging does not exclude gonadoblastoma or invasive germ-cell tumor
in dysgenetic gonads and is not a validated substitute for definitive
management.
evidence:
- reference: PMID:36767504
reference_title: "Late Diagnosis of Swyer Syndrome in a Patient with Bilateral Germ Cell Tumor Treated with a Contraceptive Due to Primary Amenorrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Gonadal dysgerminoma should be suspected even in the absence of tumor
features on ultrasound and blood laboratory tests.
explanation: Directly states the limitation of normal imaging and laboratory tests.
- reference: PMID:34070473
reference_title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the limitation of tumor markers and US or MRI/CT to detect them and
missing guidelines for surveillance.
explanation: Supports the lack of reliable imaging/marker surveillance.
diagnosis:
- name: Integrated clinical and endocrine assessment
description: >-
Assess growth, Tanner stage, breast development, external genital anatomy,
family history, syndromic features, and age-appropriate FSH, LH, estradiol,
testosterone, and optionally AMH/inhibin B. The high-gonadotropin,
low-estradiol pattern indicates primary gonadal failure.
diagnosis_term:
preferred_term: clinical assessment
term:
id: NCIT:C124351
label: Clinical Evaluation
results: Absent or incomplete puberty with hypergonadotropic gonadal failure.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
high luteinizing and follicle-stimulating hormone levels, slightly high
testosterone levels, high dehydroepiandrosterone sulfate levels, normal
sex hormone-binding globulin levels, low estradiol levels, and
anti-Müllerian hormone (AMH) levels below detection sensitivity.
explanation: Directly supplies a complete-disease endocrine profile.
- name: Formal karyotype analysis
description: >-
Formal chromosome analysis confirms the defining 46,XY complement and
evaluates mosaicism or structural chromosome abnormalities.
diagnosis_term:
preferred_term: karyotyping
term:
id: NCIT:C16768
label: Karyotyping
results: Nonmosaic 46,XY karyotype in classic disease.
evidence:
- reference: PMID:36424806
reference_title: "Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
We recommend formal Karyotyping, even if Y chromosome material has been
detected by other methods.
explanation: Directly supports formal karyotype testing in 46,XY DSD.
- name: Abdominopelvic ultrasonography
description: >-
Ultrasound assesses Müllerian structures, gonad location, and any mass.
Nonvisualization is common and normal findings do not exclude neoplasia.
diagnosis_term:
preferred_term: Ultrasound
term:
id: NCIT:C17230
label: Ultrasound Imaging
evidence:
- reference: PMID:36424806
reference_title: "Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
All patients with 46, XY DSD should undergo abdominopelvic
ultrasonography by a trained radiologist.
explanation: Directly supports ultrasound in the diagnostic workup.
- name: Pelvic MRI or laparoscopy when anatomy remains uncertain
description: >-
MRI helps define Müllerian anatomy and locate nonvisualized gonads;
laparoscopy can be used when imaging remains indeterminate or as part of
definitive gonadectomy.
diagnosis_term:
preferred_term: magnetic resonance imaging procedure
term:
id: NCIT:C16809
label: Magnetic Resonance Imaging
evidence:
- reference: PMID:36424806
reference_title: "Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
MRI of the abdomen and/or laparoscopy may be used to demonstrate the
Mullerian structure and/or to localize the gonads.
explanation: Directly supports MRI or laparoscopy for unresolved anatomy.
- name: Copy-number analysis and broad DSD molecular testing
description: >-
Testing should not stop at SRY sequencing. Copy-number analysis followed by
a phenotype-informed DSD panel or exome/genome approach can identify
sequence and regulatory causes; a negative result does not exclude the
clinical diagnosis.
diagnosis_term:
preferred_term: genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:36424806
reference_title: "Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Genetic studies, which include copy number variation (CNV) or molecular
testing of a candidate gene or next generation sequencing then should be
ordered in a stepwise manner
explanation: Directly supports CNV and sequencing-based evaluation.
- name: Tumor evaluation when a mass or malignancy is suspected
description: >-
If a mass or symptoms raise concern, obtain age-appropriate germ-cell-tumor
evaluation and oncology input. Normal laboratory tests or imaging do not
exclude gonadoblastoma or dysgerminoma and should not be treated as a
surveillance substitute for management of the susceptible gonads.
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
evidence:
- reference: PMID:36767504
reference_title: "Late Diagnosis of Swyer Syndrome in a Patient with Bilateral Germ Cell Tumor Treated with a Contraceptive Due to Primary Amenorrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Gonadal dysgerminoma should be suspected even in the absence of tumor
features on ultrasound and blood laboratory tests.
explanation: Directly supports the limitation of normal imaging and laboratory tests.
- name: Complete histopathology of bilateral gonadectomy specimens
description: >-
Resected gonads should undergo complete histopathologic examination for
fibrous dysgenesis, gonadoblastoma, germ-cell neoplasia in situ, and invasive
tumor. A benign limited biopsy should not be treated as reliable exclusion
of focal neoplasia and does not remove the susceptible tissue.
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
evidence:
- reference: PMID:34070473
reference_title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
evaluate clinical features and histopathological outcome after gonadectomy
in patients with XY-DSD
explanation: Supports histopathologic evaluation after gonadectomy.
- reference: PMID:34070473
reference_title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Tissue samples had been previously taken laparoscopically with benign
histology.
explanation: >-
A later tumor after benign samples in this mixed XY-DSD cohort illustrates
the sampling limitation without presenting it as complete-disease-specific evidence.
differential_diagnoses:
- name: Complete androgen insensitivity syndrome
description: >-
CAIS also presents with a typical female external phenotype and 46,XY
karyotype, but differentiated testes produce AMH, so the uterus is absent;
testosterone is in the male range and breast development usually occurs
through aromatization.
disease_term:
preferred_term: complete androgen insensitivity syndrome
term:
id: MONDO:0021023
label: complete androgen insensitivity syndrome
evidence:
- reference: PMID:38905377
reference_title: "Pure 46, XY gonadal dysgenesis and 46, XY complete androgen insensitivity syndrome: A case report."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
We present 2 rare cases of 46, XY DSD, specifically XY pure gonadal
dysgenesis and complete androgen insensitivity syndrome.
explanation: Supports the close clinical differential.
- name: 46,XX gonadal dysgenesis
description: >-
The endocrine and pubertal phenotype can be nearly identical, but formal
karyotype distinguishes 46,XX from 46,XY disease and only the latter carries
the Y-associated gonadal tumor substrate.
disease_term:
preferred_term: 46,XX gonadal dysgenesis
term:
id: MONDO:0009299
label: 46 XX gonadal dysgenesis
evidence:
- reference: PMID:21982289
reference_title: "Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
normal karyotype (46,XX or 46,XY)
explanation: Shows that complete gonadal dysgenesis occurs with either karyotype.
- name: Turner syndrome
description: >-
Turner syndrome can also cause streak gonads, hypergonadotropic hypogonadism,
and absent puberty. Formal chromosome analysis and assessment for associated
features distinguish it from nonmosaic 46,XY complete gonadal dysgenesis.
evidence:
- reference: PMID:31809259
reference_title: "Misdiagnosis of Mullerian agenesis in a patient with 46, XX gonadal dysgenesis: a missed opportunity for prevention of osteoporosis."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
There was no feature suggestive of Turner syndrome and no skeletal
deformity was found.
explanation: >-
Shows Turner syndrome being considered during a gonadal-dysgenesis
differential; the evidence does not define the full Turner spectrum.
- name: 45,X/46,XY mixed gonadal dysgenesis
description: >-
Sex-chromosome mosaic mixed gonadal dysgenesis is a separate chromosome-DSD
diagnosis, often with asymmetric gonadal development rather than the
nonmosaic 46,XY bilateral complete phenotype. Formal chromosome analysis
distinguishes it from this root.
evidence:
- reference: PMID:34070473
reference_title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
supports: PARTIAL
evidence_source: OTHER
snippet: >-
sex chromosome DSD (Klinefelter or Turner Syndrome, chimerism), XX-DSD,
and 46 XY-DSD
explanation: >-
Supports separation of sex-chromosome mosaic DSD from the 46,XY DSD
category; the detailed asymmetric phenotype is clinical synthesis.
- name: Partial or mixed 46,XY gonadal dysgenesis
description: >-
Partial or mixed disease is a distinct tumor-prone category that does not
meet the complete bilateral streak-gonad case definition; residual testicular
differentiation and the full genital and gonadal phenotype must be assessed.
evidence:
- reference: PMID:34070473
reference_title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
gonadoblastoma, which is commonly observed in complete or partial
dysgenesis
explanation: Supports complete and partial dysgenesis as distinct tumor-prone categories.
- name: Testicular regression syndrome
description: >-
Testicular regression syndrome reflects loss of previously differentiated
testicular tissue and spans absent or variable residual gonads and genital
phenotypes. Evidence of prior fetal testicular function distinguishes it
from complete failure of testis differentiation with bilateral streak gonads.
evidence:
- reference: PMID:40026690
reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
supports: PARTIAL
evidence_source: OTHER
snippet: >-
in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts,
they have a high detection rate.
explanation: >-
Establishes testicular regression and gonadal dysgenesis as separately
named DHX37-associated cohorts; detailed distinguishing features are
clinical synthesis rather than a claim from this snippet.
- name: Mayer-Rokitansky-Küster-Hauser syndrome
description: >-
MRKH causes primary amenorrhea with uterine and upper-vaginal aplasia or
hypoplasia in a 46,XX individual who has functioning ovaries and spontaneous
pubertal breast development; fallopian-tube anatomy can be variable.
disease_term:
preferred_term: Mayer-Rokitansky-Kuster-Hauser syndrome
term:
id: MONDO:0017771
label: Mayer-Rokitansky-Kuster-Hauser syndrome
evidence:
- reference: PMID:31809259
reference_title: "Misdiagnosis of Mullerian agenesis in a patient with 46, XX gonadal dysgenesis: a missed opportunity for prevention of osteoporosis."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with Mullerian agenesis lack all derivatives of the mullerian
ducts (fallopian tubes, uterus, cervix, and upper vagina) but have ovaries
and undergo puberty, with appropriately timed breast development
explanation: >-
Directly distinguishes ovarian function and uterine/upper-vaginal anatomy;
its blanket statement about all duct derivatives is not universally applicable.
- name: Central hypogonadism
description: >-
Hypothalamic or pituitary gonadotropin deficiency can cause absent puberty
and amenorrhea, but FSH and LH are low or inappropriately normal rather than
elevated; it does not explain streak gonads with a 46,XY karyotype.
evidence:
- reference: PMID:39149602
reference_title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
high luteinizing and follicle-stimulating hormone levels
explanation: The observed high-gonadotropin pattern argues against central hypogonadism.
- name: 46,XY androgen synthesis or action disorders
description: >-
Steroidogenic defects, 5-alpha-reductase deficiency, and androgen receptor
defects cause under-masculinization despite differentiated testicular tissue.
AMH production and Müllerian regression, hormone profiles, and molecular
testing distinguish them from complete testis-development failure.
evidence:
- reference: PMID:34070473
reference_title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
46 XY-DSD (disorders of testicular development and disorders of androgen
synthesis or action)
explanation: Supports the mechanistic distinction within 46,XY DSD.
- name: Syndromic gonadal dysgenesis
description: >-
Gonadal dysgenesis accompanied by neuropathy or other extra-gonadal features
does not meet this nonsyndromic root and requires syndrome-specific
evaluation. Biallelic DHH disease, for example, can occur with or without
polyneuropathy.
evidence:
- reference: PMID:30298535
reference_title: "In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
46,XY gonadal dysgenesis (GD), associated or not with polyneuropathy.
explanation: Supports separation of nonsyndromic and neuropathy-associated DHH disease.
treatments:
- name: Bilateral gonadectomy for nonfunctional dysgenetic gonads
action_category: THERAPEUTIC
description: >-
Once classic complete 46,XY gonadal dysgenesis is confirmed, current expert
practice favors arranging bilateral removal of nonfunctional
streak/dysgenetic gonads without avoidable delay after informed,
developmentally appropriate discussion. The gonads provide no useful
pubertal function and retain clinically important tumor risk, but the
literature does not define a precise post-diagnosis interval. Numerical risk
estimates should be presented as cohort-dependent rather than as precise
population probabilities.
treatment_term:
preferred_term: gonadectomy
term:
id: NCIT:C15329
label: Surgical Procedure
target_mechanisms:
- target: Dysgenetic Y-bearing germ-cell niche
treatment_effect: INHIBITS
description: Gonadectomy removes the susceptible Y-bearing dysgenetic tissue.
evidence:
- reference: PMID:38337479
reference_title: "A Risk of Gonadoblastoma in Familial Swyer Syndrome-A Case Report and Literature Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The management of such patients is based on preventive excision of
dysgenetic gonads
explanation: Supports preventive excision as disease management.
target_phenotypes:
- preferred_term: Gonadoblastoma
term:
id: HP:0000150
label: Gonadoblastoma
evidence:
- reference: PMID:38337479
reference_title: "A Risk of Gonadoblastoma in Familial Swyer Syndrome-A Case Report and Literature Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The management of such patients is based on preventive excision of
dysgenetic gonads and long-term hormonal replacement therapy.
explanation: Supports gonadectomy together with long-term hormone replacement.
- reference: PMID:36767504
reference_title: "Late Diagnosis of Swyer Syndrome in a Patient with Bilateral Germ Cell Tumor Treated with a Contraceptive Due to Primary Amenorrhea."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Early prophylactic gonadectomy could protect patients from developing
tumors in dysgenetic gonads.
explanation: >-
Supports early preventive gonadectomy as current expert practice; it does
not establish an evidence-defined surgical interval.
- name: Physiologic pubertal induction and maintenance hormone replacement
action_category: THERAPEUTIC
description: >-
Hormone treatment proceeds in parallel with tumor-risk management; it is not
contingent on waiting until after surgery. Near the expected age of puberty,
use low-dose physiologic 17-beta-estradiol with gradual individualized
escalation; later diagnosis can justify a faster individualized induction.
If an endometrium-bearing uterine cavity is present, add progestogen to avoid
unopposed estrogen; with patent outflow, cyclic progesterone is generally
introduced after about two years of estrogen or first breakthrough bleeding.
Obstructed or noncommunicating anatomy requires specialist management of the
outflow and hormone regimen. Replacement usually continues through the
expected age of natural menopause, followed by individualized reassessment.
Treatment induces secondary sexual development and, when anatomy permits,
scheduled withdrawal bleeding; it does not restore spontaneous menarche or
ovulatory menstrual cycles. These regimen details derive from broader
congenital gonadal-hormone-deficiency guidance and expert practice, not
Swyer-specific comparative trials.
treatment_term:
preferred_term: Hormone Replacement Therapy
term:
id: NCIT:C15599
label: Hormone Replacement Therapy
therapeutic_agent:
- preferred_term: estradiol
term:
id: CHEBI:23965
label: estradiol
- preferred_term: progesterone
term:
id: CHEBI:17026
label: progesterone
target_mechanisms:
- target: Absent pubertal gonadal hormone secretion
treatment_effect: BYPASSES
description: Exogenous sex steroids bypass absent gonadal secretion.
evidence:
- reference: PMID:35353710
reference_title: "Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
recommendations for puberty induction with oestrogen or testosterone.
explanation: Supports estrogen-based induction for gonadal hormone deficiency.
target_phenotypes:
- preferred_term: Delayed puberty
term:
id: HP:0000823
label: Delayed puberty
- preferred_term: Breast hypoplasia
term:
id: HP:0003187
label: Breast hypoplasia
- preferred_term: Reduced bone mineral density
term:
id: HP:0004349
label: Reduced bone mineral density
evidence:
- reference: PMID:35353710
reference_title: "Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Puberty induction should be individualised but considered at 11 years in
girls
explanation: Supports individualized timely pubertal induction.
- reference: PMID:38337479
reference_title: "A Risk of Gonadoblastoma in Familial Swyer Syndrome-A Case Report and Literature Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
long-term hormonal replacement therapy.
explanation: Supports long-term replacement in Swyer syndrome.
- name: Endocrine, uterine, bone, and cardiometabolic monitoring
action_category: MONITORING
description: >-
Provide individualized multidisciplinary follow-up during induction and
maintenance, assessing pubertal and uterine response, adherence, and adverse
effects. Bone and cardiometabolic assessment should reflect the duration and
severity of hypoestrogenism, baseline findings, and individual risk. Exact
tests and intervals are extrapolated from broader hypogonadism guidance
rather than established by Swyer-specific outcome studies.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:35353710
reference_title: "Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
pubertal induction or sex hormone replacement to sustain puberty should be
cared for by a multidisciplinary team.
explanation: Supports multidisciplinary follow-up during induction and maintenance.
- reference: PMID:31809259
reference_title: "Misdiagnosis of Mullerian agenesis in a patient with 46, XX gonadal dysgenesis: a missed opportunity for prevention of osteoporosis."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
The improvement of bone mineral density was observed at the repeated DEXA
scan at 18 months
explanation: >-
A broader gonadal-dysgenesis case shows that bone density can respond to
hormone replacement; it does not establish a Swyer-specific DXA schedule.
- name: Donor-oocyte or donor-embryo in vitro fertilization
action_category: THERAPEUTIC
description: >-
Classic complete disease lacks usable gonadal gametes, but donor-oocyte or
donor-embryo IVF can achieve pregnancy when estrogen treatment produces an
adequate uterine response. Preconception uterine assessment and
maternal-fetal-medicine counseling are appropriate; evidence consists mainly
of case reports and small series.
treatment_term:
preferred_term: In Vitro Fertilization
term:
id: NCIT:C16580
label: In Vitro Fertilization
target_phenotypes:
- preferred_term: Female infertility
term:
id: HP:0008222
label: Female infertility
evidence:
- reference: PMID:40097859
reference_title: "Infertility management in a patient with Swyer syndrome: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The IVF treatment using donor oocytes led to a successful pregnancy
without complications.
explanation: Directly documents successful donor-oocyte IVF.
- name: Gene-specific genetic counseling
action_category: COUNSELING_INFORMATIONAL
description: >-
Explain gene- and lesion-specific inheritance, penetrance, variant origin,
and recurrence risk; offer parental or cascade testing when a cause is
identified. Evaluate subtype-specific associated risks when relevant, such
as adrenal disease in selected NR5A1 presentations or later neuropathy in
biallelic DHH disease.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:31365064
reference_title: "Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
importance of establishing a molecular diagnosis
explanation: Supports molecular diagnosis as a basis for individualized lifelong care.
- name: Psychosocial, disclosure, infertility, and sexual-health support
action_category: COUNSELING_INFORMATIONAL
description: >-
Provide staged, confidential, developmentally appropriate disclosure;
psychological and peer support; infertility and reproductive counseling;
sexual-health care; and support for autonomy and gender identity. Care
should be coordinated by an experienced multidisciplinary DSD team.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:35353710
reference_title: "Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Psychological aspects of puberty and fertility issues are especially
important to address in individuals with sex development disorders
explanation: Directly supports psychosocial and fertility-focused support.
- reference: PMID:31365064
reference_title: "Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
long-term quality of life, sexual function, involvement with intimate
partners, and optimizing fertility potential.
explanation: Supports lifelong quality-of-life, sexual, relationship, and fertility care.
clinical_trials: []
datasets: []
discussions:
- discussion_id: gap_xy_cgd_tumor_risk_and_gonadectomy_timing
prompt: >-
In confirmed classic 46,XY complete gonadal dysgenesis with bilateral
nonfunctional streak gonads, what disease-specific age-stratified tumor-risk
estimate should be communicated, how promptly should bilateral gonadectomy
follow diagnosis, do genotype or familial status modify risk, and is any
imaging, marker, or biopsy surveillance strategy reliable enough to
recommend if surgery is deferred?
kind: KNOWLEDGE_GAP
status: OPEN
rationale: >-
Published percentages mix familial and sporadic cases, mass-enriched
referrals, pathology-selected series, ages, and complete, partial, mixed,
CAIS, or other XY DSD diagnoses. These data establish clinically important
risk and support current practice favoring timely gonadectomy but do not
establish a precise population probability, an evidence-defined surgical
interval, or a validated surveillance alternative.
attaches_to:
- pathophysiology#Gonadal germ-cell neoplasia risk
evidence:
- reference: PMID:32905884
reference_title: "Risk of gonadal neoplasia in patients with disorders/differences of sex development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
complete GD (33 %)
explanation: Supplies a multicenter adult cohort estimate with mixed ascertainment.
- reference: PMID:34070473
reference_title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Guidelines concerning the necessity of gonadectomy to avoid malignant
transformation are still lacking.
explanation: Explicitly identifies the management-guideline gap.
- reference: PMID:38337479
reference_title: "A Risk of Gonadoblastoma in Familial Swyer Syndrome-A Case Report and Literature Review."
supports: PARTIAL
evidence_source: OTHER
snippet: >-
the risk of gonadal tumors could be increased in familial compared to
sporadic cases (66.6% vs. 15-45%, respectively).
explanation: Raises a possible familial modifier from a small literature review.
references:
- reference: PMID:35720238
title: "Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature."
findings: []
- reference: PMID:33570214
title: "A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female."
findings: []
- reference: PMID:30298535
title: "In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis."
findings: []
- reference: PMID:34515237
title: "DMRT1: An Ancient Sexual Regulator Required for Human Gonadogenesis."
findings: []
- reference: PMID:35290982
title: "Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review."
findings: []
- reference: PMID:29373757
title: Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies.
findings: []
- reference: PMID:30552336
title: Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9.
findings: []
- reference: PMID:40026690
title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
findings: []
- reference: PMID:39149602
title: "Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus."
findings: []
- reference: PMID:17504899
title: "Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene."
findings: []
- reference: PMID:19246354
title: Mutations in NR5A1 associated with ovarian insufficiency.
findings: []
- reference: PMID:21982289
title: "Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases."
findings: []
- reference: PMID:32905884
title: Risk of gonadal neoplasia in patients with disorders/differences of sex development.
findings: []
- reference: PMID:34070473
title: "Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature."
findings: []
- reference: PMID:36767504
title: Late Diagnosis of Swyer Syndrome in a Patient with Bilateral Germ Cell Tumor Treated with a Contraceptive Due to Primary Amenorrhea.
findings: []
- reference: PMID:36424806
title: "Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement."
findings: []
- reference: PMID:35353710
title: "Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline."
findings: []
- reference: PMID:31365064
title: "Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life."
findings: []
- reference: PMID:37994022
title: A rare case of Swyer syndrome from Pakistan in a young girl with primary amenorrhea and 46XY genotype.
findings: []
- reference: PMID:38337479
title: A Risk of Gonadoblastoma in Familial Swyer Syndrome-A Case Report and Literature Review.
findings: []
- reference: PMID:40097859
title: "Infertility management in a patient with Swyer syndrome: a case report."
findings: []
- reference: PMID:31809259
title: "Misdiagnosis of Mullerian agenesis in a patient with 46, XX gonadal dysgenesis: a missed opportunity for prevention of osteoporosis."
findings: []
- reference: PMID:38905377
title: "Pure 46, XY gonadal dysgenesis and 46, XY complete androgen insensitivity syndrome: A case report."
findings: []
- reference: PMID:34781289
title: "Establishing a Molecular Genetic Diagnosis in Children with Differences of Sex Development: A Clinical Approach."
findings: []
notes: >-
The root is deliberately restricted to classic nonsyndromic complete disease.
CBX2 is not promoted because the canonical reported phenotype had ovarian-like
rather than bilateral streak gonads. ZFPM2 is not promoted because the current
GeneReviews gene table does not treat it as established, despite an older
small report containing one complete presentation; this warrants separate
gene-validity review. Syndromic WT1 or SOX9 coding disease, large syndromic 9p
deletions, PPP2R3C-related disease, DHH-related neuropathy, partial/mixed
dysgenesis, CAIS, and androgen synthesis/action disorders remain separate from
this root. Published tumor-risk percentages are retained only with
ascertainment caveats. Relevant MONDO phenotype-series cross-references are
retained as curation notes rather than structured mappings because the current
local disease-term enum rejects these active classes: SRY MONDO:0020712,
NR0B1 MONDO:0010226, NR5A1 MONDO:0013066, DMRT1 MONDO:0007938, MAP3K1
MONDO:0013410, DHH MONDO:0009301, SOX9-regulatory MONDO:0014634, and DHX37
MONDO:8000015.
References & Deep Research
References
24Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature.
No top-level findings curated for this source.
A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female.
No top-level findings curated for this source.
In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis.
No top-level findings curated for this source.
DMRT1: An Ancient Sexual Regulator Required for Human Gonadogenesis.
No top-level findings curated for this source.
Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review.
No top-level findings curated for this source.
Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies.
No top-level findings curated for this source.
Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9.
No top-level findings curated for this source.
Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development.
No top-level findings curated for this source.
Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus.
No top-level findings curated for this source.
Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene.
No top-level findings curated for this source.
Mutations in NR5A1 associated with ovarian insufficiency.
No top-level findings curated for this source.
Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases.
No top-level findings curated for this source.
Risk of gonadal neoplasia in patients with disorders/differences of sex development.
No top-level findings curated for this source.
Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature.
No top-level findings curated for this source.
Late Diagnosis of Swyer Syndrome in a Patient with Bilateral Germ Cell Tumor Treated with a Contraceptive Due to Primary Amenorrhea.
No top-level findings curated for this source.
Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.
No top-level findings curated for this source.
Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
No top-level findings curated for this source.
Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life.
No top-level findings curated for this source.
A rare case of Swyer syndrome from Pakistan in a young girl with primary amenorrhea and 46XY genotype.
No top-level findings curated for this source.
A Risk of Gonadoblastoma in Familial Swyer Syndrome-A Case Report and Literature Review.
No top-level findings curated for this source.
Infertility management in a patient with Swyer syndrome: a case report.
No top-level findings curated for this source.
Misdiagnosis of Mullerian agenesis in a patient with 46, XX gonadal dysgenesis: a missed opportunity for prevention of osteoporosis.
No top-level findings curated for this source.
Pure 46, XY gonadal dysgenesis and 46, XY complete androgen insensitivity syndrome: A case report.
No top-level findings curated for this source.
Establishing a Molecular Genetic Diagnosis in Children with Differences of Sex Development: A Clinical Approach.
No top-level findings curated for this source.
Deep Research
2
Asta
▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of 46,XY complete gonadal dysgenesis. Core disease mechanisms, molecular and...
This report is retrieval-only and is generated directly from Asta results.
- Papers retrieved: 19
- Snippets retrieved: 20
Relevant Papers
[1] Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature
- Authors: A. Jakovleva, Zanna Kovaļova
- Year: 2021
- Venue: Medicine and Pharmacy Reports
- URL: https://www.semanticscholar.org/paper/6c4bdafa150014706ced5f2b1ea479f8f69b558e
- DOI: 10.15386/mpr-2064
- PMID: 35720238
- PMCID: 9177091
- Citations: 7
- Influential citations: 1
- Summary: The study showed the median time between diagnosis and gonadectomy was suboptimal and women with amenorrhea and lack of secondary sexual characteristics require careful investigation, and early diagnosis of Swyer syndrome is necessary.
- Evidence snippets:
- Snippet 1 (score: 0.625) > In recent years, the issue of diagnosing rare genetic diseases has become increasingly topical in the world. The process of gender development is an extremely complex mechanism that requires a thorough understanding of gender development. > Disorders of sex development (DSD) are congenital conditions with atypical development of chromosomal, gonadal, and anatomical sex [1]. 46,XY gonadal dysgenesis consists of various clinical conditions in which fetal gonadal development is abnormal and it includes both partial and complete forms [2]. 46,XY gonadal dysgenesis partial forms are characterized by partially developed internal ducts with a variable degree of testicular development and testicular function [2,3]. Patients with complete gonadal dysgenesis are phenotypically women with fully or partially developed Miller wire structures and dysgenetic gonads [1]. > Complete gonadal dysgenesis or Swyer syndrome was described by G. Swyer in 1955. He presented two women with 46,XY karyotype, normal external and internal female genitalia and primary amenorrhea [4]. The exact incidence of the condition is unknown but literature data suggest that the approximate incidence ranges from 1: 80 000 [5][6][7] to 1: 100 000 [8][9][10]. According to the literature, complete gonadal dysgenesis has a high tumor development incidence in 20-30% of the cases. The presence of the Y chromosome increases the risk of germ cell neoplasms [11]. In most cases bilateral gonadoblastoma, dysgerminoma in 5% and less frequently embryonal carcinoma were found [10,12,13]. To prevent the development of malignancy, early surgical treatment is required [14]. > To evaluate the prevalence of complete gonadal dysgenesis in general, a careful study of this syndrome is required in many countries of the world, including Latvia. This study will give some insight into the prevalence, diagnosis, and treatment of the complete gonadal dysgenesis. In medical literature, complete gonadal dysgenesis of Swyer syndrome patients has been chiefly reported as case presentations. In our study, we summarize some of the available cases in order
[2] MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences of Sex Development
- Authors: Hong Chen, Qingqing Chen, Yilin Zhu, K. Yuan, Huizhu Li et al.
- Year: 2022
- Venue: Frontiers in Genetics
- URL: https://www.semanticscholar.org/paper/e8963cb4a28e32b244c1b95c9ddf96d1c3502702
- DOI: 10.3389/fgene.2022.736988
- PMID: 35309143
- PMCID: 8927045
- Citations: 10
- Summary: This study identified a missense MAP3K1 variant associated with 46,XY DSD that enhances binding to the RhoA and improves its own stability, resulting in the activation of the Wnt4/β-catenin/FOXL2 pathway.
- Evidence snippets:
- Snippet 1 (score: 0.581) > Background: 46,XY disorders/differences of sex development (46,XY DSD) are congenital conditions that result from abnormal gonadal development (gonadal dysgenesis) or abnormalities in androgen synthesis or action. During early embryonic development, several genes are involved in regulating the initiation and maintenance of testicular or ovarian-specific pathways. Recent reports have shown that MAP3K1 genes mediate the development of the 46,XY DSD, which present as complete or partial gonadal dysgenesis. Previous functional studies have demonstrated that some MAP3K1 variants result in the gain of protein function. However, data on possible mechanisms of MAP3K1 genes in modulating protein functions remain scant. Methods: This study identified a Han Chinese family with the 46,XY DSD. To assess the history and clinical manifestations for the 46,XY DSD patients, the physical, operational, ultra-sonographical, pathological, and other examinations were performed for family members. Variant analysis was conducted using both trio whole-exome sequencing (trio WES) and Sanger sequencing. On the other hand, we generated transiently transfected testicular teratoma cells (NT2/D1) and ovary-derived granular cells (KGN), with mutant or wild-type MAP3K1 gene. We then performed functional assays such as determination of steady-state levels of gender related factors, protein interaction and luciferase assay system. Results: Two affected siblings were diagnosed with 46,XY DSD. Our analysis showed a missense c.556A > G/p.R186G variant in the MAP3K1 gene. Functional assays demonstrated that the MAP3K1R186G variant was associated with significantly decreased affinity to ubiquitin (Ub; 43–49%) and increased affinity to RhoA, which was 3.19 ± 0.18 fold, compared to MAP3K1. The MAP3K1R186G led to hyperphosphorylation of p38 and GSK3β, and promoted hyperactivation of the Wnt4/β-catenin signaling. In addition, there was increased recruitment of β-catenin into the nucleus, which enhanced
[3] A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female
- Authors: P. Ambulkar, J. Waghmare, Poonam Verma Shivkumar, P. Narang, A. Pal
- Year: 2021
- Venue: Andrologia
- URL: https://www.semanticscholar.org/paper/08a243f0291219997afeb12d85bf4106eb3f7d5c
- DOI: 10.1111/and.14011
- PMID: 33570214
- Citations: 2
- Summary: Clinical phenotypes and in silico analysis confirmed that missense substitution (p.Arg76Ser) impaired nNLS binding Calmodulin‐mediated nuclear transport of SRY from cytoplasm to nucleus and the mutation affects down regulation of male sex differentiation pathway and is responsible for 46,XY sex reversal female with gonadal dysgenesis.
- Evidence snippets:
- Snippet 1 (score: 0.577) > The SRY initiates cascade of gene expression that transforms the undifferentiated gonad, genital ridge into testis. Mutations of the SRY gene is associated with complete gonadal dysgenesis in females with 46,XY karyotype. Primary amenorrhea is one of the clinical findings to express the genetic cause in 46,XY sex reversal. Here, we report a 26‐year‐old married woman presenting with primary amenorhea and complete gonadal dysgenesis. The clinical phenotypes were hypoplastic uterus with streak gonad and underdeveloped secondary sexual characters. The cytogenetic analysis confirmed 46,XY sex reversal karyotype of a female. Using molecular approach, we screened open reading frame of the SRY gene by PCR and targeted DNA Sanger sequencing. The patient was confirmed with nucleotide substitution (c.226C>A; p.Arg76Ser) at in HMG box domain of SRY gene that causes 46,XY sex reversal female. Mutation prediction algorithms suggest that alteration might be disease causing mutation and mutated (p.Arg76Ser) amino acid deleteriously affects HMG box nNLS region of SRY protein. Clinical phenotypes and in silico analysis confirmed that missense substitution (p.Arg76Ser) impaired nNLS binding Calmodulin‐mediated nuclear transport of SRY from cytoplasm to nucleus. The mutation affects down regulation of male sex differentiation pathway and is responsible for 46,XY sex reversal female with gonadal dysgenesis.
[4] Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development
- Authors: Huifang Peng, Wenyuan Peng, Jiali Chen, Keyan Hu, Yingyu Zhang et al.
- Year: 2025
- Venue: Frontiers in Endocrinology
- URL: https://www.semanticscholar.org/paper/ff11ed0f8a3776fc0ef16b1d0673cc0735fc84a2
- DOI: 10.3389/fendo.2025.1507749
- PMID: 40026690
- PMCID: 11867910
- Citations: 1
- Summary: Although the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear, ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways may be affected.
- Evidence snippets:
- Snippet 1 (score: 0.575) > The RNA helicase DHX37 gene is involved in ribosomal biological processes, and linked to human genetic diseases associated with 46,XY disorders of sex development (46,XY DSD) or neurodevelopment. Recently, relevant reports have primarily focused on 46,XY DSD. However, there is still a lack of overall understanding of the genetic characteristics, phenotype, etc. of the DHX37 gene in human genetic diseases, and its molecular mechanism is not fully understood. We searched literature databases and summarized and analyzed all the literature related to DHX37 to date, including case reports, cohort studies, and molecular mechanism studies, to comprehensively demonstrate the role of DHX37 in human genetic diseases. Sixty patients were reported to have DHX37-related 46,XY DSD, with p.R308Q, p.R674W variants being the two most common mutation hotspots, accounting for 36.67% and 11.67% of cases respectively. In DSD cohorts, DHX37 gene mutations have different detection frequencies (0.77%–45.45%), whereas in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts, they have a high detection rate. The gonadal development and fertility of female (46,XX) carriers with DHX37 gene mutations are not affected; however, incomplete penetrance may be observed in males (46,XY). The treatments are primarily surgical intervention and hormone replacement therapy administered at appropriate times; however, the long-term prognosis remains unknown. Although the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear, ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways may be affected. This review summarizes the profile of DHX37 defects in human genetic diseases.
[5] Case Report: Novel Compound Heterozygotic Variants in PPP2R3C Gene Causing Syndromic 46, XY Gonadal Dysgenesis and Literature Review
- Authors: Wei Zhang, J. Mao, Xi Wang, B. Sun, Zhi-ru Zhao et al.
- Year: 2022
- Venue: Frontiers in Genetics
- URL: https://www.semanticscholar.org/paper/be30a6be8c8e40b00da619a8d7656d2ed12dbd7f
- DOI: 10.3389/fgene.2022.871328
- PMID: 35812758
- PMCID: 9259967
- Citations: 7
- Summary: Novel compound heterozygous variants in PPP2R3C cause specific syndromic 46, XY gonadal dysgenesis with multiple extragonadal anomalies, which broadened the pathogenic variants spectrum of PPP3C.
- Evidence snippets:
- Snippet 1 (score: 0.571) > Purpose: Patients with syndromic 46, XY disorders/differences of sex development (DSD) are characterized by gonadal and phenotypic genders inconsistent with their chromosomal sexes as well as abnormalities of multiple extragonadal organs. They are caused by mutations in specific genes, which are expressed in the affected organs and regulate their development, and over fourteen genes have been identified. In this study, we aimed to determine the underlying cause of a patient with syndromic 46, XY DSD and review the clinical presentations and genetic findings of all reported similar cases. Methods: Whole-exome sequencing (WES) was performed to find a molecular cause of the patient. In silico tools were used to analyze the pathogenicity of the variants. Reports of cases with similar clinical features and involved genes were summarized by searching through PubMed/MEDLINE using keywords “PPP2R3C” or “G5PR” and “46,XY disorders of sex development”. Results: Compound heterozygous variants (p.F229del/p.G417E) in PPP2R3C were identified in the 24-year-old female by WES and verified by Sanger sequencing. The patient presents complete testicular dysgenesis, low birth weight, facial deformity, cubitus valgus, and decreasing number of CD19+ B lymphocytes and CD4+ T lymphocytes. A total of thirteen 46, XY DSD cases with four homozygous PPP2R3C mutations (p.Leu103Pro, p.Leu193Ser, p.Phe350Ser, and p.Ser216_Tyr218dup) have been reported previously, and their clinical manifestations are roughly similar to those of our patient. Conclusion: Novel compound heterozygous variants in PPP2R3C cause specific syndromic 46, XY gonadal dysgenesis, which broadened the pathogenic variants spectrum of PPP2R3C. The typical phenotype of PPP2R3C mutation is complete 46, XY gonadal dysgenesis with multiple extragonadal anomalies, including facial deformities, skeletal system
[6] In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis
- Authors: A. Tajouri, M. Kharrat, S. Hizem, Hajer Zaghdoudi, R. M’rad et al.
- Year: 2018
- Venue: Human Mutation
- URL: https://www.semanticscholar.org/paper/8ff3d8a9ac98fd508fa127657444864ce2caf79b
- DOI: 10.1002/humu.23664
- PMID: 30298535
- Citations: 13
- Influential citations: 2
- Summary: A model that may explain the differences between Schwann and Leydig cell development by autocrine versus paracrine DHh signaling is proposed, which suggests differences in the processing mechanism between the two species.
- Evidence snippets:
- Snippet 1 (score: 0.560) > Sex development requires a complex intracellular signaling and locally secreted and circulating sex hormones that interact together in a defined time. This process contributes to the development of the gonad (sex determination) and subsequent differentiation of the internal and external genitalia (sex differentiation) resulting in a female or male phenotype (Morel, Roucher, Mallet, & Plotton, 2014). > Failure of testis determination can result in partial gonadal dysgenesis (PGD) or complete gonadal dysgenesis (CGD) manifested clinically by a discrepancy between an individual's phenotype and karyotype. > Individuals with 46,XY CGD present a 46 XY karyotype, bilateral streak gonads consisting mainly of fibrous tissue and variable amounts of ovarian stroma, normally developed Müllerian ducts, and female external genitalia (Berkovitz et al., 1991). By contrast, individuals with 46,XY PGD have different degrees of ambiguous external genitalia, a mix of Müllerian and Wolffian structures, and dysgenetic gonads. These gonads usually consist of disorganized seminiferous tubules admixed with stroma (Berkovitz et al., 1991). Although SRY is the most important testis-determining gene, mutations in this gene have been found to account only for approximately 15% of CGD cases and less than 1% of cases of partial forms (Assumpcao et al., 2002). Thus, the remaining cases may bear mutations in the SRY regulatory elements or in other genes involved in the sex determination pathway. > An important gene involved in the regulation and maintenance of the crucial male determining pathway is Desert Hedgehog (DHH), a member of the hedgehog family of signaling proteins. In humans, DHH is located at 12q12.13, is composed of three exons, and encodes a protein of 396 amino acids (Tate, Satoh, Endo, & Mitsuya, 2000). The DHH product is specifically expressed in Sertoli cells (Bitgood & McMahon, 1995) and Schwann cells along peripheral nerves (Parmantier et al., 1999). In mice,
[7] Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature
- Authors: Sahra Steinmacher, S. Brucker, A. Kölle, B. Krämer, D. Schöller et al.
- Year: 2021
- Venue: International Journal of Environmental Research and Public Health
- URL: https://www.semanticscholar.org/paper/e9db0233c1472d7ab0868b02609a3194ae8d5e16
- DOI: 10.3390/ijerph18115648
- PMID: 34070473
- PMCID: 8197511
- Citations: 8
- Summary: Preventive gonadectomy in patients with XY-DSD should be taken into consideration to assess the risk of malignant transformation to gonadal germ cell tumors, and guidelines concerning the necessity of Gonadectomy to avoid malignant Transformation are still lacking.
- Evidence snippets:
- Snippet 1 (score: 0.544) > Disorders of sex development (DSD) are defined as congenital conditions with atypical gonadal, chromosomal, or anatomical sex. They usually present with atypical genitalia in the newborn or delayed puberty in the adolescent period [1]. > According to the Chicago classification of DSD, patients are classified into the categories sex chromosome DSD (Klinefelter or Turner Syndrome, chimerism), XX-DSD, and 46 XY-DSD (disorders of testicular development and disorders of androgen synthesis or action) [2]. DSD affects 1 in 4500-5000 live births, mostly due to genetic defects during sexual differentiation [3]. XY-DSD in particular affects 1 in 20,000 births [4]. > Variants of DSD patients with female phenotype and Y chromosome include 46 XY pure gonadal dysgenesis, 46 XY partial gonadal dysgenesis, androgen insensitivity syndrome (complete or partial) or 46, XY 17 alpha hydroxylase/17, 20-lyase deficiency among others. > In pure gonadal dysgenesis, normal gonadal development is inhibited and patients are phenotypically female [5]. In partial dysgenesis, testis determination is incomplete, leading to a phenotype which depends on the degree of gonadal function [5]. > Androgen insensitivity syndrome is based on the mutation of a gene coding for the androgen receptor. This X-linked recessive disease leads to insensitivity for circulating androgens, resulting in chromosomal and gonadal male individuals, but who are phenotypically females [6]. In complete androgen insensitivity syndrome (cAIS), mutations of the androgen receptor (AR) can be seen in 95% of all patients, whereas in partial androgen insensitivity syndrome it can be detected in up to 50%. Diagnosis is verified through identifications of mutations in the AR gene [7]. > In the management of patients with XY-DSD, the increased risk of invasive germ cell tumors compared to the general population has to be taken into consideration, as the presence of Y chromosomal material serves as a risk factor for malignant transformation [5
[8] A novel variant in the MAP3K1 genomic locus reveals abnormal cell apoptosis as a potential pathogenic mechanism in 46, XY disorders of sex development
- Authors: Yu Lu, Sijia Wei, Shuang Wang, Jingzhi Zhang, Yongjie Xu et al.
- Year: 2025
- Venue: Molecular Medicine Reports
- URL: https://www.semanticscholar.org/paper/2799a19a1fd170b1fea72ad9ddd73906ece00960
- DOI: 10.3892/mmr.2025.13589
- PMID: 40476564
- PMCID: 12175139
- Summary: A novel gain-of-function variant was identified in the mitogen-activated protein 3 kinase 1 (MAP3K1) gene, contributing to 46, XY DSD through the induction of abnormal cell apoptosis through the induction of abnormal cell apoptosis.
- Evidence snippets:
- Snippet 1 (score: 0.542) > disorders of sex development (dSds) represent a broad and heterogeneous group of congenital conditions, characterized by discordance between chromosomal, gonadal and anatomical sex (1). The clinical presentation of dSds is highly variable, encompassing numerous conditions, such as hypospadias, ambiguous genitalia and complete sex reversal in 46, XX or 46, XY individuals (2). in 2006, the chicago consensus redefined DSD classifications into three major categories based on karyotype; namely, sex chromosome dSds, 46, XY dSds and 46, XX dSds (3). among these, 46, XY dSds exhibit the greatest level of complexity, often involving atypical female genitalia, incomplete intrauterine masculinization and the absence of Müllerian structures (4,5). androgen receptor dysfunction remains the most prevalent etiology in these cases. The psychological, physical and reproductive consequences of dSds are profound, with patients facing an elevated risk of sex cord-stromal tumors, such as gonadoblastoma and experiencing considerable social and medical burdens (6). > The clinical heterogeneity of dSds complicates the accuracy of diagnosis based solely on phenotypic assessments (6). Genetic factors underlying dSd pathogenesis remain to be elucidated, necessitating molecular diagnostics to complement clinical evaluations. The mitogen-activated protein 3 kinase 1 (MaP3K1) gene plays a crucial role in the genetic network associated with gonadal development (7). MaP3K1 mediates sex differentiation through modulating the balance between the pro-testicular SoX9/FGF9 pathway and the pro-ovarian WnT/β-catenin pathway (4,8,9).
[9] Anomalies in Human Sex Determination: Usefulness of a Combined Cytogenetic Approach to Characterize an Additional Case with Xp Functional Disomy Associated with 46,XY Gonadal Dysgenesis
- Authors: khouloud Rjiba, W. Slimani, Meriem Gaddas, Ikbel Hadj Hassine, Afef Jelloul et al.
- Year: 2022
- Venue: Journal of Clinical Research in Pediatric Endocrinology
- URL: https://www.semanticscholar.org/paper/1c760b618f45fb3a23fc77c890ce9384640910d3
- DOI: 10.4274/jcrpe.galenos.2022.2022-3-15
- PMID: 35984215
- PMCID: 9976160
- Citations: 4
- Summary: The findings suggest that when duplicated, the NR0B1 and MAGEB genes could be a major cause of XY GD, and emphasize the usefulness of a combined cytogenetic approach in order to provide an accurate genetic diagnosis for those patients having syndromic XY DSD in a clinical setting.
- Evidence snippets:
- Snippet 1 (score: 0.532) > Objective: Disorders of sexual development (DSD) are a heterogeneous group of genital defects affecting chromosomal, gonadal and anatomical sex. 46,XY DSD is a subset of DSD which covers a wide range of phenotypes in which 46,XY gonadal dysgenesis (GD) is the most severe form. In this study, we report on the clinical and molecular cytogenetic findings of a study on a Tunisian girl with the syndromic form of 46,XY DSD. Methods: This case was a phenotypic female patient having several congenital anomalies including growth retardation. Karyotype, fluorescence in situ hybridization and array Comparative Genome Hybridization (array CGH) were performed. Results: The proband exhibited a de-novo 46,X,der(Y) karyotype. Array CGH revealed a pathogenic 27.5Mb gain of an Xp21.2 chromosome segment leading to Xp functional disomy. No deletion was observed in the Y-chromosome. The duplicated region encompassed the NR0B1 (DAX1) and MAGEB genes, located within the dosage sensitive sex (DSS) reversal locus, known as promote genes responsible for human sex reversal and testis repression. The extra-dosage and interactions of these genes with different specific genes could result in the impairment of the male sex pathway. Over-dosage of KAL1 and IL1RAPL1 genes fall within the somatic features observed in the patient. Conclusion: To the best of our knowledge, we report on the fourth case of Xp21.2-pter duplication within Xp;Yp translocation associated with XY GD. Our findings suggest that when duplicated, the NR0B1 and MAGEB genes could be a major cause of XY GD. Therefore, we emphasize the usefulness of a combined cytogenetic approach in order to provide an accurate genetic diagnosis for those patients having syndromic XY DSD in a clinical setting.
[10] Short Stature on a Boy: Mosaicism with an Isodicentric Y Chromosome
- Authors: C. Silvestre, J. Dupont, Rosário Silveira Santos, Brígida Robalo, C. Pereira et al.
- Year: 2019
- Venue: Case Reports in Pediatrics
- URL: https://www.semanticscholar.org/paper/9e43b39836a0c6a18b211fc36ac26d4a13da51e6
- DOI: 10.1155/2019/8563095
- PMID: 31110831
- PMCID: 6487124
- Citations: 5
- Influential citations: 1
- Summary: A case of a 14-year-old adolescent with short stature and delayed puberty, who was admitted in a Paediatric Endocrinology outpatient clinic and found to have a 45,X/46,X,idic(Y)(p11.32) mosaicism is presented.
- Evidence snippets:
- Snippet 1 (score: 0.531) > e term "disorders of sexual development" (DSD) refers to congenital conditions in which development of chromosomal, gonadal, and/or anatomical sex is atypical. Nowadays, this set of pathologies can be subdivided into three main groups in order to simplify clinical evaluation [8,9]: müllerian structures persistence and different degrees of masculinization can be observed. Although it is associated to various karyotypes, 45,X/46,XY mosaicism is most frequent, found in 35% of these patients [10,11]. Mosaicism induces a highly variable phenotype; 45,X/ 46,XY mosaicism can be observed in Turner syndrome patients, mixed gonadal dysgenesis and, furthermore, apparently normal men just like the reported case. Clinical manifestations can range from partial virilisation and genital ambiguity at birth to patients with complete female or male phenotype. Sexual determination in these patients with mosaicism is dependent on the dominant cell line in undifferentiated gonads, i.e., 45,X presence gives rise to Turner syndrome, 46,XY presence gives rise to male phenotype, and existence of both lines originate mixed gonadal dysgenesis. e presence of cell lines with 45,X is frequently associated with rearranged Y chromosomes which, in turn, also influence phenotype [5,11,12]. It is known from studies with transgenic mice that the presence of SRY gene alone is sufficient to initiate testicular development. us, the presence or absence of SRY gene in an abnormal Y chromosome constitutes another factor of phenotypic diversity [5]. e structural anomaly of Y chromosome, isodicentric, detected in the present case has a particularity despite being one of the most common anomalies of Y chromosome. e level at which the breakpoint on the short arm was identified, Yp11.32, is unusual, with a few cases published: four with Turner syndrome phenotype (karyotype 45,X/46,X,idic (Y)) [2,[13][14][15], three azoospermic men (two with 45,X/ 46,X,idic(Y) karyotype [
[11] Digenic Origin of Difference of Sex Development in a Patient Harbouring DHX37 and MAMLD1 Variants
- Authors: K. Margiotti, F. Libotte, M. Fabiani, A. Mesoraca, Claudio Giorlandino
- Year: 2024
- Venue: Case Reports in Pediatrics
- URL: https://www.semanticscholar.org/paper/ea0e8d225cbbc11e81f0843a349fc5b38f85ac0c
- DOI: 10.1155/2024/4896940
- PMID: 38962685
- PMCID: 11221946
- Citations: 4
- Summary: This is the first case with the combined presence of pathogenic mutations in the MAMLD1 gene and DHX37 gene in a patient with gonadal dysgenesis, and a digenic inheritance due to two known pathogenic mutations in the DHX37 gene and the MAMLD1 gene is investigated.
- Evidence snippets:
- Snippet 1 (score: 0.521) > In the year 2006, a novel terminology, namely, "disorders of sex development" (DSDs), was introduced.Tis term encompasses a group of congenital conditions characterized by atypical development of chromosomes, gonads, or anatomical sex [1].Te genetic cause of DSD still cannot be determined in about half of the cases.DSD is characterized by a wide clinical severity spectrum, ranging from genital ambiguity to moderate hypospadias or unilateral cryptorchidism to phenotypes that are so attenuated that they can go unnoticed.Complex genetic networks and hormonal signalling govern the development of the gonads.Comprehensive genetic testing is widely acknowledged as an essential element in the assessment of individuals with DSDs, owing to the intricate nature of gonad production and diferentiation.Disorders of sex development comprise a wide range of clinical presentations that can be identifed at various stages of life, spanning from the newborn period to late adulthood.However, a main common clinical characteristic observed in nearly all cases is infertility.Te estimated incidence of severe 46, XY and 46, XX DSD with uncertain sex is 2.2 per 10,000 births [2,3].Te observed syndrome exhibits a spectrum of manifestations, including variations in genital development such as ambiguous genitalia, moderate hypospadias, or unilateral cryptorchidism.Consequently, categorizing patients with similar or nearly identical phenotypes becomes challenging due to the presence of diverse etiologies and genetic mechanisms underlying this condition [4].Numerous fundamental factors have been identifed as possible causes, including mutations in genes encoding proteins involved in sex determination and development as well as genital development [5].Nevertheless, the assessment of genotype-phenotype relationships remains challenging because of the considerable variability in both phenotypic and genotypic characteristics observed among people.Next-generation sequencing (NGS) technology has led to the identifcation of several novel DSD-causing genes and an improved understanding of the genetic basis and therapeutic management of the disease [6,7].Much is still unclear about the transmission of this pathology; mono-and oligogenic models are hypothesized [8].
[12] Case report of whole genome sequencing in the XY female: identification of a novel SRY mutation and revision of a misdiagnosis of androgen insensitivity syndrome
- Authors: S. M. De Sousa, K. Kassahn, Liam C. McIntyre, Chan-Eng Chong, H. Scott et al.
- Year: 2016
- Venue: BMC Endocrine Disorders
- URL: https://www.semanticscholar.org/paper/6fa32a4cffdba9347c9d8a702ab6f6ba22f4a0b2
- DOI: 10.1186/s12902-016-0141-7
- PMID: 27821113
- PMCID: 5100246
- Citations: 10
- Summary: A novel and likely pathogenic missense variant in SRY, one of the major genes implicated in complete gonadal dysgenesis, is revealed, securing this condition over androgen insensitivity syndrome as the cause of the patient’s disorder of sexual development.
- Evidence snippets:
- Snippet 1 (score: 0.520) > BackgroundThe 46,XY female is characterised by a male karyotype and female phenotype arising due to any interruption in the sexual development pathways in utero. The cause is usually genetic and various genes are implicated.Case presentationHerein we describe a 46,XY woman who was first diagnosed with androgen insensitivity syndrome (testicular feminisation) at 18 years; however, this was later questioned due to the presence of intact Müllerian structures. The clinical phenotype suggested several susceptibility genes including SRY, DHH, NR5A1, NR0B1, AR, AMH, and AMHR2. To study candidate genes simultaneously, we performed whole genome sequencing. This revealed a novel and likely pathogenic missense variant (p.Arg130Pro, c.389G>C) in SRY, one of the major genes implicated in complete gonadal dysgenesis, hence securing this condition over androgen insensitivity syndrome as the cause of the patient’s disorder of sexual development.ConclusionThis case highlights the emerging clinical utility of whole genome sequencing as a tool in differentiating disorders of sexual development.
[13] Two Cases of 46,XY Differences of Sex Development Due to Gonadal Dysgenesis Associated With Novel NR5A1 Variants
- Authors: Joshua V Gialouris, P. L. Cheong, Stipe Zekanovic, Mawson Wang, A. Wijewardene
- Year: 2025
- Venue: JCEM Case Reports
- URL: https://www.semanticscholar.org/paper/31bbd93c04fdc3b8b7d3ed856501e0313601104d
- DOI: 10.1210/jcemcr/luaf187
- PMID: 40860577
- PMCID: 12371325
- Summary: 2 cases of 46,XY DSD due to complete gonadal dysgenesis due to complete gonadal dysgenesis, a 16-year-old female and a 45-year-old female, who both presented with primary amenorrhea and hirsutism are described.
- Evidence snippets:
- Snippet 1 (score: 0.515) > Normal male sex development can be broadly understood as the consequence of 2 processes which occur in utero: sex determination, in which testes form from the primitive, bipotential gonads as a result of the complex interplay between numerous transcription factors and cells, and sex differentiation, in which male internal and external genitalia differentiate as a result of hormones secreted by the fetal testis [1]. > Differences of sex development (DSD) describes a group of rare conditions in which development of chromosomal, gonadal, or anatomical sex is atypical [2]. These conditions can result from a disturbance at any stage of normal male sex development. 46,XY DSDs encompass a spectrum of conditions, relating to the degree of androgenization that occurs in a 46,XY individual. Affected individuals can present with micropenis, atypical, or female external genitalia. Müllerian structures (embryonic precursor of female reproductive organs) can be present or absent [1]. > Gonadal dysgenesis, initially termed "Swyer syndrome" after Gerald Swyer who first described the condition in the mid-1950s, is a form of 46,XY DSD [3]. This condition results from an early defect in testis development, leading to complete or partial gonadal dysgenesis. Phenotype ranges from female external and internal genitalia, normal-tall stature, and a lack of female secondary sexual characteristics in the complete form to a spectrum of atypical genitalia with or without Müllerian structures in the partial form [1]. > Nuclear receptor subfamily 5 group A member 1 (NR5A1), is a gene located on chromosome 9q33.3 and is commonly known by the protein it encodes: steroidogenic factor-1 (SF-1). SF-1 plays an important role in sex determination via gonadal development, as well as adrenal development and steroidogenesis [4]. Mutations in NR5A1/SF-1 have led to both 46,XY and 46,XX gonadal dysgenesis [4], adrenal insufficiency [4], splenic abnormalities [5], and other organ malformations [6].
[14] Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation
- Authors: N. Gomes, Tarini Chetty, A. Jørgensen, R. Mitchell
- Year: 2020
- Venue: International Journal of Molecular Sciences
- URL: https://www.semanticscholar.org/paper/d0dfb5c994ec41ff0a02ae7c647c4838e1898e99
- DOI: 10.3390/ijms21072282
- PMID: 32224856
- PMCID: 7178030
- Citations: 45
- Influential citations: 5
- Summary: This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadel development and the pathogenesis of DSD.
- Evidence snippets:
- Snippet 1 (score: 0.511) > Complete gonadal dysgenesis in 46,XY individuals results from mutations in key testisdetermining genes in a phenotypic female with internal Mullerian structures and bilateral streak gonads.The lack of either testicular or ovarian tissue means that it is not possible to obtain spermatozoa or oocytes from these individuals and therefore infertility is universal.However, the presence of Mullerian structures means that pregnancy may be possible using donor eggs or embryos and IVF, as illustrated by a recent report of successful pregnancies in two sisters, with a healthy live birth in one and an ongoing pregnancy in the other [155]. > Individuals with 46,XY partial gonadal dysgenesis (PGD) present with variable genital ambiguity and varying degrees of testicular dysgenesis or streak gonads [156].Whilst severe oligozoospermia has been reported in a long-term follow-up study of males with PGD [156], for phenotypic males with mild abnormalities of gonadal development or external genitalia (e.g., hypospadias), fertility may be possible. > Options for fertility preservation in 46,XY gonadal dysgenesis DSD are summarized in Figure 5. Complete gonadal dysgenesis in 46,XY individuals results from mutations in key testis-determining genes in a phenotypic female with internal Mullerian structures and bilateral streak gonads.The lack of either testicular or ovarian tissue means that it is not possible to obtain spermatozoa or oocytes from these individuals and therefore infertility is universal.However, the presence of Mullerian structures means that pregnancy may be possible using donor eggs or embryos and IVF, as illustrated by a recent report of successful pregnancies in two sisters, with a healthy live birth in one and an ongoing pregnancy in the other [155]. > Individuals with 46,XY partial gonadal dysgenesis (PGD) present with variable genital ambiguity and varying degrees of testicular dysgenesis or streak gonads [156].
[15] Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome
- Authors: Hao Yang, Xiuqi Ma, H. Tian, Jinna Yuan, Dehua Wu et al.
- Year: 2023
- Venue: Sexual Development
- URL: https://www.semanticscholar.org/paper/9c005f7448b3a0a08e3a8c6fb6682e3beee70e8f
- DOI: 10.1159/000534086
- PMID: 37717579
- PMCID: 11232946
- Citations: 4
- Summary: The findings broaden the variant spectrum of DHX37 in 46,XY differences of sex development (DSD) individuals by reporting two additional cases with different clinical presentations carrying two novel variants in the DHX37 gene.
- Evidence snippets:
- Snippet 1 (score: 0.485) > DHX37 (DEAH-Box Helicase 37), a member of the DEAH/RHA RNA helicase family, plays an essential role in ribosome biogenesis [Bleichert and Baserga, 2007]. Heterozygous variants in DHX37 have been associated with a range of 46,XY disorders of gonadal development types, particularly 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome (TRS), with the phenotypes ranging from phenotypic females to males with atypical external genitalia or micropenis with cryptorchidism [da Silva et al., 2019;McElreavey et al., 2020;Buonocore et al., 2019;Zidoune et al., 2021;Wan et al., 2023]. The exact role of DHX37 in gonadal development is unknown, but recurrent variants in or adjacent to the highly conserved motifs within two RecA-like domains (RecA1 and RecA2) clearly establish a genotype-phenotype correlation between 46,XY gonadal dysgenesis and DHX37 variants [da Silva et al., 2019;McElreavey et al., 2020;Buonocore et al., 2019;Zidoune et al., 2021;Wan et al., 2023]. Although DHX37 variants account for approximately 10-15% non-syndromic 46,XY complete gonadal dysgenesis (CGD), and 20% 46,XY TRS, so far, only 12 different variants affecting 10 amino acids in or adjacent to the highly conserved RecA-like domains of DHX37 have been reported, all of them are missense variants [da Silva et al., 2019;McElreavey et al., 2020;Buonocore et al., 2019;Zidoune et al., 2021;Wan et al., 2023].
- Snippet 2 (score: 0.477) > The exact mechanism responsible for failed testicular determination associated with DHX37 variant remains unknown. Mammalian sex determination is regulated by two opposing genetic pathways, with imbalances potentially leading to DSD [Gonen et al., 2018;Harris et al., 2018;Eozenou et al., 2020]. Our report of two cases with missense variants in the same domain of Two Novel DHX37 Variants Cause 46,XY DSD the DHX37 protein, resulting in completely contrasting sex phenotypes, adds to the complexity of understanding DHX37's mechanism. The most compelling theory proposed so far is the nucleolar stress model [McElreavey et al., 2022], which suggests that nucleolar stress from DHX37 variants leads to a rapid, transient increase in WNT signaling and subsequent β-catenin stabilization [Dannheisig et al., 2021]. This disruption may interfere with testis determination and result in 46,XY gonadal dysgenesis (CGD/ PGD). WNT signaling in XY somatic cells of the developing gonad could then trigger a p53-dependent pro-apoptotic response [Bursać et al., 2012], causing an absence of gonadal tissue and thus lead to TRS. This raises the possibility that DSD caused by DHX37 variants may be ribosomopathies [Boneberg et al., 2019;McElreavey et al., 2022], but the underlying mechanism requires further investigation. > In conclusion, we identified two novel heterozygous missense DHX37 variants, p.G478R and p.L627F, in a 46,XY TRS boy and a 46,XY GD girl. These variants, located in the IV and Va motifs within the RecA2 domain, expand the currently limited variant spectrum of DHX37 in 46,XY DSD.
[16] The clinical diversity and molecular etiology in 46, XY disorders of sex development patients without uterus
- Authors: Leilei Ding, Min Luo, Shan Deng, Duoduo Zhang, Q. Tian
- Year: 2025
- Venue: Orphanet Journal of Rare Diseases
- URL: https://www.semanticscholar.org/paper/79cebf24a2578f28753ef4e75967370f3d3b0a5d
- DOI: 10.1186/s13023-025-03719-y
- PMID: 40247401
- PMCID: 12007265
- Citations: 1
- Summary: Several novel variants broadening the mutation spectrum of 46, XY DSD without uterus are identified, including several novel variants broadening the mutation spectrum of 46, XY DSD without uterus.
- Evidence snippets:
- Snippet 1 (score: 0.483) > Precision medicine uses modern genetics and bioinformatics technology to determine patients' genetic background and disease characteristics. As an important tool in precision medicine, reverse phenotyping predicts phenotypes from genotypes, to achieve accurate classification and molecular etiology diagnosis of diseases [13]. This study identified the molecular etiology of 21 cases of 46, XY DSD patients without uterus in 2 years of our hospital based on WES, combined with the clinical phenotypes, revealing one patient with LCH, five patients with 17OHD, two patients with 5α-RD2, and eleven patients with AIS. What's more, two patients with misdiagnosed PAIS were found to have 46, XY PGD(OMIM:617480). This further emphasizes the importance of reversing phenotyping based on genetic results. > An important finding in this study is variants in NR5A1, which correct the misdiagnosis of PAIS in two patients with 46, XY partial gonadal dysgenesis (OMIM:617480). 46, XY PGD is characterized by partial testis differentiation. External genital virilization degrees vary based on the amount of functional testicular tissue present in the individual's gonad [14]. NR5A1 mutations are linked to a broad range of gonadal development disorders, spanning from DSD to oligo/azoospermia in 46XY individuals and 46XX ovotesticular and testicular phenotypes to primary ovarian failure in 46XX individuals. Studies had indicated that polygenic inheritance or pathogenic variants in other testis/ovarian-determining gene might account for the extensive phenotypic variability associated with NR5A1 gene mutations [15]. Here, we identified two patients carrying the heterozygous NR5A1 variant (p.Arg84His and p.Met455-Gln457del), who presented with partial virilization and absence of Mullerian duct structures, overlapping with the phenotype of PAIS, which led to our misdiagnosis. The variant of p.Arg84His has been reported.
[17] Broad-spectrum XX and XY gonadal dysgenesis in patients with a homozygous L193S variant in PPP2R3C
- Authors: D. Çiçek, N. Warr, G. Yeşil, Hatice Koçak Eker, F. Baş et al.
- Year: 2021
- Venue: European Journal of Endocrinology
- URL: https://www.semanticscholar.org/paper/8d4f01a72ba63cde4eefb71c6de454d5f3ad3835
- DOI: 10.1530/EJE-21-0910
- PMID: 34714774
- PMCID: 8679844
- Citations: 5
- Summary: The essential roles for PPP2R3C in mouse and human development are indicated and loss of function of Ppp2r3c is not compatible with viability in mice and results in embryonic death from 7.5 dpc or earlier.
- Evidence snippets:
- Snippet 1 (score: 0.482) > Our case series refines the GD spectrum of MEGD syndrome, describing four new patients with a homozygous c.578T>C (p.L193S) variant in the PPP2R3C gene and the functional impact of Ppp2r3c in the mouse model. This showed that variants in PPP2R3C are associated with GD of variable severity, both in 46,XX and 46,XY. Four of our Human sexual development starts at the 5th-6th embryonic weeks. The genital ridges are converted to bipotential gonads, which subsequently differentiate into ovaries or testes. In the XY foetus, expression of testis-determining SRY triggers upregulation of SOX9 expression, leading to testis formation (15). On the other hand, in the absence of SRY, the WNT/β-catenin signalling opposes testis determination and directs a female-specific molecular cascade and ovary formation (16). These pathways are regulated by a network of genes controlled by various transcriptional factors operating in a delicate equilibrium. These core, and mutually antagonistic, sexdetermining gene regulatory networks are also conserved in mice (14,17). Disturbances in these early developmental mechanisms result in GD in 46,XX and 46,XY individuals, causing a broad spectrum of clinical phenotypes ranging from primary amenorrhea to ambiguous genitalia and complete gonadal sex reversal. > Molecular defects causing XX-GD include RSPO1, LARS2, HSD17B4, HARS2, TWNK, ERAL1, and CLPP, while ARX, ATRX, DHH, GATA4, HHAT, SOX9, WT1, and ZFPM2 gene defects are associated with syndromic XY-GD (18). Extra-gonadal phenotypes of these syndromes include malformations of various organs including CNS and brain, bone, heart, kidney, etc.
[18] 46, XY disorders of sex development combined with aceruloplasminaemia: a case report and review of the literature
- Authors: Yanju Li, Mei Zhao, Yang Liu, Lan Wang, Yi Huang et al.
- Year: 2025
- Venue: Orphanet Journal of Rare Diseases
- URL: https://www.semanticscholar.org/paper/cf77b3dfdcf5d1b054348575e75ecce9e1165128
- DOI: 10.1186/s13023-025-03626-2
- PMID: 40082989
- PMCID: 11905553
- Summary: Clinicians are advised to be aware of the possibility of coexisting chromosomal abnormalities that emphasize the value of genetic testing in patients with atypical presentations, and clinicians are advised to be aware of the possibility of coexisting chromosomal abnormalities that emphasize the value of genetic testing.
- Evidence snippets:
- Snippet 1 (score: 0.475) > 46, XY DSD is a rare genetic disease characterized by gonadal dysgenesis and androgen synthesis defects or dysfunctions depending on the underlying mechanism. The genetic background of this disease is complex and involves a variety of genetic factors. Gonadal dysgenesis is related to many genes, such as SRY, SOX9, MAP3K1 and NR5A1 or DMRT1. Gene mutations may cause abnormal levels of enzymes involved in androgen synthesis [8]. Therefore, the clinical manifestations of 46, XY DSD are heterogeneous. > Single-gene genetic diseases are rare, and the probability of two genetic diseases occurring simultaneously is low, potentially leading to a missed diagnosis or misdiagnosis. The development of genetic testing technology and improvements in clinicians' understanding of the disease have increased. The occurrence of two rare genetic diseases simultaneously accounts for approximately 4.3% (1.4% ~ 7.2%) of the confirmed cases of genetic diseases [9,10]. These cases include patients with 46, XY DSD with other congenital anomalies, Frasier syndrome, Denys-Drash syndrome, or congenital diaphragmatic hernia [11][12][13], but reports of DSD combined with ACP are lacking. Consanguinity and multisystem disease appear to increase the likelihood of multiple genetic diagnoses in a family. Although a definitive causative relationship has not been established, possible genetic or environmental interactions between these two diseases cannot be excluded. Therefore, we conducted a systematic review of ACP research. > Epidemiology ACP is an adult-onset autosomal recessive disorder characterized by CP deficiency and iron metabolism disorders, with typical clinical manifestations in the triad of neurological symptoms, diabetes, and retinopathy. Since 1987, more than 130 ACP patients have been reported [14]. According to epidemiologic data derived from estimations in Japan, in which the greatest number of cases has been reported, the incidence of ACP was estimated to be approximately 1/2,000,000 in the offspring of nonconsanguineous marriages [15]. The median age of onset is 40 years, ranging from 25 to 60 years.
[19] Mammalian sex determination—insights from humans and mice
- Authors: Stefanie Eggers, A. Sinclair
- Year: 2012
- Venue: Chromosome Research
- URL: https://www.semanticscholar.org/paper/0a909bcf754669f63c97047b3cf4152af3b3606c
- DOI: 10.1007/s10577-012-9274-3
- PMID: 22290220
- PMCID: 3279640
- Citations: 154
- Influential citations: 10
- Summary: Current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models is reviewed.
- Evidence snippets:
- Snippet 1 (score: 0.474) > DSD are congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical (Hughes et al. 2006). DSD covers a wide spectrum of different phenotypes with hypospadias being the most common defect with an average of 1 in 250-350 male births. In addition, 1 in 4,500 babies worldwide is born with significant ambiguous genitalia (Hughes et al. 2006) and significantly, DSDs account for 7.5% of all birth defects. Furthermore, DSD phenotypes are often associated with other syndromes, such as Mayer-Rokitansky-Kuster-Hauser syndrome, Smith-Lemli-Opitz syndrome or genitopalato-cardiac syndrome (Porter 2008;Sultan et al. 2009). Since the discovery of the sex-determining region Y (SRY) in 1990 (Sinclair et al. 1990), there have been considerable advances in understanding the genetic factors involved in gonad differentiation. Nevertheless, it has been estimated that a molecular diagnosis is made in only approximately 20% of DSD cases (Hughes et al. 2006), and that up to 50% of 46, XY DSD patients cannot be provided with an accurate diagnosis. Furthermore, for approximately 80% of 46, XY DSD complete gonadal dysgenesis patients and about 20% of 46,XX testicular DSD patients, the causative mutation remains unknown (Hughes et al. 2006). DSD represents a major pediatric concern, due to the difficulty of clinical management of these complex conditions and their common sequelae of gonad cancer and infertility. The cause of these DSD conditions is most often the breakdown of the complex network of gene regulation and gene expression, essential for proper development of testes or ovaries in the embryo.
Notes
- This provider combines
search_papers_by_relevancewithsnippet_search. - No synthesis or second-stage model call is performed.
Falcon
▸
46,XY Complete Gonadal Dysgenesis (Swyer syndrome): Comprehensive Disease Characteristics Research Report
Executive summary
46,XY complete gonadal dysgenesis (CGD), commonly called Swyer syndrome, is a Mendelian (single‑gene/oligogenic) 46,XY difference/disorder of sex development (DSD) characterized by nonfunctional “streak” gonads, female external genitalia, and typically preserved Müllerian internal structures due to failure of fetal testicular hormone production. The most clinically consequential feature is a high risk of gonadal germ‑cell neoplasia in Y‑chromosome–containing dysgenetic gonads, motivating prophylactic gonadectomy plus puberty induction and lifelong hormone replacement therapy (HRT). Recent literature (2023–2024) emphasizes early genetic diagnosis using NGS and risk‑stratified long‑term care, while acknowledging persistent diagnostic yield limits in 46,XY DSD. (o’connell2023establishingamolecular pages 5-6, o’connell2023establishingamolecular pages 10-11, o’connell2023establishingamolecular pages 2-3, rudnicka2024ariskof pages 1-2)
Key recent sources (2023–2024 prioritized)
| Topic area | Key findings/statistics | Evidence type | Publication (authors, journal) | Year-month | Identifier | URL |
|---|---|---|---|---|---|---|
| Definition / phenotype | Swyer syndrome = 46,XY complete gonadal dysgenesis with female phenotype; typical presentation is primary amenorrhea, delayed/absent puberty, hypergonadotropic hypogonadism, streak gonads, and usually a small/hypoplastic uterus; incidence reported as ~1:80,000 in a case report (sandilya2023swyersyndromea pages 1-2, sowinskaprzepiera2023latediagnosisof pages 1-2) | Case report / review | Sandilya & Jha, Journal of Rare Diseases | 2023-09 | DOI: 10.1007/s44162-023-00016-9 | https://doi.org/10.1007/s44162-023-00016-9 |
| Definition / phenotype / genetics | Phenotypic female with 46,XY karyotype, primary amenorrhea, lack of secondary sexual characteristics, infantile uterus, streak gonads; genetics summarized as SRY mutation in 10–20% while most have normal SRY; other implicated genes include DHH, NR5A1, DAX1 duplication, and gain-of-function MAP3K1 variants (jawed2023ararecase pages 2-4) | Case report / review | Jawed et al., Women’s Health | 2023-01 | DOI: 10.1177/17455057231213270 | https://doi.org/10.1177/17455057231213270 |
| Tumor risk / management | Tumor risk rises with age: ~5% by age 15 and 27.5% by age 30; gonadectomy recommended for every diagnosed patient; prophylactic bilateral gonadectomy/salpingectomy emphasized (oryani2024dysgerminomaina pages 5-5, oryani2024dysgerminomaina pages 5-7) | Case report + literature review | Oryani et al., Journal of Obstetrics, Gynecology and Cancer Research | 2024-08 | DOI: 10.30699/jogcr.9.5.591 | https://doi.org/10.30699/jogcr.9.5.591 |
| Tumor risk / management | Reported malignancy risk 37–45% overall; dysgenetic gonads carry ~30% risk of gonadoblastoma; gonadoblastoma may transform to malignant germ-cell tumor in 50–60% of cases; prophylactic gonadectomy and estrogen-based HRT recommended (adra2024seminomain46 pages 2-3) | Case report + literature review | Adra et al., Journal of Clinical Research in Pediatric Endocrinology | 2024-04 | DOI: 10.4274/jcrpe.galenos.2023.2023-12-11 | https://doi.org/10.4274/jcrpe.galenos.2023.2023-12-11 |
| Tumor risk / management | Gonadoblastoma occurs in about 20–30%; >40% of gonadoblastomas reported as bilateral; early prophylactic gonadectomy, HRT for pubertal induction/bone health, and fertility via donor oocytes/ART discussed (jawed2023ararecase pages 2-4) | Case report / review | Jawed et al., Women’s Health | 2023-01 | DOI: 10.1177/17455057231213270 | https://doi.org/10.1177/17455057231213270 |
| Familial tumor risk / genetics | In reviewed familial cases, 27/30 underwent gonadectomy and 18/27 (66.6%) had gonadal tumors; tumors reported only in patients >10 years; familial heterogeneity includes MAP3K1, DHH, SRY, NR5A1, DAX1-related findings (rudnicka2024ariskof pages 4-4) | Case report + literature review | Rudnicka et al., Journal of Clinical Medicine | 2024-01 | DOI: 10.3390/jcm13030785 | https://doi.org/10.3390/jcm13030785 |
| Diagnostics / tumor prevention | Early workup of primary amenorrhea and absent puberty should include imaging, karyotype/cytogenetics, hormone testing, and histology when needed; prophylactic gonadectomy can prevent dysgenetic-gonad tumors; DSD prevalence broadly cited as ~1:1000 births in review context (sowinskaprzepiera2023latediagnosisof pages 1-2, sowinskaprzepiera2023latediagnosisof pages 2-6) | Case report / review | Sowińska-Przepiera et al., International Journal of Environmental Research and Public Health | 2023-01 | DOI: 10.3390/ijerph20032139 | https://doi.org/10.3390/ijerph20032139 |
| Genetics / molecular diagnosis | Early genomic testing recommended; up to 2/3 of 46,XY DSD may remain without molecular diagnosis; gene evidence table includes NR5A1 (high evidence) among 46,XY gonadal dysgenesis genes; stepwise testing: chromosomal sex confirmation, rapid Y/SRY tests, microarray/CNV analysis, targeted panels, then WES (o’connell2023establishingamolecular pages 7-8, o’connell2023establishingamolecular pages 10-11, o’connell2023establishingamolecular pages 1-2, o’connell2023establishingamolecular pages 2-3, o’connell2023establishingamolecular pages 3-4) | Clinical review | O’Connell et al., Hormone Research in Paediatrics | 2023-11 | DOI: 10.1159/000520926 | https://doi.org/10.1159/000520926 |
| Diagnostics / yield | DSD gene panels reported diagnostic yields of 20–45%; WES useful for unsolved cases and novel/oligogenic causes but may miss noncoding/CNV changes; a UK cohort cited 52% of genetically confirmed 46,XY DSD had apparently normal hormone profiles, supporting genomic testing beyond endocrine screening (o’connell2023establishingamolecular pages 5-6, o’connell2023establishingamolecular pages 10-11) | Clinical review | O’Connell et al., Hormone Research in Paediatrics | 2023-11 | DOI: 10.1159/000520926 | https://doi.org/10.1159/000520926 |
| Genetics / worldwide diagnostic landscape | Approximately 50% of 46,XY DSD patients lack a molecular diagnosis; most commonly mutated gonadal-development genes are NR5A1 and MAP3K1; review states WES generally gives higher diagnostic yield than panel sequencing, although cohort performance varies by ascertainment and method (jiali2024worldwidecohortstudy pages 1-2) | Worldwide cohort review | Chen Jiali et al., Frontiers in Genetics | 2024-06 | DOI: 10.3389/fgene.2024.1387598 | https://doi.org/10.3389/fgene.2024.1387598 |
| Genetics / diagnostic yield statistics | Across cohorts, molecular diagnostic rates ranged 24.3%–64.3%; one summary reported 43% of 46,XY DSD receiving a possible genetic diagnosis; common genes include AR, SRD5A2, NR5A1, with MAP3K1 also recurrent in some cohorts (jiali2024worldwidecohortstudy pages 4-6, jiali2024worldwidecohortstudy pages 6-7, jiali2024worldwidecohortstudy pages 3-4) | Worldwide cohort review | Chen Jiali et al., Frontiers in Genetics | 2024-06 | DOI: 10.3389/fgene.2024.1387598 | https://doi.org/10.3389/fgene.2024.1387598 |
| Genetics / mechanism / counseling | NR5A1 variants show broad phenotypic range including complete gonadal dysgenesis; lack of clear genotype-phenotype correlation; possible oligogenic contribution; early genetic testing and fertility counseling/preservation are advised (luppino2024roleofnr5a1 pages 5-7, luppino2024roleofnr5a1 pages 1-2) | Gene-focused review | Luppino et al., Current Issues in Molecular Biology | 2024-05 | DOI: 10.3390/cimb46050274 | https://doi.org/10.3390/cimb46050274 |
| Diagnostic workflow figure | Figure 1 presents a practical stepwise diagnostic/genetic workflow for DSD: clinical suspicion → rapid Y/SRY detection (esp. neonates) → baseline hormones → microarray/CNV assessment → targeted testing or exome-based DSD analysis (o’connell2023establishingamolecular media 9ea011f5) | Figure / workflow from review | O’Connell et al., Hormone Research in Paediatrics | 2023-11 | DOI: 10.1159/000520926 | https://doi.org/10.1159/000520926 |
Table: This table summarizes key 2023-2024 sources for 46,XY complete gonadal dysgenesis/Swyer syndrome across phenotype, genetics, tumor risk, diagnostics, and management. It highlights the most actionable statistics and recent diagnostic-yield statements for rapid evidence review.
1. Disease information
1.1 Concise overview (what is the disease?)
Swyer syndrome is 46,XY complete (pure) gonadal dysgenesis, in which gonads are completely dysgenetic and nonfunctional despite a 46,XY karyotype, leading to absent testicular hormone secretion (AMH/testosterone) and a phenotypic female presentation that is typically detected at puberty as primary amenorrhea and delayed puberty. (rudnicka2024ariskof pages 1-2, sandilya2023swyersyndromea pages 1-2, sowinskaprzepiera2023latediagnosisof pages 1-2)
1.2 Common synonyms / alternative names
- Swyer syndrome; Gordon Swyer syndrome (rudnicka2024ariskof pages 1-2)
- 46,XY complete gonadal dysgenesis (CGD) (rudnicka2024ariskof pages 1-2, adra2024seminomain46 pages 2-3)
- 46,XY pure gonadal dysgenesis (sandilya2023swyersyndromea pages 1-2, sowinskaprzepiera2023latediagnosisof pages 1-2)
- 46,XY gonadal dysgenesis (GD) / 46,XY CGD (adra2024seminomain46 pages 2-3)
- “XY female” / “XY‑female” (usage in case‑based literature) (rudnicka2024ariskof pages 4-6)
1.3 Key identifiers (OMIM, Orphanet, ICD‑10/ICD‑11, MeSH, MONDO)
Not available in the retrieved full‑text evidence. The accessible papers did not report OMIM/Orphanet/ICD‑10/ICD‑11/MeSH/MONDO codes for Swyer syndrome. (rudnicka2024ariskof pages 1-2, sandilya2023swyersyndromea pages 1-2, sowinskaprzepiera2023latediagnosisof pages 1-2)
1.4 Evidence sources: patient-level vs aggregated resources
The retrieved evidence is primarily case reports and case‑based literature reviews (patient-level) for Swyer syndrome, complemented by DSD diagnostic/genomics reviews and global cohort summaries (aggregated) describing genetic testing approaches and diagnostic yields for 46,XY DSD broadly. (sowinskaprzepiera2023latediagnosisof pages 1-2, o’connell2023establishingamolecular pages 10-11, jiali2024worldwidecohortstudy pages 1-2)
2. Etiology
2.1 Disease causal factors
Primary cause: genetic disruption of the testis‑determination / gonadal differentiation pathway in a 46,XY individual, leading to failure of testicular differentiation and endocrine function. (adra2024seminomain46 pages 2-3, rudnicka2024ariskof pages 4-6)
Genes implicated (examples from recent reviews/case-based syntheses): * SRY (Y‑linked testis determining factor) (adra2024seminomain46 pages 2-3, rudnicka2024ariskof pages 4-6) * SOX9, FGF9 (testis pathway) (rudnicka2024ariskof pages 4-6) * NR5A1 (SF‑1) (early gonadal development; supports SOX9 and AMH/steroidogenic programs) (o’connell2023establishingamolecular pages 2-3) * MAP3K1, DHH, WT1, DMRT1, NR0B1 (DAX1) (duplication), GATA4 (jawed2023ararecase pages 2-4, rudnicka2024ariskof pages 4-6, idris2025genomictechnologiesand pages 1-2)
SRY mutation frequency: multiple sources note that SRY mutations account for a minority (e.g., ~10–20% or ~15% depending on series/review). (jawed2023ararecase pages 2-4, adra2024seminomain46 pages 3-5)
2.2 Risk factors
- Presence of Y‑chromosome material in dysgenetic gonads is a major risk factor for gonadal tumors (gonadoblastoma/germinoma spectrum). (rudnicka2024ariskof pages 1-2, sowinskaprzepiera2023latediagnosisof pages 1-2)
- Increasing age increases risk of neoplasia in Swyer syndrome (age‑stratified estimates reported in recent case‑based reviews). (oryani2024dysgerminomaina pages 5-5, jawed2023ararecase pages 1-2)
2.3 Protective factors
No protective genetic or environmental factors were identified in the retrieved full‑text evidence.
2.4 Gene–environment interactions
No gene–environment interaction evidence was identified in the retrieved full‑text evidence.
3. Phenotypes
3.1 Core clinical phenotype (typical)
Onset/trigger for recognition: usually adolescence with delayed puberty and primary amenorrhea. (sandilya2023swyersyndromea pages 1-2, rudnicka2024ariskof pages 1-2, sowinskaprzepiera2023latediagnosisof pages 2-6)
Anatomy: typically female external genitalia with Müllerian structures present (uterus/fallopian tubes/upper vagina) because AMH is not produced in fetal life; gonads are streak/dysgenetic. (rudnicka2024ariskof pages 1-2, rudnicka2024ariskof pages 4-6)
Hormone profile: classic hypergonadotropic hypogonadism (high FSH/LH with low estradiol; often very low AMH/inhibin B where measured). Example values across reports include: * FSH 76.25 UI/L, LH 16.08 UI/L, estradiol <10 pg/mL, testosterone <0.02 ng/mL, AMH <1 pmol/L, inhibin B ~10 pg/mL (adra2024seminomain46 pages 2-3) * FSH 56.7 mIU/mL, LH 19.8 mIU/mL, estradiol <5 pg/mL (sowinskaprzepiera2023latediagnosisof pages 2-6) * FSH 96.73 mIU/mL, LH 26.84 mIU/mL with very low estradiol (sandilya2023swyersyndromea pages 1-2)
Secondary sexual characteristics: minimal/absent spontaneous breast development; sparse or absent pubic/axillary hair can occur, though adrenal androgens may contribute. (sandilya2023swyersyndromea pages 1-2, sowinskaprzepiera2023latediagnosisof pages 2-6)
3.2 Phenotype characteristics
- Severity: usually severe gonadal failure (complete dysgenesis) with absent endogenous puberty (rudnicka2024ariskof pages 1-2, adra2024seminomain46 pages 2-3)
- Progression/course: congenital gonadal defect; clinical detection often delayed until adolescence; tumor risk increases with age (oryani2024dysgerminomaina pages 5-5, jawed2023ararecase pages 1-2)
- Frequency among affected: quantitative symptom frequencies were not provided in the retrieved texts; key manifestations are repeatedly described as typical. (rudnicka2024ariskof pages 1-2, sandilya2023swyersyndromea pages 1-2)
3.3 Quality‑of‑life impact
Quantitative QoL instruments (e.g., SF‑36/EQ‑5D) were not reported in the retrieved evidence. Case reports and DSD care reviews note the need for psychological support and counseling, and delayed diagnosis may contribute to psychosocial distress. (sowinskaprzepiera2023latediagnosisof pages 2-6, krygere2025infertilitymanagementin pages 1-3)
3.4 Suggested HPO terms (examples)
- Primary amenorrhea — HP:0000786
- Delayed puberty — HP:0000823
- Hypergonadotropic hypogonadism — HP:0000044
- Streak gonads / gonadal dysgenesis — HP:0000135 (gonadal dysgenesis)
- Female external genitalia with 46,XY karyotype (sex reversal/DSD) — HP:0000069 (ambiguous genitalia; if applicable) and broader DSD terms
- Hypoplastic uterus — HP:0001107
- Gonadoblastoma / germ cell tumor — HP:0002893 (neoplasm)
(Note: HPO codes are provided as commonly used terms; they were not enumerated in the retrieved texts.)
4. Genetic / molecular information
4.1 Causal genes (high‑confidence examples in retrieved sources)
- SRY (Y‑linked; classic testis‑determining gene) (adra2024seminomain46 pages 2-3, rudnicka2024ariskof pages 4-6)
- NR5A1 (SF‑1) (promotes SOX9/AMH/steroidogenic programs) (o’connell2023establishingamolecular pages 2-3)
- SOX9, DHH, MAP3K1, WT1, DMRT1, NR0B1/DAX1 (duplication) (jawed2023ararecase pages 2-4, idris2025genomictechnologiesand pages 1-2)
4.2 Pathogenic variant classes (general)
DSD gene tables and Swyer‑focused reviews cite multiple variant classes including SNVs, deletions/duplications (CNVs), and structural rearrangements across sex determination genes. (o’connell2023establishingamolecular pages 2-3, o’connell2023establishingamolecular pages 3-4)
4.3 Inheritance patterns and genetic architecture
Familial cases are described as uncommon but documented; inheritance can be autosomal dominant, autosomal recessive, or X‑linked depending on gene, and oligogenic contributions are recognized in DSD genetics. (rudnicka2024ariskof pages 4-6, luppino2024roleofnr5a1 pages 5-7)
4.4 Epigenetics / chromosomal abnormalities
No Swyer‑specific epigenetic signatures were identified in the retrieved evidence. Chromosomal testing is central (46,XY), and mosaicism is mentioned as a consideration in gonadal dysgenesis contexts. (sandilya2023swyersyndromea pages 1-2)
5. Environmental information
No environmental, lifestyle, or infectious causal factors were identified in the retrieved evidence; Swyer syndrome is treated as primarily genetic. (rudnicka2024ariskof pages 1-2, rudnicka2024ariskof pages 4-6)
6. Mechanism / pathophysiology
6.1 Causal chain (current understanding)
- Upstream genetic disruption of testis determination (commonly SRY pathway and/or downstream regulators such as SOX9/NR5A1, plus other genes such as MAP3K1/DHH/WT1) prevents normal Sertoli/Leydig lineage differentiation. (adra2024seminomain46 pages 2-3, rudnicka2024ariskof pages 4-6, o’connell2023establishingamolecular pages 2-3)
- Absent fetal AMH and testosterone:
- Lack of AMH → persistence of Müllerian ducts → uterus, fallopian tubes, upper vagina. (rudnicka2024ariskof pages 1-2, rudnicka2024ariskof pages 4-6)
- Lack of testosterone → absent Wolffian development and absent masculinization → female external phenotype. (rudnicka2024ariskof pages 4-6)
- Streak/dysgenetic gonads fail to produce sex steroids at puberty → hypergonadotropic hypogonadism (high FSH/LH, low estradiol) → delayed/absent puberty and primary amenorrhea. (rudnicka2024ariskof pages 1-2, adra2024seminomain46 pages 2-3)
- Tumor predisposition: dysgenetic gonads with Y‑chromosome material have high gonadal tumor risk; Y‑linked factors such as TSPY1 are implicated in gonadoblastoma pathogenesis, and gonadoblastoma can transform to malignant germ cell tumors. (rudnicka2024ariskof pages 1-2, adra2024seminomain46 pages 2-3)
6.2 Pathways and processes (ontology suggestions)
GO biological processes (suggested): * Sex determination (GO:0007530) * Gonad development (GO:0008406) * Sertoli cell differentiation (GO:0060009) * Anti‑Müllerian hormone signaling / Müllerian duct regression (process concept supported by AMH deficiency; term selection may vary) (rudnicka2024ariskof pages 4-6, adra2024seminomain46 pages 2-3)
Cell types (Cell Ontology suggestions): * Sertoli cell — CL:0000096 * Leydig cell — CL:0000179 * Primordial germ cell — CL:0000670
7. Anatomical structures affected
7.1 Organ level
- Gonads (dysgenetic/streak gonads) (rudnicka2024ariskof pages 1-2)
- Reproductive tract: uterus/fallopian tubes/upper vagina typically present (rudnicka2024ariskof pages 1-2, rudnicka2024ariskof pages 4-6)
7.2 Suggested UBERON terms (examples)
- Gonad — UBERON:0000990
- Ovary / testis (context-specific; dysgenetic gonads) — UBERON:0000992 / UBERON:0000473
- Uterus — UBERON:0000995
- Fallopian tube — UBERON:0003889
- Vagina — UBERON:0000996
8. Temporal development
8.1 Onset
Congenital developmental condition; typically diagnosed at puberty due to lack of spontaneous pubertal progression and primary amenorrhea. (sandilya2023swyersyndromea pages 1-2, rudnicka2024ariskof pages 1-2)
8.2 Progression / critical periods
- Puberty is a critical window for recognition and intervention (HRT, counseling). (sandilya2023swyersyndromea pages 1-2, adra2024seminomain46 pages 2-3)
- Tumor risk is described as highest at/after puberty and increasing with age in reviewed series. (adra2024seminomain46 pages 2-3, oryani2024dysgerminomaina pages 5-5)
9. Inheritance and population
9.1 Epidemiology
- Incidence estimates reported: ~1:80,000 (case report) and ~1:80,000–100,000 births (review). (sandilya2023swyersyndromea pages 1-2, rudnicka2024ariskof pages 1-2)
- For context, DSD overall reported as ~1:1000 births in a DSD review/case report. (sowinskaprzepiera2023latediagnosisof pages 1-2)
9.2 Inheritance
Heterogeneous inheritance depending on gene; familial cases exist and may show elevated tumor frequency in a literature review dataset. (rudnicka2024ariskof pages 4-6, rudnicka2024ariskof pages 1-2)
10. Diagnostics
10.1 Clinical evaluation (real-world implementation)
Common diagnostic elements include: * History/physical: primary amenorrhea, absent puberty, undervirilization; Tanner staging (sowinskaprzepiera2023latediagnosisof pages 2-6) * Hormonal profile: FSH/LH/estradiol ± testosterone; AMH and inhibin B can support absent Sertoli function (adra2024seminomain46 pages 2-3) * Imaging: pelvic ultrasound and/or MRI to evaluate uterus and locate gonads, which may be small or not visualized (sowinskaprzepiera2023latediagnosisof pages 2-6) * Cytogenetics/molecular: karyotype confirming 46,XY; SRY detection/testing (sowinskaprzepiera2023latediagnosisof pages 2-6) * Histopathology following gonadectomy/biopsy to assess malignancy (sowinskaprzepiera2023latediagnosisof pages 1-2)
10.2 Genetic testing approach (2023 workflow)
A 2023 DSD genetics review recommends early integration of genomic testing and describes a stepwise strategy including rapid Y/SRY testing (FISH/QF‑PCR), karyotype/microarray for CNVs, targeted panels, and WES when needed; DSD gene panels have reported diagnostic yields 20–45% and up to two‑thirds of 46,XY DSD may lack a molecular diagnosis in some cohorts. (o’connell2023establishingamolecular pages 10-11, o’connell2023establishingamolecular pages 2-3)
Figure evidence: A DSD diagnostic/genetic workflow is shown in O’Connell et al. (Figure 1). (o’connell2023establishingamolecular media 9ea011f5)
11. Outcome / prognosis
11.1 Major complication: gonadal malignancy
Quantitative malignancy risk estimates vary across reviews/series: * Overall malignancy risk reported 37–45% in a 2024 review/case report context; dysgenetic gonads carry ~30% risk of gonadoblastoma; malignant transformation potential 50–60%. (adra2024seminomain46 pages 2-3) * Age-related neoplasm risk estimates: ~5% by age 15 and 27.5% by age 30 in a 2024 literature review; other sources cite risk rising further by age 40. (oryani2024dysgerminomaina pages 5-5, jawed2023ararecase pages 1-2) * Familial case literature review: among gonadectomized familial cases, 18/27 (66.6%) had tumors; compared with 15–45% cited for sporadic cases in that review. (rudnicka2024ariskof pages 1-2)
11.2 Follow-up outcomes
A 2023 case report of bilateral dysgerminoma reports 5-year follow-up without changes suspected of invasion after gonadectomy. (sowinskaprzepiera2023latediagnosisof pages 1-2)
12. Treatment
12.1 Surgical
Prophylactic bilateral gonadectomy is consistently recommended once Swyer syndrome is diagnosed due to high tumor risk in dysgenetic Y‑containing gonads. (adra2024seminomain46 pages 2-3, sandilya2023swyersyndromea pages 1-2)
MAXO suggestion: gonadectomy — MAXO:0001024 (suggested term; not provided in retrieved text).
12.2 Hormone replacement therapy (HRT)
HRT is used to induce and maintain secondary sexual characteristics, uterine/endometrial maturation, bleeding cycles, and bone health. * One case report describes “estrogen first followed by cyclical estrogen and progesterone,” with menstruation by 6 months. (sandilya2023swyersyndromea pages 1-2) * A familial case series describes 17‑β estradiol titration up to 2 mg daily with addition of dydrogesterone 10 mg in sequential therapy after bleeding. (rudnicka2024ariskof pages 2-4)
MAXO suggestions: estrogen replacement therapy; progestin therapy (suggested; not provided as MAXO terms in retrieved text).
12.3 Bone health and supportive care
Estrogen replacement is described as important to prevent osteoporosis; calcium/vitamin D supplementation is used in case-based management. (jawed2023ararecase pages 2-4, yu2024pure46xy pages 1-2)
12.4 Fertility and real-world reproductive outcomes
Pregnancy is possible using assisted reproductive technologies (ART), particularly IVF with donor oocytes. A 2025 assisted reproduction case report describes successful IVF with donated oocytes leading to delivery of a healthy infant. (krygere2025infertilitymanagementin pages 1-3)
12.5 Psychosocial care
Psychological support/counseling is highlighted in case management (individual/group support; long-term psychotherapy in ART case). (sowinskaprzepiera2023latediagnosisof pages 2-6, krygere2025infertilitymanagementin pages 1-3)
13. Prevention
Primary prevention is not established (genetic developmental condition). Secondary/tertiary prevention focuses on: * Early detection (karyotype/genetic testing in primary amenorrhea/delayed puberty workup) (sowinskaprzepiera2023latediagnosisof pages 1-2) * Cancer prevention via early prophylactic gonadectomy (adra2024seminomain46 pages 2-3) * Genetic counseling for family planning (rudnicka2024ariskof pages 4-6)
14. Other species / natural disease
No comparative veterinary/natural disease evidence was identified in the retrieved corpus.
15. Model organisms
No Swyer‑specific model organism data were identified in the retrieved corpus.
Recent developments and expert analysis (2023–2024 emphasis)
- Earlier genetic diagnosis is increasingly recommended in DSD care pathways because hormonal/imaging phenotypes overlap substantially; diagnostic yields for DSD gene panels are commonly reported as 20–45%, and “up to two‑thirds” of 46,XY DSD may lack a molecular diagnosis in some settings, motivating broader sequencing and reanalysis strategies. (o’connell2023establishingamolecular pages 10-11, o’connell2023establishingamolecular pages 2-3)
- Global diagnostic yield remains limited: a 2024 worldwide cohort review states ~50% of 46,XY DSD patients cannot obtain a molecular diagnosis, while noting NR5A1 and MAP3K1 are among the most commonly mutated gonadal-development genes. (jiali2024worldwidecohortstudy pages 1-2)
- Risk‑stratified surgical decision-making is evolving in broader 46,XY DSD contexts (especially NR5A1-related forms), but for classic Swyer syndrome (streak, intra‑abdominal dysgenetic gonads with Y material), the prevailing recommendation in recent Swyer‑focused reports remains early gonadectomy. (adra2024seminomain46 pages 2-3, rudnicka2024ariskof pages 2-4)
Evidence gaps (from retrieved sources)
- Standardized identifiers (OMIM/Orphanet/ICD/MeSH/MONDO) were not present in accessible full text. (rudnicka2024ariskof pages 1-2, sandilya2023swyersyndromea pages 1-2)
- Limited systematic QoL outcome statistics specific to Swyer syndrome in 2023–2024 accessible corpus; evidence is largely qualitative. (sowinskaprzepiera2023latediagnosisof pages 2-6)
- Few disease-specific interventional trials; management is largely guideline/consensus and case-series driven.
URLs and publication dates (examples)
- O’Connell et al., Hormone Research in Paediatrics, Nov 2023, https://doi.org/10.1159/000520926 (o’connell2023establishingamolecular pages 10-11)
- Sowińska-Przepiera et al., Int J Environ Res Public Health, 24 Jan 2023, https://doi.org/10.3390/ijerph20032139 (sowinskaprzepiera2023latediagnosisof pages 1-2)
- Rudnicka et al., Journal of Clinical Medicine, Jan 2024, https://doi.org/10.3390/jcm13030785 (rudnicka2024ariskof pages 4-4)
- Adra et al., J Clin Res Pediatr Endocrinol, Apr 2024, https://doi.org/10.4274/jcrpe.galenos.2023.2023-12-11 (adra2024seminomain46 pages 2-3)
References
-
(o’connell2023establishingamolecular pages 5-6): Michele A. O’Connell, Gabby Atlas, Katie Ayers, and Andrew Sinclair. Establishing a molecular genetic diagnosis in children with differences of sex development: a clinical approach. Hormone Research in Paediatrics, 96:128-143, Nov 2023. URL: https://doi.org/10.1159/000520926, doi:10.1159/000520926. This article has 43 citations and is from a peer-reviewed journal.
-
(o’connell2023establishingamolecular pages 10-11): Michele A. O’Connell, Gabby Atlas, Katie Ayers, and Andrew Sinclair. Establishing a molecular genetic diagnosis in children with differences of sex development: a clinical approach. Hormone Research in Paediatrics, 96:128-143, Nov 2023. URL: https://doi.org/10.1159/000520926, doi:10.1159/000520926. This article has 43 citations and is from a peer-reviewed journal.
-
(o’connell2023establishingamolecular pages 2-3): Michele A. O’Connell, Gabby Atlas, Katie Ayers, and Andrew Sinclair. Establishing a molecular genetic diagnosis in children with differences of sex development: a clinical approach. Hormone Research in Paediatrics, 96:128-143, Nov 2023. URL: https://doi.org/10.1159/000520926, doi:10.1159/000520926. This article has 43 citations and is from a peer-reviewed journal.
-
(rudnicka2024ariskof pages 1-2): Ewa Rudnicka, Aleksandra Jaroń, Jagoda Kruszewska, Roman Smolarczyk, Krystian Jażdżewski, Paweł Derlatka, and Anna Małgorzata Kucharska. A risk of gonadoblastoma in familial swyer syndrome—a case report and literature review. Journal of Clinical Medicine, 13:785, Jan 2024. URL: https://doi.org/10.3390/jcm13030785, doi:10.3390/jcm13030785. This article has 9 citations.
-
(sandilya2023swyersyndromea pages 1-2): Ujjwala Sandilya and Sangam Jha. Swyer syndrome: a rare cause of primary amenorrhea. Journal of Rare Diseases, 2:1-3, Sep 2023. URL: https://doi.org/10.1007/s44162-023-00016-9, doi:10.1007/s44162-023-00016-9. This article has 1 citations.
-
(sowinskaprzepiera2023latediagnosisof pages 1-2): Elżbieta Sowińska-Przepiera, Mariola Krzyścin, Adam Przepiera, Agnieszka Brodowska, Ewelina Malanowska, Mateusz Kozłowski, and Aneta Cymbaluk-Płoska. Late diagnosis of swyer syndrome in a patient with bilateral germ cell tumor treated with a contraceptive due to primary amenorrhea. International Journal of Environmental Research and Public Health, 20:2139, Jan 2023. URL: https://doi.org/10.3390/ijerph20032139, doi:10.3390/ijerph20032139. This article has 4 citations.
-
(jawed2023ararecase pages 2-4): Inshal Jawed, Ayesha Azhar Javed, Syeda Alisha Johar, Daayl N Mirza, Ayesha A Abdani, and Asad Ali Khan. A rare case of swyer syndrome from pakistan in a young girl with primary amenorrhea and 46xy genotype. Women's Health, Jan 2023. URL: https://doi.org/10.1177/17455057231213270, doi:10.1177/17455057231213270. This article has 4 citations and is from a peer-reviewed journal.
-
(oryani2024dysgerminomaina pages 5-5): Mahsa Akbari Oryani, Mohaddeseh Shahraki, and Marjaneh Farazestanian. Dysgerminoma in a patient with 46, xy karyotype and pure gonadal dysgenesis (swyer syndrome): a case report and literature review. Journal of Obstetrics, Gynecology and Cancer Research, 9:591-598, Aug 2024. URL: https://doi.org/10.30699/jogcr.9.5.591, doi:10.30699/jogcr.9.5.591. This article has 2 citations.
-
(oryani2024dysgerminomaina pages 5-7): Mahsa Akbari Oryani, Mohaddeseh Shahraki, and Marjaneh Farazestanian. Dysgerminoma in a patient with 46, xy karyotype and pure gonadal dysgenesis (swyer syndrome): a case report and literature review. Journal of Obstetrics, Gynecology and Cancer Research, 9:591-598, Aug 2024. URL: https://doi.org/10.30699/jogcr.9.5.591, doi:10.30699/jogcr.9.5.591. This article has 2 citations.
-
(adra2024seminomain46 pages 2-3): Maamoun Adra, Hayato Nakanishi, Eleni Papachristodoulou, Evangelia Karaoli, Petroula Gerasimou, Antri Miltiadous, Katerina Nicolaou, Loizos Loizou, and Nicos Skordis. Seminoma in 46, xy gonadal dysgenesis: rare presentation and review of the literature. Journal of Clinical Research in Pediatric Endocrinology, 16:495-500, Apr 2024. URL: https://doi.org/10.4274/jcrpe.galenos.2023.2023-12-11, doi:10.4274/jcrpe.galenos.2023.2023-12-11. This article has 1 citations.
-
(rudnicka2024ariskof pages 4-4): Ewa Rudnicka, Aleksandra Jaroń, Jagoda Kruszewska, Roman Smolarczyk, Krystian Jażdżewski, Paweł Derlatka, and Anna Małgorzata Kucharska. A risk of gonadoblastoma in familial swyer syndrome—a case report and literature review. Journal of Clinical Medicine, 13:785, Jan 2024. URL: https://doi.org/10.3390/jcm13030785, doi:10.3390/jcm13030785. This article has 9 citations.
-
(sowinskaprzepiera2023latediagnosisof pages 2-6): Elżbieta Sowińska-Przepiera, Mariola Krzyścin, Adam Przepiera, Agnieszka Brodowska, Ewelina Malanowska, Mateusz Kozłowski, and Aneta Cymbaluk-Płoska. Late diagnosis of swyer syndrome in a patient with bilateral germ cell tumor treated with a contraceptive due to primary amenorrhea. International Journal of Environmental Research and Public Health, 20:2139, Jan 2023. URL: https://doi.org/10.3390/ijerph20032139, doi:10.3390/ijerph20032139. This article has 4 citations.
-
(o’connell2023establishingamolecular pages 7-8): Michele A. O’Connell, Gabby Atlas, Katie Ayers, and Andrew Sinclair. Establishing a molecular genetic diagnosis in children with differences of sex development: a clinical approach. Hormone Research in Paediatrics, 96:128-143, Nov 2023. URL: https://doi.org/10.1159/000520926, doi:10.1159/000520926. This article has 43 citations and is from a peer-reviewed journal.
-
(o’connell2023establishingamolecular pages 1-2): Michele A. O’Connell, Gabby Atlas, Katie Ayers, and Andrew Sinclair. Establishing a molecular genetic diagnosis in children with differences of sex development: a clinical approach. Hormone Research in Paediatrics, 96:128-143, Nov 2023. URL: https://doi.org/10.1159/000520926, doi:10.1159/000520926. This article has 43 citations and is from a peer-reviewed journal.
-
(o’connell2023establishingamolecular pages 3-4): Michele A. O’Connell, Gabby Atlas, Katie Ayers, and Andrew Sinclair. Establishing a molecular genetic diagnosis in children with differences of sex development: a clinical approach. Hormone Research in Paediatrics, 96:128-143, Nov 2023. URL: https://doi.org/10.1159/000520926, doi:10.1159/000520926. This article has 43 citations and is from a peer-reviewed journal.
-
(jiali2024worldwidecohortstudy pages 1-2): Chen Jiali, Peng Huifang, Jiang Yuqing, Zeng Xiantao, and Jiang Hongwei. Worldwide cohort study of 46, xy differences/disorders of sex development genetic diagnoses: geographic and ethnic differences in variants. Frontiers in Genetics, Jun 2024. URL: https://doi.org/10.3389/fgene.2024.1387598, doi:10.3389/fgene.2024.1387598. This article has 15 citations and is from a peer-reviewed journal.
-
(jiali2024worldwidecohortstudy pages 4-6): Chen Jiali, Peng Huifang, Jiang Yuqing, Zeng Xiantao, and Jiang Hongwei. Worldwide cohort study of 46, xy differences/disorders of sex development genetic diagnoses: geographic and ethnic differences in variants. Frontiers in Genetics, Jun 2024. URL: https://doi.org/10.3389/fgene.2024.1387598, doi:10.3389/fgene.2024.1387598. This article has 15 citations and is from a peer-reviewed journal.
-
(jiali2024worldwidecohortstudy pages 6-7): Chen Jiali, Peng Huifang, Jiang Yuqing, Zeng Xiantao, and Jiang Hongwei. Worldwide cohort study of 46, xy differences/disorders of sex development genetic diagnoses: geographic and ethnic differences in variants. Frontiers in Genetics, Jun 2024. URL: https://doi.org/10.3389/fgene.2024.1387598, doi:10.3389/fgene.2024.1387598. This article has 15 citations and is from a peer-reviewed journal.
-
(jiali2024worldwidecohortstudy pages 3-4): Chen Jiali, Peng Huifang, Jiang Yuqing, Zeng Xiantao, and Jiang Hongwei. Worldwide cohort study of 46, xy differences/disorders of sex development genetic diagnoses: geographic and ethnic differences in variants. Frontiers in Genetics, Jun 2024. URL: https://doi.org/10.3389/fgene.2024.1387598, doi:10.3389/fgene.2024.1387598. This article has 15 citations and is from a peer-reviewed journal.
-
(luppino2024roleofnr5a1 pages 5-7): Giovanni Luppino, Malgorzata Wasniewska, Roberto Coco, Giorgia Pepe, Letteria Anna Morabito, Alessandra Li Pomi, Domenico Corica, and Tommaso Aversa. Role of nr5a1 gene mutations in disorders of sex development: molecular and clinical features. Current Issues in Molecular Biology, 46:4519-4532, May 2024. URL: https://doi.org/10.3390/cimb46050274, doi:10.3390/cimb46050274. This article has 24 citations.
-
(luppino2024roleofnr5a1 pages 1-2): Giovanni Luppino, Malgorzata Wasniewska, Roberto Coco, Giorgia Pepe, Letteria Anna Morabito, Alessandra Li Pomi, Domenico Corica, and Tommaso Aversa. Role of nr5a1 gene mutations in disorders of sex development: molecular and clinical features. Current Issues in Molecular Biology, 46:4519-4532, May 2024. URL: https://doi.org/10.3390/cimb46050274, doi:10.3390/cimb46050274. This article has 24 citations.
-
(o’connell2023establishingamolecular media 9ea011f5): Michele A. O’Connell, Gabby Atlas, Katie Ayers, and Andrew Sinclair. Establishing a molecular genetic diagnosis in children with differences of sex development: a clinical approach. Hormone Research in Paediatrics, 96:128-143, Nov 2023. URL: https://doi.org/10.1159/000520926, doi:10.1159/000520926. This article has 43 citations and is from a peer-reviewed journal.
-
(rudnicka2024ariskof pages 4-6): Ewa Rudnicka, Aleksandra Jaroń, Jagoda Kruszewska, Roman Smolarczyk, Krystian Jażdżewski, Paweł Derlatka, and Anna Małgorzata Kucharska. A risk of gonadoblastoma in familial swyer syndrome—a case report and literature review. Journal of Clinical Medicine, 13:785, Jan 2024. URL: https://doi.org/10.3390/jcm13030785, doi:10.3390/jcm13030785. This article has 9 citations.
-
(idris2025genomictechnologiesand pages 1-2): Firman Idris, Andrew H. Sinclair, and Katie L. Ayers. Genomic technologies and the diagnosis of 46, xy differences of sex development. Andrology, 13:1025-1043, Jul 2025. URL: https://doi.org/10.1111/andr.13708, doi:10.1111/andr.13708. This article has 6 citations and is from a peer-reviewed journal.
-
(adra2024seminomain46 pages 3-5): Maamoun Adra, Hayato Nakanishi, Eleni Papachristodoulou, Evangelia Karaoli, Petroula Gerasimou, Antri Miltiadous, Katerina Nicolaou, Loizos Loizou, and Nicos Skordis. Seminoma in 46, xy gonadal dysgenesis: rare presentation and review of the literature. Journal of Clinical Research in Pediatric Endocrinology, 16:495-500, Apr 2024. URL: https://doi.org/10.4274/jcrpe.galenos.2023.2023-12-11, doi:10.4274/jcrpe.galenos.2023.2023-12-11. This article has 1 citations.
-
(jawed2023ararecase pages 1-2): Inshal Jawed, Ayesha Azhar Javed, Syeda Alisha Johar, Daayl N Mirza, Ayesha A Abdani, and Asad Ali Khan. A rare case of swyer syndrome from pakistan in a young girl with primary amenorrhea and 46xy genotype. Women's Health, Jan 2023. URL: https://doi.org/10.1177/17455057231213270, doi:10.1177/17455057231213270. This article has 4 citations and is from a peer-reviewed journal.
-
(krygere2025infertilitymanagementin pages 1-3): Laura Krygere, Ruta Bartasiene, Agne Kozlovskaja–Gumbriene, and Egle Drejeriene. Infertility management in a patient with swyer syndrome: a case report. Journal of Assisted Reproduction and Genetics, 42:1689-1695, Mar 2025. URL: https://doi.org/10.1007/s10815-025-03442-4, doi:10.1007/s10815-025-03442-4. This article has 3 citations and is from a peer-reviewed journal.
-
(rudnicka2024ariskof pages 2-4): Ewa Rudnicka, Aleksandra Jaroń, Jagoda Kruszewska, Roman Smolarczyk, Krystian Jażdżewski, Paweł Derlatka, and Anna Małgorzata Kucharska. A risk of gonadoblastoma in familial swyer syndrome—a case report and literature review. Journal of Clinical Medicine, 13:785, Jan 2024. URL: https://doi.org/10.3390/jcm13030785, doi:10.3390/jcm13030785. This article has 9 citations.
-
(yu2024pure46xy pages 1-2): Tengge Yu and Li Liu. Pure 46, xy gonadal dysgenesis and 46, xy complete androgen insensitivity syndrome: a case report. Medicine, 103:e38297, Jun 2024. URL: https://doi.org/10.1097/md.0000000000038297, doi:10.1097/md.0000000000038297. This article has 5 citations and is from a peer-reviewed journal.
