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_relevance with snippet_search.
• No synthesis or second-stage model call is performed.

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)

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)

1. 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)
2. Absent fetal AMH and testosterone:
3. Lack of AMH → persistence of Müllerian ducts → uterus, fallopian tubes, upper vagina. (rudnicka2024ariskof pages 1-2, rudnicka2024ariskof pages 4-6)
4. Lack of testosterone → absent Wolffian development and absent masculinization → female external phenotype. (rudnicka2024ariskof pages 4-6)
5. 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)
6. 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)

1. 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)
2. 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)
3. 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

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2. (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.

3. (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.

4. (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.

5. (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.

6. (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.

7. (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.

8. (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.

9. (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.

10. (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.

11. (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.

12. (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.

13. (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.

14. (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.

15. (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.

16. (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.

17. (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.

18. (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.

19. (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.

20. (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.

21. (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.

22. (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.

23. (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.

24. (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.

25. (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.

26. (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.

27. (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.

28. (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.

29. (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.

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