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46,XY complete gonadal dysgenesis

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of 46,XY complete gonadal dysgenesis. Core disease mechanisms, molecular and...

2026-04-14
Asta MONDO:0010765 Model: Asta Scientific Corpus Retrieval 19 citations

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

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