Primary ovarian insufficiency (POI) is a heterogeneous condition that worldwide affects up to 3.7% of women under 40 years of age. POI manifestations are diverse, ranging from ovarian dysgenesis and primary amenorrhea to a later onset ovarian dysfunction, secondary amenorrhea, and diminished ovarian reserve. These conditions result in infertility and elevated risk for osteoporosis and cardiovascular disease. Over the past decade, substantial progress has been made in understanding the complexities of ovarian biology and oocyte development, particularly in identifying involved pathways, etiology, underlying mechanisms, and POI-associated genes. In this review, we focus on chromosomal and monogenic causes of POI leading to syndromic and isolated forms in humans. We provide an updated summary on 272 genes reported in at least two unrelated individuals with a clinical diagnosis of POI. This information supports healthcare professionals in making informed decisions regarding genetic testing and genetic counseling. This review underlines the critical role of molecular diagnosis in understanding and managing POI, highlighting both the current progress and the existing limitations in translating genetic findings and knowledge into effective diagnostic practice.

The pre-B cell leukemia transcription factor encoded by PBX1 is expressed throughout human embryonic stages. Accumulating cases with differences of sex development (DSDs) have been reported harboring PBX1 variants, suggesting a yet elusive role of PBX1 in the gonadal differentiation and sexual development processes. We report a syndromic case of 46,XY DSD presenting severely undervirilized genitalia and gonadal dysgenesis with mixed ovarian and testicular differentiation, where whole-exome sequencing analysis identified a novel missense variant c.710G>C (p.R237T) in the highly conserved nuclear localization sequence in the TALE domain of PBX1. Compared with WT PBX1, PBX1 p.R237T reduced protein stability and hampered nuclear translocation of PBX1 in the inducible Flp-In TREx HEK293 cells. Induction with tetracycline significantly decreased cell proliferation both in Flp-In HEK293 PBX1 WT and p.R237T cells compared to untransfected HEK293 cells, while adhesive ability was not different. RNA sequencing identified differentially expressed genes (DEGs) in DSD-related genes, including MAP3K4, EMX2, KISS1R, and HOXA13 in cells expressing PBX1 p.R237T when compared to cells expressing WT PBX1. Altogether, our results demonstrated the deleterious functional consequences of the rare PBX1 p.R237T variant identified in Taiwanese proband with 46,XY DSD.

Disorder of Sex Development in an Adolescent: Case of 46 XY Partial Gonadal Dysgenesis

Perspective on postoperative hormone replacement therapy and fertility preservation in Swyer syndrome with dysgerminoma: a case series and literature review.

Gonadal dysgenesis (GD) due to NR0B1 duplication is a subset of 46,XY disorder of sexual differentiation (DSD) characterised by variable external genitalia phenotypes ranging from complete GD (CGD) to partial GD (PGD) and may have syndromic associations. The DSD-phenotype spectrum and its correlation with genotype have not been systematically studied. A systematic review of 46,XY GD with NR0B1 duplication (n = 47, including two patients from our centre) was conducted to understand DSD phenotypes and their genotypic correlations. Large and submicroscopic duplications were observed in 61.7% and 38.3%, respectively, and maternal inheritance (asymptomatic carriers, except one) was reported in 63.3%. Median age at presentation was 1.0 (birth to 38) years, and syndromic manifestations were the cause in 55.3% and gonadal dysfunction-related symptoms in 42.5%. CGD, PGD, and typical male genitalia were seen in 66%, 27.7%, and 6.4%, respectively. Gender incongruence and fertility (except for one reported paternity) have not been reported. Gonadoblastoma and gonadal germ cell cancer were noted in 17% (median age: 11 years) and 2.1% (15 years of age) of cases, respectively. Compared with submicroscopic duplications, large duplications were associated with earlier presentation (0.7 vs. 15 years; p = 0.008) and higher prevalence of syndromic features (96.6% vs. 22.2%; p = 0.0001), while external genital phenotype, cryptorchidism, presence of mullerian structures, and gonadoblastoma rates were comparable. 46,XY GD phenotype with NR0B1 duplication does not correlate with duplicated segment size. A delineated spectrum of gonadal dysfunction, gender identity, fertility, and gonadal malignancy risk presented here can help to optimise patient management.

Disorders of sexual development (DSD) comprise a group of congenital conditions, occurring in approximately 1 in 4,500 to 5,500 newborns. Over a 3-year period, seven cases presented with ambiguous genitalia, primary amenorrhea, and abdominal masses and were admitted to our hospital's General Surgery and Gynaecology wards. Radiological, cytogenetics, and hormonal evaluation was done, followed by surgical excision and histopathological examination of the gonads. The study was conducted with proper written informed consent from parents and received approval from the Institutional Ethics Committee. Out of four cases diagnosed with mixed gonadal dysgenesis (MGD), one had dysgerminoma, one had both dysgerminoma and gonadoblastoma, and another had bilateral gonadoblastoma. Three other cases were diagnosed as ovo-testicular DSD. We experienced varied presentations of dysgenetic gonads in DSD - ovotestis to streak gonad and dysgenetic testis. Early diagnosis and categorization of disorders of sex development (DSD) are crucial to prevent adverse outcomes and ensure optimal management.

IntroductionSwyer syndrome is a genetic abnormality characterized by a 46,XY karyotype in a phenotypically female individual. Affected individuals typically have average or tall stature, unambiguous genitalia at birth, the presence of Müllerian structures, and bilateral streak gonads. Familial Swyer syndrome is extremely rare, and we identified only two case reports describing families with two and three sisters affected by this syndrome. Individuals with Swyer syndrome have an increased risk of developing gonadal malignancies.CaseA 19‐year‐old patient with primary amenorrhea, who had been followed up with a diagnosis of Swyer syndrome, was referred to our hospital due to a complaint of progressive abdominal distension and a 5‐month history of lower abdominal pain. Karyotype analysis had been performed at another hospital when her older sibling was diagnosed with Swyer syndrome. However, she did not undergo bilateral gonadectomy after the diagnosis was confirmed, as her family postponed the procedure due to the COVID‐19 pandemic. Surgical debulking of ovarian cancer was performed, and histopathology revealed a dysgerminoma, FIGO Stage IIIC.ConclusionEarly diagnosis of Swyer syndrome is essential, considering the significant risk of malignant gonadal tumors that may arise at an early age. Prepubertal female siblings of patients diagnosed with Swyer syndrome should be screened. Early diagnosis and prompt prophylactic gonadectomy can allow for a conservative treatment plan that may preserve fertility and improve patient survival.

46,XY complete gonadal dysgenesis, also known as Swyer syndrome, is a rare disorder of sex development characterized by female phenotype, presence of Müllerian structures, and non-functional streak gonads. These patients typically present with primary amenorrhea and require assisted reproductive techniques using donor gametes to achieve pregnancy. Reports of twin pregnancies in such women are exceedingly rare. We report a 32-year-old phenotypic female with primary amenorrhea who was found to have a 46,XY karyotype. Pelvic imaging revealed a normally formed uterus and vagina with streak gonads. Diagnostic hysteroscopy confirmed a normal uterine cavity. Pregnancy was achieved through assisted reproduction using donor gametes. A twin intrauterine pregnancy was diagnosed at 6 weeks scan. Cervical length was found to be on the lower side at NT scan and prophylactic cervical cerclage was performed. At 24 weeks of gestation, the patient developed pregnancy-induced hypertension, which was managed successfully with oral labetalol. The pregnancy progressed without major complications, and an elective cesarean section was performed at 37 weeks of gestation due to twin pregnancy with breech presentation of the first twin. Two healthy female neonates were delivered. This case highlights the reproductive potential of women with 46,XY gonadal dysgenesis and emphasizes the importance of meticulous antenatal surveillance in achieving favorable outcomes, even in twin gestations.

The objective of this systematic review was to identify the evidence of testicular cancer risk for people with intersex conditions. This assessment is hoped to help refine risk stratification tools for assessing gonadal malignancy risk and guide the development of more robust evidence-based management strategies. The literature was searched in Ovid MEDLINE, Embase, and Cumulative Index of Nursing and Allied Health using a search string developed by a multidisciplinary team. The protocol was registered at Prospective Register of Systematic Reviews as CRD42021231313. A total of 3608 articles were found. After selection, 301 publications were included (1215 individuals). The results identified significant evidence that pre-pubertal gonadectomy may be linked to lower rates of malignant gonadal changes for patients with partial gonadal dysgenesis, Turner's syndrome with Y-chromosome material, complete androgen insensitivity, partial androgen insensitivity, and patients with ovotestis/es. The evidence was not significant for patients with complete gonadal dysgenesis, Klinefelter syndrome, nor WT1-related syndromes. Specific cancer outcomes were unable to be assessed due to small sample sizes and thus it is unknown if clinically significant cancer outcomes are meaningfully altered by pre-pubertal gonadectomy. Importantly, the quality of data on the topic of gonadal malignancy in intersex patients with testicular tissue was determined to be poor overall. The quality was relatively more robust regarding the conditions of Complete Androgen Insensitivity, Klinefelter syndrome, and patients with ovotestis/es. More high-quality research is needed to draw specific conclusions on the risks and benefits of performing pre-pubertal gonadectomy for intersex patients. When counseling these patients, clinicians should be transparent regarding the paucity of data supporting pre-pubertal gonadectomy.

The aim of this study was to evaluate muscle mass and strength in children and adolescents with disorders of sex development (DSD) whose sex assignment was determined by a multidisciplinary team, comparing these parameters both among the DSD cases and with healthy controls, and to assess the impact of hormone replacement therapy (HRT) on these outcomes. 78 DSD cases and 118 healthy controls were included. Gender assignment followed multidisciplinary council decisions; some DSD cases underwent gender-appropriate surgical interventions, and HRT was initiated as puberty approached. Participants were divided into four age groups (<5, 5-10, 10-15, and ≥15 years), and anthropometric measures, pubertal status, muscle mass and strength, skinfold thickness, and sex hormone profiles were assessed. Among DSD cases, 30.8% had 46,XX DSD, 53.8% had 46,XY DSD, and 15.4% had mixed gonadal dysgenesis (MGD); ambiguous genitalia was the most common referral reason, and CYP21A2 was the most frequently identified mutation. In individuals aged ≥15 years, 46,XX DSD cases, regardless of gender of rearing, had lower height standard deviation scores (SDS) than healthy peers, whereas 46,XY DSD cases raised as females had higher height SDS than other DSD subgroups (p<0.01). In Individuals aged ≥15 years, muscle strength was highest in 46,XY DSD males and healthy males (p<0.01). Participation in sports was associated with higher muscle mass in both groups (p=0.03). Muscle strength correlated positively with serum testosterone (p< 0.001, R = 0.563). Chromosomal sex predominantly influenced final height, whereas muscle strength aligned with gender of rearing and testosterone levels.

To report a novel variant in the NR5A1 gene as a cause of 46,XY complete gonadal dysgenesis (Swyer syndrome). A 12.5-year-old prepubertal girl presented with the complaint of short stature and was evaluated in our clinic after pelvic ultrasonography revealed an absent uterus and ovaries. In pubertal examination, she was at Tanner stage I, had a fully female phenotype, and no clitoromegaly. Gonads were not palpable on examination. Laboratory investigations, including hemogram and biochemical tests, were normal. Celiac antibodies were negative, and thyroid function tests were within normal limits. Patient’s serum LH level was 11.7 mIU/mL, FSH 81.3 mIU/mL, estradiol

Klinefelter syndrome (KS) and Turner syndrome (TS) are sex chromosome disorders with distinct genetic mechanisms and clinical consequences. KS, characterized by a 47, XXY karyotype, leads to primary hypogonadism and infertility in males, while TS, resulting from monosomy X (45, X) or X chromosome abnormalities, causes ovarian dysgenesis and infertility in females. Both conditions exhibit wide phenotypic variability, often leading to delayed or obscured diagnosis. Early craniofacial and dental features, such as taurodontism in KS and a high-arched palate in TS, can serve as crucial diagnostic indicators, guiding timely genetic evaluation and management. Dentists play a vital role in identifying these manifestations, facilitating early genetic diagnosis and multidisciplinary care. Timely recognition enables healthcare providers to offer individualized support, including hormone therapy, speech therapy, and orthodontic treatment, ultimately improving long-term outcomes and quality of life. This presentation highlights the importance of early detection and collaborative care in optimizing outcomes for individuals with KS and TS. This review synthesizes current evidence on dental and orthodontic considerations, providing strategies to enhance oral health and overall quality of life for individuals affected by these conditions.

In this report, we present an adolescent patient with a 46,XY karyotype and phenotypically female genitalia secondary to campomelic dysplasia who presented with primary amenorrhea. This patient is unique both for her extended survival and presentation of hypogonadotropic hypogonadism, an unexpected finding in a disease characterised by gonadal dysgenesis that does not normally affect the central pituitary axis. Furthermore, while we might have expected elevated gonadotropins consistent with primary gonadal failure, this patient instead demonstrated low gonadotropin levels with minimally detectable sex steroids, reflecting central hypogonadism and complete functional gonadal failure. This patient was treated with a ¼ of a 0.025 mg estradiol patch (equating to a dose of 0.00625 mg) with plans to titrate to increased doses over the course of 1 year in order to induce puberty, promote bone growth and allow for gender identity concordance.

Swyer syndrome is a rare condition of complete gonadal dysgenesis due to mutations in the Y chromosome SRY gene, leading to testicular underdevelopment. In this condition individuals present with a female phenotype despite having a male karyotype (46, XY). This retrospective review of five cases of Swyer Syndrome at our centre since 2013. All five patients, raised as girls, presented at 18-31 years with primary amenorrhea; one had hyposmia. Breast development ranged from Tanner stage 1-4 with varying axillary hair. Internal exams showed an infantile uterus and cervix. Imaging revealed small to normal uterus and streak gonads. Elevated serum FSH and low testosterone confirmed the diagnosis (46, XY karyotype). Three patients underwent laparoscopic gonadectomy due to gonadoblastona risk; two were lost to follow-up. All received Estrogens and Progesterone replacement therapy development of secondary sexual characters. Swyer syndrome requires high clinical suspicion for diagnosis. Early identification allows timely hormone therapy and consideration of gonadectomy to prevent gonadoblastona.

Introduction. Male infertility has a heterogeneous etiology, most commonly caused by disorders of spermatogenesis, clinically manifested as azoospermia or severe oligospermia. Genetic factors account for approximately 30% of male infertility cases associated with azoospermia. This high frequency is due to the involvement of numerous genes in the regulation of sexual development and reproduction. Among the various genetic causes of spermatogenic failure, chromosomal abnormalities are among the most clinically significant. The objective of the study was to evaluate the profile of chromosomal variations in infertile men with azoospermia, to optimize assisted reproductive strategies in infertile couples. Material and methods. A group of 96 azoospermic men underwent karyotype analysis. The diagnosis of azoospermia was established based on at least two consecutive semen analyses performed according to the guidelines of the World Health Organization (WHO). Cytogenetic analysis was carried out on peripheral blood lymphocytes, with results interpreted according to the 2016 International System for Human Cytogenetic Nomenclature (ISCN). Hormonal profiles (FSH, LH, prolactin, testosterone) were correlated with chromosomal findings. Statistical analysis was performed using SPSS (Statistical Package for the Social Sciences), version 22.0. Results. Cytogenetic investigations in azoospermic patients (n = 96) revealed karyotype variations in 25.0% of cases, including sex chromosome abnormalities in 16.7%: 47,XXY - Klinefelter syndrome (11.5%); microscopic structural variations of the Y chromosome (2.1%); and single cases of 47,XYY - Jacobs syndrome; 46,XX male - sex reversal; and 45,X/46,XY - mixed gonadal dysgenesis. Autosomal abnormalities were found in 8.3% of cases: translocations (3.1%), inversions (2.1%), chromosomal polymorphisms (2.1%), and one case with 46,XY,fra(17)(p12). Patients with sex chromosome abnormalities exhibited significantly higher FSH and LH levels compared to those with autosomal abnormalities (p less than 0.05), whereas prolactin and testosterone levels did not differ significantly between the groups. Conclusions. The high prevalence of chromosomal abnormalities in azoospermic men supports the inclusion of cytogenetic testing in the routine evaluation of male infertility. Identifying the type of chromosomal defect allows for appropriate genetic counseling and aids in decision-making regarding assisted reproductive options.

Kallmann syndrome (KS) is a rare inherited disorder characterized by congenital hypogonadotropic hypogonadism and reduced or absent olfactory function. In addition to gonadal dysgenesis and structural abnormalities, KS patients may present with extensive psychosocial dysfunction and behavioral changes. This study aims to evaluate the effects of self-stigma, impulsivity, and insomnia on anxiety and depression in KS patients and to explore the interrelationships among these factors. A total of 206 patients with confirmed KS were recruited from the Xiangya Hospital and Henan Provincial People's Hospital. Multivariable Logistic regression analysis was used to identify independent factors associated with anxiety and depression, and a serial multiple-mediator model was applied to characterize pathway effects. The cohort of KS patients demonstrated substantial psychological and social burden, including self-stigma, impulsivity, insomnia, loneliness, anxiety, depression, and overall social isolation tendencies. Logistic regression analysis indicated that self-stigma (OR=1.112, P=0.003), loneliness (OR=1.198, P=0.007), and insomnia (OR=1.098, P=0.017) were independent factors the presence of anxiety and depression in KS patients. Mediation-effect modeling further showed that impulsivity and insomnia significantly mediated the effect of self-stigma on anxiety and depression in KS (indirect effect 3=0.013, P=0.008; 95% CI 0.004 to 0.024; c'=0.147, P<0.001; 95% CI 0.091 to 0.201). This study preliminarily identified the major modifiable factors associated with anxiety and depression in KS patients, including self-stigma, loneliness, and insomnia. Impulsivity and insomnia demonstrated significant serial mediation effects linking self-stigma to affective outcomes. Multidimensional intervention strategies targeting stigma reduction, impulsivity regulation, and sleep-quality improvement may help alleviate anxiety-depression symptoms and ultimately improve overall quality of life in patients with KS.

46,XY gonadal dysgenesis, characterised by absent or defective testicular development in individuals with a 46,XY karyotype, results from disruptions in the genetic programme governing testis determination and differentiation during embryogenesis. While monogenic causes explain approximately 50% of cases, emerging evidence suggests an oligogenic basis in some patients. However, many cases remain without a definitive molecular diagnosis. In this study, we investigated a patient with 46,XY gonadal dysgenesis to explore the underlying genetic aetiology. Whole-exome sequencing in the patient did not reveal any pathogenic variants in genes previously associated with this condition. Instead, it detected rare variants in STARD9 and CDK5RAP2, which encode centrosomal proteins known to interact with each other. Gene expression analysis of embryonic gonads revealed that STARD9 is sexually dimorphic, with the highest expression in testis-specific Sertoli cells, while CDK5RAP2 is ubiquitously expressed, including in Sertoli cells. These findings suggest a role for both genes in Sertoli cell development, implicating them in the pathogenesis of 46,XY gonadal dysgenesis. To evaluate the functional relevance of the identified variants, we performed molecular dynamics simulations, which suggest that these variants may impair the individual and/or combined functions of STARD9 and CDK5RAP2 proteins. This study is the first to propose a role for STARD9 and CDK5RAP2 genes in human Sertoli cell development and highlights their potential contribution to 46,XY gonadal dysgenesis.

Mixed gonadal dysgenesis is characterized by abnormal genital appearance and chromosomal mosaicism. A wide spectrum of clinical manifestations can occur, ranging from females (with or without Turner syndrome) to phenotypically normal males with some degree of genital ambiguity. In this context, uncommon mosaic karyotypes are associated with distinctive phenotypic characteristics. Here, we present the case of an 18-year-old girl with primary amenorrhea, delayed puberty, and a rare mosaic karyotype pattern. Clinical data were collected, and karyotyping was performed on peripheral blood samples. Polymerase chain reaction amplification for the sex-determining region Y protein (SRY) gene was also conducted. The patient presented with delayed puberty and primary amenorrhea. Her hormonal profile was consistent with hypergonadotropic hypogonadism. Pelvic magnetic resonance imaging revealed a small uterus. Echocardiography identified the presence of a bicuspid aortic valve. Karyotyping demonstrated a 46,XY/45,X/46,X,r(Y) pattern, indicating mosaicism for monosomy X and two cell lines: 45,X and 46,X,r(Y). The SRY gene was detected. Gonadal pathological investigation confirmed streak gonads consistent with gonadal dysgenesis and evidence of gonadoblastoma. Complicated cases with mosaic chromosomal patterns can exhibit a wide range of phenotypic features, from apparently normal males with variable external genitalia to females with or without characteristics of Turner syndrome. These phenotypic discrepancies are not directly related to the number of mosaic cells or the specific location of Y chromosome breakage. Therefore, in cases of primary amenorrhea with genotype-phenotype discrepancies, a multidisciplinary approach is essential to guide appropriate sex determination and management.

Campomelic dysplasia (CD) is a rare congenital skeletal dysplasia frequently associated with differences of sex development (DSD). In about 10% of affected individuals, the bowing of the long bones (campomelia) is absent, referred to as acampomelic campomelic dysplasia (ACD). Most patients with ACD carry heterozygous pathogenic variants within the SOX9 coding region or balanced chromosomal rearrangements involving the 17q24 region. A rarer mechanism involves deletions located upstream of the SOX9 gene. Only five ACD cases with upstream deletions of SOX9 have been reported in the medical literature. We report a female patient affected by ACD with Pierre Robin sequence, complete gonadal dysgenesis (CGD), and hypotonia. Genetic testing revealed a de novo 1.671 Mb deletion located 191 kb upstream of the SOX9 gene. This chromosomal aberration represents the second-largest deletion upstream of SOX9 reported to date. In addition, we describe the patient's endocrine profile, which revealed an absent gonadotropin rise during minipuberty, followed by a delayed increase in infancy. This study expands the clinical and molecular spectrum of ACD, enhancing our understanding of genotype-phenotype correlations of this condition. The phenotypic and endocrinological description of the proband may be helpful for clinicians who consult patients with DSD and skeletal dysplasia.

Introduction: 46,XY gonadal dysgenesis is a rare entity within disorders of sexual development. This case is unique because it describes a patient who underwent irreversible sex assignment surgeries during childhood without histological confirmation, which contrasts with current recommendations. Its contribution to the literature lies in highlighting the diagnostic and psychosocial challenges of these conditions, even when molecular studies yield negative results. Case presentation: A 19-year-old woman, student, with a history of bilateral orchiectomy and penectomy at 2 years of age. She presented with primary amenorrhea and absence of secondary sexual characteristics. Physical examination revealed severe hypogonadism, hypergonadotropism, absence of uterus and adnexa, and a 17% reduction in bone mineral density. Karyotype confirmed 46,XY with a positive SRY gene, and a panel of 53 genes associated with disorders of sexual development was negative. Interventions and outcomes: Management included hormone replacement therapy with estradiol and medroxyprogesterone, calcium and vitamin D supplementation, and psychiatric treatment with escitalopram for depression and anxiety. As part of her gender affirmation process, she underwent breast implants with good postoperative evolution. She is currently under multidisciplinary follow-up with subjective improvement in mood and clinical stability. Conclusions: The main lessons from this case are the importance of avoiding early irreversible surgeries, recognizing the limitations of molecular studies, ensuring a comprehensive approach that includes psychosocial support, and guaranteeing the active participation of the patient in therapeutic decisions to optimize health and quality of life in 46,XY disorders of sexual development.