OBJECTIVE: To summarize the clinical and genetic characteristics of a child with 46,XX Ovotesticular disorder of sex development (46,XX OTDSD) due to copy number variation of SOX3 gene. METHODS: A 46,XX male patient presented at the Capital Center for Children's Health, Capital Medical University in November 2024 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples were taken from the child and his parents and subjected to trio whole-genome sequencing. Skewed X-chromosome inactivation was tested in the child and his mother. A literature review was carried out on 46,XX males associated with mutations of the SOX3 gene. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: SHERLL2025056). RESULTS: The 10-year-old boy presented with hypospadias and cryptorchidism at birth. Chromosome analysis at one year and a half revealed a 46,XX karyotype. Gonadal biopsy showed testicular tissue, while ultrasound at the age of 10 detected ovotesticular tissue. Whole-genome sequencing identified a 660 kb duplication in the Xq27.1 region, which was derived from his mother. X-chromosome inactivation testing showed random inactivation in the child and mild non-random inactivation in the mother. Literature review has found 11 publications involving 15 patients (including our case), among whom 14 had a male social gender. They had primarily presented with hypospadias at birth but had no significant endocrine abnormalities. Most patients had experienced testicular failure after puberty. SOX3 related 46,XX males are mainly caused by de novo duplications, although a few maternal carriers had been discovered. CONCLUSION Duplication of the SOX3 gene probably underlay the pathogenesis is this 46,XX male. Individuals with 46,XX SRY negative male phenotypes should be routinely screened for SOX3 gene variants. Structural variations of the SOX3 gene can lead to complete or partial sex reversal in 46,XX individuals with minimal impact on intellectual and motor development, as well as other endocrine hormones.
Child ; Humans ; Male ; 46, XX Disorders of Sex Development/genetics* ; DNA Copy Number Variations ; Gene Duplication ; Phenotype ; SOXB1 Transcription Factors/genetics*

OBJECTIVE: To investigate the detection patterns, clinical phenotypic characteristics, and differences in diagnostic timeliness of Klinefelter syndrome (KS) across prenatal and postnatal stages, with an aim to provide a basis for optimizing strategies for early screening, diagnosis, and intervention. METHODS: A retrospective study was conducted to analyze data from two phases. The prenatal diagnosis group included 33,302 pregnant women who underwent amniocytic karyotyping due to advanced maternal age, abnormal ultrasound findings, or high-risk non-invasive prenatal testing (NIPT). The postnatal diagnosis group included 52,101 patients who underwent peripheral blood karyotyping due to primary infertility, abnormal external genitalia, or growth and developmental abnormalities. Additionally, medical histories of adult diagnosed patients were reviewed retrospectively to identify early occult symptoms. This study was approved by the Medical Ethics Committee of Chengdu Women's and Children's Central Hospital (Ethics No.: LCYJ-2025-030). RESULTS: In the prenatal group, 96 cases of KS were detected (detection rate 0.29%). The primary indications for referral were NIPT indicating sex chromosome abnormalities (45.83%), advanced maternal age (16.66%), and ultrasound abnormalities (17.70%). In the postnatal group, 128 cases of KS were detected (detection rate 0.25%). Clinical presentations were primarily primary infertility/azoospermia (77.34%), and the patients were predominantly adults (84.40%). Retrospective analysis revealed that adult patients presented with specific physical signs that had been overlooked during childhood. CONCLUSION As KS lacks typical early clinical manifestations, diagnosis is often delayed until adulthood when reproductive needs arise, showing a pattern of "passive detection" and resulting in missed opportunities for optimal intervention. By conducting a comparative analysis of prenatal diagnostic data and postnatal retrospective data, a risk association model linking prenatal screening indications with childhood-specific signs was developed. This study has provided empirical evidence for establishing a multidisciplinary, full life-cycle management system of "screening ~ diagnosis ~ monitoring ~ intervention" helping to shift from "passive detection in adulthood" to "proactive management across the entire life course," and laid a foundation for improving early diagnosis rate and long-term quality of life for patients.
Humans ; Klinefelter Syndrome/genetics* ; Female ; Adult ; Pregnancy ; Retrospective Studies ; Prenatal Diagnosis/methods* ; Male ; Phenotype ; Karyotyping ; Young Adult ; Adolescent ; Middle Aged

Introduction: Swyer syndrome (46, XY gonadal dysgenesis) is a rare disorder of sex development, characterized by a phenotypic female with streak gonads and hypergonadotropic hypogonadism. It presents with primary amenorrhea and delayed puberty. Overlapping clinical features with Turner syndrome may cause diagnostic uncertainty, highlighting the role of karyotypic evaluation in diagnosis. Case: A 35-year-old phenotypic female was first evaluated at age 27 during admission for an acute viral illness, when incidental findings of primary amenorrhea, short stature (height 131 cm), webbed neck, pectus excavatum, and absent secondary sexual characteristics raised suspicion of Turner syndrome. She had hypertension, with initial imaging suggesting coarctation of the thoracic aorta. CT angiography showed focal narrowing of the descending aorta; multidisciplinary review favored aortic folding, and she was managed conservatively. Endocrine evaluation demonstrated hypergonadotropic hypogonadism, with markedly elevated follicle-stimulating hormone (FSH 108.6 IU/L) and luteinizing hormone (LH 23.16 IU/L) in the presence of low estradiol levels. Pelvic imaging revealed an atrophic uterus with absence of bilateral ovaries, consistent with gonadal dysgenesis. Karyotypic analysis was performed, demonstrating a 46, XY genotype with confirmed SRY gene presence, establishing the diagnosis of Swyer syndrome. DEXA scan demonstrated osteoporosis, in keeping with prolonged hypogonadism. She was commenced on hormone replacement therapy, resulting in the development of secondary sexual characteristics and regular withdrawal bleeding. She remains under structured multidisciplinary follow-up, with endocrine-led management of hypothyroidism and osteoporosis, alongside cardiology follow-up and gynecological surveillance. Conclusion This case highlights the diagnostic complexity of disorders of sex development with overlapping phenotypes and the need for re-evaluation when clinical progression is atypical. Diagnosis enables hormone replacement therapy for induction of secondary sexual characteristics and preservation of bone health. Integration of clinical, biochemical, and genetic data within a multidisciplinary framework is essential to achieve diagnostic accuracy and optimize outcomes.
Turner Syndrome

Introduction: Steroid cell tumors are rare sex cord-stromal tumors, accounting for <0.1% of ovarian neoplasms. Extraovarian steroid cell tumors are exceptionally rare, often androgensecreting, and pose significant diagnostic challenges. Early recognition is essential to prevent prolonged morbidity from hyperandrogenism. Case: A 60-year-old female, 15 years after total hysterectomy and bilateral salpingo-oophorectomy for a large ovarian mass with massive ascites, presented with deranged liver function tests on routine follow-up. Ultrasonography and computed tomography imaging revealed multiple hypervascular lesions in the liver, retroperitoneum, and peritoneum, suggestive of metastatic disease, with normal-appearing adrenal glands. Biopsy of a liver lesion demonstrated a metastatic neoplasm with morphology and immunoprofile favoring a steroid cell tumor. However, metastasis from the adrenal cortex or an ovarian primary could not be excluded. Given the prior bilateral oophorectomy, metastatic adrenocortical carcinoma was initially suspected, prompting endocrine evaluation. Further history revealed a 1-year history of progressive virilization, including increased facial hair and frontal balding. Hormonal studies demonstrated elevated testosterone (12.2 mmol/L and reference range 0.1–1.42) and dehydroepiandrosterone sulfate (15.9 µmol/L and reference range 0.510–5.560) and the adrenocorticotropic hormone level of 11.7 pmol/L (reference range 1.60–13.9) with suppressed gonadotrophins. Additional workup for catecholamine, cortisol, and aldosterone excess was unremarkable. The discordance between androgen excess and normal adrenal imaging, despite absent ovarian tissue, suggested an extraadrenal androgen-secreting steroid cell tumor. A second histopathology review and multidisciplinary discussion with radiology, gynecologic oncology, and pathology teams were undertaken. As the disease was deemed inoperable, repeat retroperitoneal lesion biopsy confirmed metastatic steroid cell tumor and guided palliative chemotherapy. She was subsequently referred to gynecologic oncology for systemic chemotherapy. Conclusion Extra-adrenal steroid cell tumors, though rare, should be considered in patients with hyperandrogenism long after bilateral oophorectomy, especially when adrenal imaging is normal. Multidisciplinary evaluation and repeat biopsy are often crucial for establishing the diagnosis and guiding treatment.
Hyperandrogenism ; Ovariectomy ; Steroids ; Neoplasms

Introduction: Polycystic ovary syndrome (PCOS) is the most common cause of hyperandrogenism in women of reproductive age. However, several endocrine disorders, particularly Cushing disease (CD), can closely mimic the clinical, biochemical, and radiological features of PCOS. This overlap may lead to misdiagnosis and delayed recognition of hypercortisolism, with significant metabolic and reproductive consequences. Case: We report a 24-year-old female with young-onset diabetes mellitus who was referred for endocrine co-management during admission for recurrent mons pubis and labial abscesses with poorly controlled glycemia. She had a 5-year history of progressive hirsutism, oligomenorrhoea, scalp hair loss, significant weight gain, and insulin resistance, and had previously been labelled as having PCOS during adolescence, with subsequent default of follow-up. On examination, she was obese (body mass index 33 kg/ m²) with plethoric facies, acanthosis nigricans, proximal myopathy, and hirsutism (Ferriman–Gallwey score 10), without overt virilization or acromegalic features. Biochemical evaluation demonstrated severe hyperandrogenism with markedly elevated total testosterone (7.05 nmol/L), suppressed gonadotropins, and adrenocorticotropic hormone (ACTH)-dependent hypercortisolism. Cortisol failed to suppress on low-dose dexamethasone testing, and 24-hour urinary free cortisol was markedly elevated (>4,900 nmol/24 h). Pelvic ultrasonography and computed tomography imaging showed polycystic ovarian morphology without evidence of an ovarian mass. Pituitary magnetic resonance imaging revealed a small right-sided pituitary microadenoma measuring 2.6 × 3.7 mm. Inferior petrosal sinus sampling demonstrated a central-to-peripheral ACTH gradient with adequate prolactin ratios, confirming pituitary CD. Conclusion This case highlights how Cushing disease can closely mimic PCOS, including polycystic ovarian morphology and hyperandrogenism. Progressive symptoms, severe biochemical androgen excess, and marked insulin resistance should prompt evaluation for secondary causes of hyperandrogenism, particularly hypercortisolism, to avoid delayed diagnosis and prolonged morbidity.
Female ; Hyperandrogenism ; Pituitary ACTH Hypersecretion ; Polycystic Ovary Syndrome

Introduction: Short stature and delayed puberty characterize Turner syndrome (TS). The 2024 international clinical practice guidelines recommend growth hormone (GH) for latediagnosed patients if epiphyses remain open. For patients with remaining growth potential, initiating GH alongside low-dose estrogen effectively balances linear growth with the need for timely pubertal induction. Case: A 15-year-old female, born prematurely at 6 months gestation, presented with delayed puberty, primary amenorrhea, and short stature. Examination revealed a height of 122 cm (<5th percentile), weight of 26 kg, with no syndromic facies, and Tanner stage 1. Investigations confirmed hypergonadotropic hypogonadism. Metabolic screening, including thyroid, renal, and liver profile, was normal. Her baseline insulin-like growth factor 1 (IGF-1) was low at 117.5 ng/mL (127.5–541.5). Karyotyping confirmed mosaic TS (45,X/46,Xr). Her skeletal bone age was delayed at 12 years, indicating a viable window for linear growth prior to complete epiphyseal fusion. Subcutaneous GH was initiated at 0.3 mg up titrated to 1.2 mg (0.45 µg/kg) daily over 4 weeks, then 1.35 mg (50 µg/kg) daily at month 5. Low-dose oral estradiol (0.5 mg three times weekly) was introduced for pubertal induction at month 4. After 9 months of combined GH and estrogen therapy, the patient achieved a height increment of 6 cm, reaching 128 cm without an adverse event. To achieve the clinical target of a 10–15 cm increment in the first year, her GH dose was further increased to 1.50 mg (55 µg/kg) daily. She showed an appropriate biochemical response with IGF-1 increased to 40.2 nmol/L (16.4–67.8) with a total height gain of 6 cm over the first 9 months of GH therapy. Conclusion Concomitant GH and estrogen therapy in late-diagnosed TS successfully induced clinically significant height gain. This dual approach maximized the limited window for linear growth, without delaying pubertal induction and compromising patient’s psychosocial well-being.
Turner Syndrome

Introduction: Central precocious puberty (CPP) is defined as the early occurrence of puberty before the age of 8 years in girls and 9 years in boys. CPP has many implications for the patient’s physical, emotional, and psychological aspects. The most soughtafter benefit of the treatment is the preservation of the growth potential of final adult height. This study aims to evaluate the predicted and final adult height in girls with CPP who received treatment in the University Malaya Medical Centre (UMMC), Malaysia. Methodology: In this retrospective longitudinal study, 32 CPP patients who received treatment with GnRH analogs in UMMC between 2010 and 2025 were identified. The demographic and clinical data of the patients were retrieved from the medical record system and analyzed. Results: The study revealed that predicted adult height (PAH) by using bone age closely approximated the actual final adult height (FAH) with no significant difference observed (p = 0.793), and a strong positive correlation (r = 0.75, p <0.001). The predicted height based on the genetic potential of mid-parental target height (MPTH) showed a significant underestimation of FAH (mean difference = -1.89 cm, p <0.01), although it remained a robust predictor (r = 0.75, p <0.01). Across age groups, the correlation between PAH and FAH was strongest in girls aged 6–8 years old. Notably, girls treated before age 6 exhibited a significant height gain compared to initial prediction values, underscoring the importance of early intervention. Conclusion From this study, we concluded that the FAH outcome in girls with CPP who received treatment with GnRH analogs is preserved, similar to the PAH calculated by bone age. However, the FAH is significantly lower than the MPTH (genetic potential). The baseline height SDS appears to be a strong predictor of FAH. The bone age value is the strongest predictor of FAH. The preservation of adult height potential is more prominent when subjects developed CPP before 6 years and were treated immediately.
Adult ; Female ; Puberty, Precocious ; Gonadotropin-Releasing Hormone ; World Health Organization

Introduction: Precocious puberty is increasingly recognized in children. Effect of gonadotropin-releasing hormone agonist (GnRHa) on height velocity (HV) and body mass index (BMI) during treatment of Central Precocious Puberty (CPP) is not welldocumented. Methodology: Records of all patients treated with GnRH for CPP who attended the paediatric endocrine clinic over a 5-year period (2021–2025) [N1.1] were reviewed retrospectively for HV and BMI changes for 3 consecutive years. Basal luteinizing hormone levels ≥0.3 IU/L or stimulated levels ≥5 IU/L are considered diagnostic of CPP. Results: Twenty patients were reviewed and median age at the start of study was 7.8 years (4.3–10.3). Majority were female (n = 18, 90%) with median Tanner Stage 3 and of Malay origin (n = 18, 90%[N2.1]). Median chronological age was 7.8 years (4.3–10.3) with bone age 10.3 years (5.8–13.4). Causes of CPP were idiopathic (n = 16, 80%), CNS lesion (n = 2, 10%) and poorly controlled congenital adrenal hyperplasia (n = 2, 10%). Nine (82%) of the 11 patients who had MRI brain done had normal findings. After 1 year of treatment, the median HV SDS was −0.83 (range −2.45 to 2.42), and BMI SDS was 0.45 (−1.94 to 2.15). After 2 years (n = 12), HV SDS declined to −1.3 (−3.44 to 0.69), with BMI SDS of 0.13 (−1.16 to 1.79). After 3 years (n = 9), HV SDS declined further to −1.51 (−3.52 to 3.13), and BMI SDS was 0.16 (−0.12 to 1.25). After 1 year of treatment, 20% (n = 4) of patients were overweight and 10% (n = 2) were obese. By 3 years, 22% (n = 2) remained overweight, and none were obese. Conclusion Premature growth plate senescence induced by prior estrogen exposure may lead to HV decline. Although obesity is a risk factor for the onset of CPP, whether GnRHa treatment directly increases BMI remains controversial as our cohort’s BMI change reveals otherwise.
Child ; Body Mass Index ; Puberty, Precocious ; Hormones

OBJECTIVES: Accurate identification of risk factors for precocious puberty is essential for clinical diagnosis and management, yet the performance of natural language processing methods applied to unstructured electronic medical record (EMR) data remains to be fully evaluated. This study aims to assess the performance of a prompt engineering method for extracting individual risk factors of precocious puberty from EMRs. METHODS: Based on the capacity and role-insight-statement-personality-experiment (CRISPE) prompt framework, both simple and optimized prompts were designed to guide the large language model GLM-4-9B in extracting 10 types of risk factors for precocious puberty from 653 EMRs. Accuracy, precision, recall, and F1-score were used as evaluation metrics for the information extraction task. RESULTS: Under simple and optimized prompt conditions, the overall accuracy, precision, recall, and F1-score of the model were 84.18%, 98.09%, 81.99%, and 89.32% versus 97.15%, 98.31%, 98.16%, and 98.23%, respectively. The optimized prompts achieved more stable performance across age (<9 years vs ≥9 years) and visit-time (<2023 vs ≥2023) subgroups compared with simple prompts. The accuracy range for extracting each risk factor was 60.03%-97.24%, while with optimized prompts, the range improved to 92.19%-99.85%. The largest performance improvement occurred for "beverage intake" (60.03% vs 92.19%), and the smallest for "maternal age of menarche" (97.24% vs 99.23%). In comparing distributions among simple prompts, optimized prompts, and ground truth, statistically significant differences were observed for snack intake, beverage intake, soy milk intake, honey intake, supplement use, tonic use, sleep quality, and sleeping with the light on (all P<0.001), while exercise (P=0.966) and maternal menarche age (P=0.952) showed no significant differences. CONCLUSIONS Compared with simple prompts, optimized prompts substantially improved the extraction performance of individual risk factors for precocious puberty from EMRs, underscoring the critical role of prompt engineering in enhancing large language model performance.
Humans ; Puberty, Precocious/epidemiology* ; Risk Factors ; Electronic Health Records ; Female ; Child ; Natural Language Processing

OBJECTIVES: To evaluate the performance of a multi-constraint representation learning classification model for identifying ovarian cancer with missing laboratory indicators. METHODS: Tabular data with missing laboratory indicators were collected from 393 patients with ovarian cancer and 1951 control patients. The missing ovarian cancer laboratory indicator features were projected to the latent space to obtain a classification model using the representational learning classification model based on discriminative learning and mutual information coupled with feature projection significance score consistency and missing location estimation. The proposed constraint term was ablated experimentally to assess the feasibility and validity of the constraint term by accuracy, area under the ROC curve (AUC), sensitivity, and specificity. Cross-validation methods and accuracy, AUC, sensitivity and specificity were also used to evaluate the discriminative performance of this classification model in comparison with other interpolation methods for processing of the missing data. RESULTS: The results of the ablation experiments showed good compatibility among the constraints, and each constraint had good robustness. The cross-validation experiment showed that for identification of ovarian cancer with missing laboratory indicators, the AUC, accuracy, sensitivity and specificity of the proposed multi-constraints representation-based learning classification model was 0.915, 0.888, 0.774, and 0.910, respectively, and its AUC and sensitivity were superior to those of other interpolation methods. CONCLUSIONS The proposed model has excellent discriminatory ability with better performance than other missing data interpolation methods for identification of ovarian cancer with missing laboratory indicators.
Female ; Humans ; Ovarian Neoplasms/diagnosis* ; Machine Learning ; ROC Curve