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: 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

Y chromosome microdeletions are an important cause of male infertility. At present, research on the Y chromosome is mainly focused on analyzing the loss of large segments of the azoospermia factor a/b/c (AZFa/b/c) gene, and few studies have reported the impact of unit point deletion in the AZF band on fertility. This study analyzed the effect of sperm quality after sY1192 loss in 116 patients. The sY1192-independent deletion accounted for 41.4% (48/116). Eight patterns were found in the deletions associated with sY1192. The rate of sperm detection was similar in the semen of patients with the independent sY1192 deletion and the combined sY1192 deletions (52.1% vs 50.0%). The patients with only sY1192 gene loss had a higher probability of sperm detection than the patients whose sY1192 gene locus existed, but other gene loci were lost (52.1% vs 32.0%). The hormone levels were similar in patients with sY1192 deletion alone and in those with sY1192 deletion and other types of microdeletions in the presence of the sY1192 locus. After multiple intracytoplasmic sperm injection (ICSI) attempts, the pregnancy rate of spouses of men with sY1192-independent deletions was similar to that of other types of microdeletions, but the fertilization and cleavage rates were higher. We observed that eight deletion patterns were observed for sY1192 microdeletions of AZFb/c, dominated by the independent deletion of sY1192. After ICSI, the fertilization rate and cleavage rate of the sY1192-independent microdeletion were higher than those of other Y chromosome microdeletion types, but there was no significant difference in pregnancy outcomes.
Humans ; Female ; Pregnancy ; Male ; Chromosomes, Human, Y/genetics* ; Adult ; Chromosome Deletion ; Pregnancy Outcome/genetics* ; Infertility, Male/genetics* ; Spermatozoa/physiology* ; Semen Analysis ; Sex Chromosome Disorders of Sex Development/genetics* ; Sperm Injections, Intracytoplasmic ; Azoospermia/genetics* ; Sex Chromosome Aberrations

BACKGROUND

Turner syndrome (TS) is the most common sex chromosomal abnormality in females resulting from a missing X chromosomal material. This in turn results in a range of clinical manifestations. This study aimed to provide the data on the cases of TS confirmed via chromosomal analysis in a cytogenetics laboratory in the Philippines as well as the role of genetic counseling.

A review of the karyotyping results of the Cytogenetics Laboratory, Institute of Human Genetics, National Institutes of Health, University of the Philippine Manila from 1991 to 2020.

TS accounted for 2.64% of all the samples received from 1991 to 2020. For 30 years, the most common karyotype in TS was the classical TS or the standard monosomy 45, X noted in 195 patients or 37.69% of all patients diagnosed with TS. Mosaicism with a normal female karyotype was noted in 50 patients (9.62%). For the TS variants, the most common is isochromosome Xq seen in 125 patients (24.04%). This is followed by TS with marker chromosome in 55 patients (10.58%) and ring X chromosome in 23 patients (4.42%). Deletion Xp and deletion Xq were noted in 22 patients (4.23%) and 20 patients (3.85%), respectively.

From this study, it can be noted that chromosomal analysis or standard karyotyping is a vital and useful diagnostic tool in TS. The information obtained from it may be useful in clinical decision-making of families and healthcare providers. Its importance in providing adequate genetic counseling cannot be overemphasized.

OBJECTIVE: To analyze the results of prenatal diagnosis for fetuses with a high risk for sex chromosome aneuploidies (SCAs) indicated by non-invasive prenatal testing (NIPT), and to assess the influence of maternal chromosomal factors on the results of NIPT. METHODS: A retrospective analysis was conducted on the clinical data of 454 pregnant women with a high risk for SCAs indicated by NIPT undergoing invasive prenatal diagnosis at the Medical Genetics Center of Northwest Women's and Children's Hospital from January 2022 to September 2024. The data has included prenatal diagnosis indications, results, pregnancy outcomes, and the chromosomal results of pregnant women. RESULTS: Among the 454 women (including 10 with twin pregnancy) with a high risk for SCAs indicated by NIPT, 149 (including 4 twin cases) were diagnosed with SCAs through invasive prenatal diagnosis. These had included 47,XXX (37 cases), 47,XXY (56 cases), 47,XYY (29 cases), 45,X (1 case), 48,XXYY (1 case), mosaicism (20 cases), sex chromosome structural abnormalities (6 cases), and small-scale pathogenic copy number variations (3 cases). 383 pregnant women (including 7 with twin pregnancy) had accepted chromosomal karyotyping analysis. In total 49 cases of SCAs abnormalities were detected. Among them, 41 cases were pregnant women with SCAs but normal fetal chromosomes, which yielded a false positive rate for NIPT caused by maternal factors by 10.7%. In addition, 8 cases (including 1 twin case) had SCAs abnormalities in both the pregnant woman and the fetus. Among the 383 pregnant women, 129 cases (including 3 twin cases) of fetal SCAs were diagnosed, which yielded an overall positive predictive value (PPV) of NIPT for SCAs by 33.7% (129/383). With the 41 false positive cases caused by maternal SCAs abnormalities excluded, the PPV of NIPT for SCAs will be increased to 37.7% (129/342). Among the 454 pregnant women, twin pregnancies have accounted for 2.2% (10/454). Among the confirmed cases of SCAs abnormalities, twin cases accounted for 2.7% (4/149). Among the 383 pregnant women undergoing chromosomal karyotyping, twin cases accounted for 1.8% (7/383). Among the detected cases of chromosomal abnormalities, twin cases accounted for 2.0% (1/49). By calculation, the proportion of singleton pregnant women with a high risk for SCAs indicated by NIPT was approximately 32.1%, and the proportion of twin pregnant women was approximately 38.6%, indicating that twin pregnancies could increase the positive rate of NIPT. CONCLUSION NIPT can improve the screening efficiency for SCAs, but its PPV is limited. Therefore, pregnant women with a high risk for SCAs indicated by NIPT need to undergo invasive prenatal diagnosis for a definite diagnosis, and twin pregnancies can increase the positive rate of NIPT. The study confirmed that chromosomal abnormalities in pregnant women can significantly affect the accuracy of NIPT in detecting fetal SCAs. Therefore, when NIPT indicates SCAs abnormalities, it is recommended to simultaneously conduct chromosomal testing on the pregnant women. The combined application of chromosomal karyotyping analysis, fluorescence in situ hybridization, and copy number variation detection techniques can significantly improve the diagnostic accuracy for SCAs, especially for the detection of mosaicisms.
Humans ; Female ; Pregnancy ; Sex Chromosome Aberrations ; Adult ; Retrospective Studies ; False Positive Reactions ; Prenatal Diagnosis/methods* ; Noninvasive Prenatal Testing/methods* ; Aneuploidy ; Male ; Sex Chromosome Disorders/genetics*

OBJECTIVE: To explore the clinical characteristics and genetic etiology of a child with Oral-facial-digital syndrome type Ⅰ(OFDSⅠ). METHODS: A child with OFDSⅠ who received treatment at the Women and Children's Hospital Affiliated to Ningbo University in March 2023 was selected as the study subject. A retrospective research method was used to collect the clinical data of the child. Peripheral venous blood samples were collected from the child, her parents and sister. Genomic DNA was extracted, and whole exome sequencing (WES) was performed. Candidate variants were validated using Sanger sequencing for familial verification. According to the Standards and Guidelines for the Interpretation of Sequence Variants developed by the American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as the "ACMG Guidelines"), the pathogenicity of the candidate variant was rated. This study was approved by the Medical Ethics Committee of Ningbo University Affiliated Women and Children's Hospital (Ethic No.: EC 2024-063). RESULTS: The child was a prematurely born female with deformities of the oral cavity, fingers, and toes. She was admitted to the Neonatal Department of the Hospital where she was born due to shortness of breath 15 minutes after birth. The WES results indicated that the child has harbored a heterozygous c.710dup (p.Y238Vfs*2) frameshifting variant of the OFD1 gene. Sanger sequencing confirmed that neither of the child's parents nor her sister had carried the same variant. According to the ACMG guidelines, the variant was rated as pathogenic (PVS1+PS4_Moderate+PM2-Supporting+PM6_Supporting+PP4). CONCLUSION Children with OFDSⅠ have clinical features such as oral, finger, and toe deformities. The c.710dup (p.Y238Vfs*2) variant of the OFD1 gene probably underlay the OFDSⅠ in this child. Above result has enriched the mutational spectrum of the OFD1 gene.
Humans ; Female ; Orofaciodigital Syndromes/genetics* ; Exome Sequencing ; Retrospective Studies ; Mutation ; Child ; Proteins

OBJECTIVE: To explore the mechanism for the occurrence and phenotypic characteristics of Turner syndrome based on a prenatally diagnosed case of a mosaic karyotype containing double pseudo-isodicentric X chromosome and a review of relevant literature. METHODS: A fetus diagnosed with increased risk for trisomy 21 at the Provincial Hospital Affiliated to Shandong First Medical University in August 2023 was selected as the study subject. Clinical data of the fetus was collected. Following amniocentesis, chromosomal G-banding karyotype analysis and chromosomal microarray analysis (CMA) were carried out. This study has been approved by the Ethics Committee of the Hospital (Ethics No.: SWYX No. 2022-287). RESULTS: The early-trimester screening suggested a high risk of trisomy 21 (1/19), with free β-hCG of 116 ng/mL (MoM value 2.35), PAPP-A of 0.394 ng/mL (MoM value 0.12), and NT value of 1.3 mm, though no abnormality was found in the fetus at 19 weeks gestation. The karyotype of amniocyte was determined as 46,X,psu idic(X)(p11.21)[55]/45,X[27]/47,X,psu idic(X)(p11.21)×2[5]/46,XX[13]. CMA has yielded a result of arr[GRCh37] Xp22.33p11.21(168552_55585678)×1[0.67],Xp11.21q28(55703291_155233098)×3[0.5]. CONCLUSION Karyotypes of Turner syndrome are complex and diverse, and a rare 46,X,psu idic(X)(p11.21)[55]/45,X[27]/47,X,psu idic(X)(p11.21)×2[5]/46,XX[13] mosaic karyotype with double pseudo-isodicentric X chromosome has been identified. Literature review suggested that this karyotype may lead to phenotypic diversification and a risk of reduced sensitivity to hormone therapy.
Humans ; Turner Syndrome/diagnosis* ; Female ; Pregnancy ; Chromosomes, Human, X/genetics* ; Mosaicism ; Prenatal Diagnosis ; Karyotyping ; Adult ; Karyotype ; Amniocentesis

OBJECTIVE: To investigate the clinical phenotype and genetic etiology of a patient with tall stature and primary amenorrhea presenting with 47,XYY Disorder of sex development (DSD). METHODS: A female patient presenting with "tall stature and primary amenorrhea" at Nanjing Drum Tower Hospital in July 2024 was selected as the study subject. A retrospective study design was employed to collect the patient's clinical data. Peripheral venous blood sample was collected. Following the extraction of genomic DNA, genetic testing was performed including chromosomal karyotyping analysis, copy number variation sequencing (CNV-seq), multiplex PCR for the AZF regions and sex-determining genes Y (SRY), and whole-exome sequencing (WES). Candidate variants were validated by Sanger sequencing and classified for pathogenicity based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Nanjing Drum Tower Hospital (Ethics No.: 2022-451-01). RESULTS: The patient had a height of 188 cm and a body weight of 50 kg, in addition with infantile uterus, absent ovaries, and primary amenorrhea. G-banded karyotyping analysis of peripheral blood sample revealed 47,XYY. CNV-seq indicated Seq[GRCh37]Yp11.32q12×2. No deletion was detected in the AZF regions of Y chromosome, and SRY was positive. WES identified a heterozygous c.86C>A (p.Thr29Lys) variant of the NR5A1 gene, leading to substitution of threonine with lysine at position 29 of the encoded protein. Sanger sequencing confirmed the presence of the variant. According to the ACMG guidelines, this variant was classified as variant of uncertain significance (VUS) with supporting evidence (PS3_Moderate+PM5+PP3+PM2_Supporting+PS4_Supporting). Reviewing the nearly 60 years of previously reported cases, all 7 documented 47,XYY DSD patients were assigned a female social gender and presented with abnormal gonadal and external genitalia development. Among them, 5 cases underwent SRY testing, all of which were positive. Only 1 case underwent whole-exome sequencing (WES), but no pathogenic or likely pathogenic variants were identified. CONCLUSION This DSD patient presented with the clinical features of tall stature and primary amenorrhea. The NR5A1 gene variant c.86C>A (p.Thr29Lys) probably underlay the Disorder of sex development in this patient. Above finding has enriched the spectrum of pathogenic variants of the NR5A1 gene.
Humans ; Female ; Steroidogenic Factor 1/genetics* ; DNA Copy Number Variations/genetics* ; XYY Karyotype/genetics* ; Karyotyping ; Retrospective Studies ; Phenotype ; Sex Chromosome Disorders of Sex Development/genetics* ; Sex Chromosome Disorders

Disorders of sex development (DSD) are characterized by atypical development of chromosomal, gonadal, or phenotypic sex. 45X,46XY mosaicism is a type of sex chromosome DSD which presents with a wide heterogeneity of manifestations. We report the case of a 13-year-old phenotypically female who presented with clitoromegaly at puberty. Testosterone level was elevated on serology. Out of the 50 cells examined, 43 cells had Monosomy X while 7 cells had a normal male karyotype. She was managed by a multidisciplinary team. Due to the presence of Y chromosome, the solid nodular structure seen on the right gonad in magnetic resonance imaging and the pain caused by the phallus, Laparoscopic bilateral gonadectomy, salpingectomy and clitoroplasty were done after a shared decision making. Histopathology revealed Gonadoblastoma and Germ cell neoplasia-in-situ of the right gonad justifying timely removal. She was then maintained on estrogen for induction of secondary sexual characteristics.