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*

Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. CYP19A1 gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.
46, XX Disorders of Sex Development/genetics* ; Adult ; Aromatase/metabolism* ; Female ; Gynecomastia/genetics* ; Humans ; Infertility, Male ; Male ; Metabolism, Inborn Errors ; Mutation ; Pregnancy

ObjectiveTo identify the etiology of chromosome abnormality in an infertile man and analyze the correlation between the genotype and phenotype.

METHODSWe analyzed the karyotype of an infertile male using the routine G-banding technique and then the chromosome abnormality of the patient by Illumina Human CytoSNP-12 Beadchip array.

RESULTSNegative results were found in the examination of the sex-determining region Y (SRY) gene and the STR locus in the AZF zone of the patient. The karyotype of the patient was 46, XX. SNP array showed a 1.05 Mb 19p12 duplication and a 0.93 Mb Xq27.1 duplication.

CONCLUSIONSThe patient was confirmed as a case of 46,XX male syndrome. The increased copies of the FGF13 gene may be the major causes of abnormal sex determination and testis development.

46, XX Testicular Disorders of Sex Development ; diagnosis ; genetics ; Chromosome Aberrations ; Chromosome Banding ; Genetic Testing ; Humans ; Infertility, Male ; genetics ; Karyotype ; Karyotyping ; Male ; Phenotype ; Sex-Determining Region Y Protein ; genetics

BACKGROUND: The ideal vaginoplasty must be successful functionally as well as have a natural appearance, and also must retain its functionality and appearance over the long term. Conventional vaginoplasty techniques have functional limitations and are associated with recurrent complications, but rectosigmoid vaginoplasty is known to have a high satisfaction rate due to its functional similarity with the vagina. We conducted the present study to assess the usability of rectosigmoid vaginoplasty over the course of long-term follow-up. METHODS: From March 1992 to February 2014, 84 patients were treated with rectosigmoid vaginoplasty; 44 had gender identity disorder, 29 had vaginal agenesis, 8 had female pseudohermaphroditism, and 3 had gynecologic malignancies after radical pelvic surgery. This retrospective study was based on a review of the patients' records, clinical examinations, complications, and questionnaires about appearance, function, and sexual intercourse. RESULTS: All patients who underwent rectosigmoid vaginoplasty were discharged within 2 weeks without surgical flap loss. The early complications were partial flap necrosis, difficulty in defecation, mucous hypersecretion, and postoperative ileus. The late complications were vaginal introitus contracture, vaginal prolapse, and difficulty in urination. The mean length and diameter of the neovagina 3.4 years after rectosigmoid vaginoplasty were 13.2 cm and 3.8 cm, respectively. On questionnaires about satisfaction, 70% of patients reported excellent satisfaction, 11% good, 12% fair, and 7% poor. CONCLUSIONS: Rectosigmoid vaginoplasty is useful, safe, and well-accepted operative method with good functional and cosmetic results, such as natural lubrication and adequate vaginal length and width obtained without requiring the use of a dilator.
46, XX Disorders of Sex Development ; Coitus ; Contracture ; Defecation ; Follow-Up Studies ; Gender Identity ; Humans ; Ileus ; Lubrication ; Methods ; Necrosis ; Retrospective Studies ; Surgical Flaps ; Urination ; Uterine Prolapse ; Vagina

OBJECTIVETo introduce and evaluate the technical feasibility and anatomical and functional outcomes of one-stage vaginoplasty with autologous buccal micromucosa combined with acellular allogenic dermis.

METHODSWe retrospectively reviewed our experiences with 17 patients with Mayer- Rokitansky-Kuster-Hauser syndrome treated with primary surgery from September 2010 to April 2013. All patients underwent vaginoplasty with autologous buccal micromucosa combined with acellular allogenic dermis. We describe the details of this technique, observe the time of epithelization and evaluate the long- term anatomical, functional, and sexual outcomes.

RESULTSThe time of epithelization was 13 d (range: 12-15 d). At a mean follow-up of 15 months (range: 12-24 months), the mean postoperative dependence on the vaginal stent was 11.7 ± 1.64 months (range: 9-15 months), the mean depth of the neovagina was (9.0 ± 0.94) cm (range: 7-11 cm), the mean circumference was (12.3 ± 1.36) cm (range: 10.0-14.5 cm) and the mean volume was (105 ± 10) ml (range 85-120 ml). The mean female sexual function index score of the 12 sexually active patients was 29.5 ± 2.6. No spouse reported discomfort during intercourse.

CONCLUSIONSVaginoplasty with autologous buccal micromucosa combined with acellular allogenic dermis is an effective and feasible approach for patients with Mayer-Rokitansky-Kuster-Hauser syndrome. The procedure has satisfactory long-term anatomical and functional results. The use of the acellular allogenic dermis is limited by the high price and the potential infection.

46, XX Disorders of Sex Development ; surgery ; Acellular Dermis ; Coitus ; Congenital Abnormalities ; surgery ; Feasibility Studies ; Female ; Humans ; Mouth Mucosa ; transplantation ; Mullerian Ducts ; abnormalities ; surgery ; Postoperative Period ; Reconstructive Surgical Procedures ; methods ; Retrospective Studies ; Vagina ; abnormalities ; surgery

The 46,XX testicular disorder of sex development (DSD), also known as 46,XX male syndrome, is a rare form of DSD and clinical phenotype shows complete sex reversal from female to male. The sex-determining region Y (SRY) gene can be identified in most 46,XX testicular DSD patients; however, approximately 20% of patients with 46,XX testicular DSD are SRY-negative. The SRY-box 9 (SOX9) gene has several important functions during testis development and differentiation in males, and overexpression of SOX9 leads to the male development of 46,XX gonads in the absence of SRY. In addition, SOX9 duplication has been found to be a rare cause of 46,XX testicular DSD in humans. Here, we report a 4.2-year-old SRY-negative 46,XX boy with complete sex reversal caused by SOX9 duplication for the first time in Korea. He showed normal external and internal male genitalia except for small testes. Fluorescence in situ hybridization and polymerase chain reaction (PCR) analyses failed to detect the presence of SRY, and SOX9 intragenic mutation was not identified by direct sequencing analysis. Therefore, we performed real-time PCR analyses with specific primer pairs, and duplication of the SOX9 gene was revealed. Although SRY-negative 46,XX testicular DSD is a rare condition, an effort to make an accurate diagnosis is important for the provision of proper genetic counseling and for guiding patients in their long-term management.
46, XX Testicular Disorders of Sex Development ; Diagnosis ; Disorders of Sex Development ; Female ; Fluorescence ; Genes, sry ; Genetic Counseling ; Genitalia, Male ; Gonads ; Humans ; In Situ Hybridization ; Korea ; Male ; Phenotype ; Polymerase Chain Reaction ; Real-Time Polymerase Chain Reaction ; Sexual Development* ; Testis

Amenorrhea is one of the most taxing cases in the field of gynecologic endocrinology. Turner's and Mayer-Rokitansky-Kuster-Hauser Syndromes are the two most common separate causes of primary amenorrhea worldwide. Presented here is a rare case of an 18-year old female with Turner's Syndrome and concomitant Mayer-Rokitansky-Kuster-Hauser Syndrome. The worldwide incidence of both syndromes occurring simultaneously in an individual is 1 in 15,000,000 livebirths. The index patient presents with primary amenorrhea and chromosomal analysis revealed 45,X. Transrectal ultrasound noted absence of both the uterus and the ovaries. Early detection of this rare case is important for the initiation of hormone replacement therapy. Adoption is the only option to have a child since Assisted Reproductive Technique (ART) by means of in-vitro fertilization is not applicable for patients with both of these syndromes. Parents and children must be educated regarding the limitations of current knowledge about the management of both Turner's and Mayer-Rokitansky-Kuster-Hauser Syndromes and must be given realistic expectations with respect to sexual functionand social acceptance.

Human ; Female ; Adolescent ; Ovary ; Amenorrhea ; Mullerian Aplasia ; Turner Syndrome ; Uterus ; 46, Xx Disorders Of Sex Development ; Hormone Replacement Therapy ; Fertilization In Vitro ; Reproductive Techniques, Assisted ; Parents

OBJECTIVETo characterize molecular and cytogenetic abnormalities in six 46, XX males, and to investigate the clinical manifestations and underlying mechanisms in such patients.

METHODSClinical data of six XX male patients were collected. Karyotyping, multiple polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) were utilized to detect and locate the sex determining region (SRY) gene.

RESULTSPCR and FISH showed that all patients were SRY-positive XX males. All patients have their SRY gene located at the tip of derivative X chromosomes, which have resulted from translocation between short arms of X and Y chromosomes. High resolution karyotyping at 550-750 band level has revealed that the translocation breakpoints were at Xp22.33 and Yp11.2 in three patients. In the remaining patients, the breakpoints were either at Xp22.32 and Yp11.31 or Xp22.31 and Yp11.2. The breakpoints at Xp22.32, Xp22.31 and Yp11.31 were rarely reported. Genotype-phenotype correlation analysis indicated that the clinical manifestations were age-specific. Four adult patients have come to clinical attention due to infertility, with typical features including azoospermia and testis dysgenesis, whereas poorly developed secondary sexual characteristics and short stature were main complaints of adolescence patients, and short stature was the sole symptom in a child patient.

CONCLUSIONCombined karyotyping, PCR and FISH are important for the analysis of XX males. Particularly, high resolution karyotyping is valuable for the refinement of chromosome breakpoints and detailed analysis of genotype-phenotype correlation.

46, XX Disorders of Sex Development ; genetics ; Adolescent ; Adult ; Child, Preschool ; Chromosomes, Human, X ; Chromosomes, Human, Y ; Genetic Association Studies ; methods ; Humans ; Karyotyping ; methods ; Male ; Sex Chromosome Aberrations ; Translocation, Genetic ; Young Adult

Sex determination and differentiation require the balanced and sequential activation of transcription factors, signaling molecules, hormones and their receptors. Disorders of sex development (DSD) have heterogeneous groups of etiologies caused by mutations or deletions of genes involved in sex development. The DSD is categorized into 46, XX DSD, 46,XY DSD, sex chromosome DSD, ovotesticular DSD, and 46,XX testicular DSD. Precise diagnosis is essential for sex assignment, surgical correction of external genitalia, prevention of gonadal tumors, psychiatric support, and genetic counseling. The increased genetic knowledge in the field has opened up new diagnostic possibilities. The first line genetic testing for DSD is the assessment of the karyotype and the SRY gene. The follow-up genetic tests are performed for confirmatory diagnosis; the evaluation of copy number variants by array comparative genomic hybridization (CGH), direct sequencing of a specific gene, and functional analyses of mutations. A lot of genes can be analyzed by molecular laboratories and the number of available genes is growing. DNA analyses should be done under clinical assessment on the basis of family history, prenatal history, physical findings focused on external genitalia, endocrinologic data, and radiologic findings. Genetic counseling is essential to help patients and their families understand the disease status and the risk for recurrence in future pregnancies, and participate in the process of sex assignment. Children with DSD should be managed with a multidisciplinary team, including pediatric endocrinology, molecular genetics, cytogenetics, neonatology, urology, and psychiatry.
46, XX Disorders of Sex Development ; 46, XY Disorders of Sex Development ; Child ; Coat Protein Complex I ; Comparative Genomic Hybridization ; Cytogenetics ; Diagnosis, Differential ; Disorders of Sex Development ; DNA ; Endocrinology ; Follow-Up Studies ; Genes, sry ; Genetic Counseling ; Genetic Testing ; Genitalia ; Gonads ; Humans ; Karyotype ; Molecular Biology ; Neonatology ; Ovotesticular Disorders of Sex Development ; Pregnancy ; Recurrence ; Sex Chromosome Disorders of Sex Development ; Sexual Development ; Transcription Factors ; Urology

Sex determination and differentiation require the balanced and sequential activation of transcription factors, signaling molecules, hormones and their receptors. Disorders of sex development (DSD) have heterogeneous groups of etiologies caused by mutations or deletions of genes involved in sex development. The DSD is categorized into 46, XX DSD, 46,XY DSD, sex chromosome DSD, ovotesticular DSD, and 46,XX testicular DSD. Precise diagnosis is essential for sex assignment, surgical correction of external genitalia, prevention of gonadal tumors, psychiatric support, and genetic counseling. The increased genetic knowledge in the field has opened up new diagnostic possibilities. The first line genetic testing for DSD is the assessment of the karyotype and the SRY gene. The follow-up genetic tests are performed for confirmatory diagnosis; the evaluation of copy number variants by array comparative genomic hybridization (CGH), direct sequencing of a specific gene, and functional analyses of mutations. A lot of genes can be analyzed by molecular laboratories and the number of available genes is growing. DNA analyses should be done under clinical assessment on the basis of family history, prenatal history, physical findings focused on external genitalia, endocrinologic data, and radiologic findings. Genetic counseling is essential to help patients and their families understand the disease status and the risk for recurrence in future pregnancies, and participate in the process of sex assignment. Children with DSD should be managed with a multidisciplinary team, including pediatric endocrinology, molecular genetics, cytogenetics, neonatology, urology, and psychiatry.
46, XX Disorders of Sex Development ; 46, XY Disorders of Sex Development ; Child ; Coat Protein Complex I ; Comparative Genomic Hybridization ; Cytogenetics ; Diagnosis, Differential ; Disorders of Sex Development ; DNA ; Endocrinology ; Follow-Up Studies ; Genes, sry ; Genetic Counseling ; Genetic Testing ; Genitalia ; Gonads ; Humans ; Karyotype ; Molecular Biology ; Neonatology ; Ovotesticular Disorders of Sex Development ; Pregnancy ; Recurrence ; Sex Chromosome Disorders of Sex Development ; Sexual Development ; Transcription Factors ; Urology