Molecular diagnosis and clinical features of 206 patients with 46, XY disorders of sexual development / 中华内分泌代谢杂志

Objective:To investigate methods of molecular diagnosis and clinical features of 46, XY disorders of sexual development(DSD).Methods:A total of 206 cases of 46, XY DSD patients, who visited the Shanghai Ninth People′s Hospital, Shanghai Jiaotong University School of Medicine, from July 2009 to June 2021, underwent AA chip based on multiplex PCR and probe-capture-targeted next-generation sequencing. Clinical features of patients with genetic diagnosis were analyzed.Results:Among 206 patients, the diagnostic rate of patients with micropenis, hypospadias and cryptorchidism was the highest, up to 75.28%. Almost all patients had different degrees of undermasculinized external genitalia. The most frequent phenotype was micropenis with hypospadias(87.25%). Only one gene variant was detected in 81 patients(39.32%), multiple genetic variants were detected in 104 patients(50.49%), and no gene variant was identified in 21 patients(10.19%). 107 patients had definite genetic diagnosis, with a diagnostic rate of 51.94% by adding the pathogenic and likely pathogenic ratios following the American College of Medical Genetics and Genomics(ACMG) guidelines, including 40 patients of steroid 5α-reductase type 2(SRD5A2) variants(37.38%), 36 patients of androgen receptor(AR) variants(33.64%), 13 patients of steroidogenic factor 1(NR5A1) variants(16.82%), 6 patients of 17β-hydroxysteroid dehydrogenases 3(HSD17B3) variants(5.61%), 2 patients of 17α-hydroxylase/17, 20-lyase enzyme(CYP17A1), Wilms′ tumor 1(WT1) and GATA binding protein 4(GATA4) variants(1.87%), and one patient of luteinizing hormone receptor(LHCGR) variant(0.93%). Gynecomastia was found in 29 of 81 postpubertal patients, of which 25(86.21%) had AR variants.Conclusions:46, XY DSD presents complex clinical manifestations and molecular etiologies. Targeted nextgeneration sequencing has the advantages of high throughput, high efficiency and low cost, which has a high value especially in etiological diagnosis of 46, XY DSD with large genetic heterogeneity.

A case of 46, XY disorders of sexual development caused by the heterozygous mutation of DHX37 gene / 中华实用儿科临床杂志

A clinical data, laboratory examination, genetic test results, diagnose and treatment of a patient with 46, XY disorders of sexual development (46, XY DSD) from a family of the Asp-Glu-Ala-His-box helicase 37 ( DHX37) gene mutation were retrospectively analyzed.The child was admitted in the Department of Genetics, Endocrinology and Metabolism, Jiangxi Children′s Hospital in June 2021.The DHX37 gene mutation was confirmed as a new pathogenic gene leading to 46, XY DSD in 2019.It is featured as autosomal dominant inheritance with incomplete externality.Its clinical manifestations are abnormal external genitalia, testicular degeneration insufficiency syndrome and gonadal insufficiency.This patient is the first 46, XY DSD case caused by the heterozygous variation of DHX37 gene c. 2020C>T (p.R674W) in China.This study can provide new ideas for diagnosis and treatment of 46, XY DSD children and reliable genetic evidence for family reproduction.

A case of 46, XY disorders of sexual development caused by the heterozygous mutation of DHX37 gene / 中华实用儿科临床杂志

A clinical data, laboratory examination, genetic test results, diagnose and treatment of a patient with 46, XY disorders of sexual development (46, XY DSD) from a family of the Asp-Glu-Ala-His-box helicase 37 ( DHX37) gene mutation were retrospectively analyzed.The child was admitted in the Department of Genetics, Endocrinology and Metabolism, Jiangxi Children′s Hospital in June 2021.The DHX37 gene mutation was confirmed as a new pathogenic gene leading to 46, XY DSD in 2019.It is featured as autosomal dominant inheritance with incomplete externality.Its clinical manifestations are abnormal external genitalia, testicular degeneration insufficiency syndrome and gonadal insufficiency.This patient is the first 46, XY DSD case caused by the heterozygous variation of DHX37 gene c. 2020C>T (p.R674W) in China.This study can provide new ideas for diagnosis and treatment of 46, XY DSD children and reliable genetic evidence for family reproduction.

Application of next-generation sequencing in the diagnosis of sexual development disorders / 中华内分泌代谢杂志

Disorders of sexual development (DSD) are rare conditions with abnormal sex determination and gender differentiation. There exists divergence of changes in chromosomal mutation, gonadal or genitalia abnormalities in DSD patients. The etiology of DSD is intricate, and the inheritance is regarded as classically Mendelian in most of the cases. Approximately, 20％ of patients could receive an accurate genetic diagnosis by Sanger sequencing. Nowadays, with the development of Next-generation sequencing technology, the potential disease-causing genes of DSD are emerging. In additional, oligogenic forms of DSD were increasing identified, indicating the complexity of the pathogenesis of the disorders. The emergence of Next-generation sequencing technology is helpful to early diagnosis and gender assignment, also contributing to long-term treatment strategy selection by Multi-discipline Team ( MDT). Meanwhile, the oligogenic transmission will take great challenges to making genetic counseling.

Two Korean girls with complete androgen insensitivity syndrome diagnosed in infancy

Androgen insensitivity syndrome (AIS) is a rare genetic disease caused by various abnormalities in the androgen receptor (AR). The AR is an essential steroid hormone receptor that plays a critical role in male sexual differentiation and development and preservation of the male phenotype. Mutations in the AR gene on the X chromosome cause malfunction of the AR so that a 46,XY karyotype male has some physical characteristics of a woman or a full female phenotype. Depending on the phenotype, AIS can be classified as complete, partial or mild. Here, we report 2 cases of complete AIS in young children who showed complete sex reversal from male to female as a result of AR mutations. They had palpable inguinal masses and normal female external genitalia, a blind-end vagina and absent Müllerian duct derivatives. They were both 46,XY karyotype and AR gene analysis demonstrated pathologic mutations in both. Because AIS is inherited in an X-linked recessive manner, we performed genetic analysis of the female family members of each patient and found the same mutation in the mothers of both patients and in the female sibling of case 2. Gonadectomy was performed in both patients to avoid the risk of malignancy in the undescended testicles, and estrogen replacement therapy is planned for their adolescence. Individuals with complete AIS are usually raised as females and need appropriate care.

Trastornos de diferenciación sexual

Objetivo: Presentar la clínica, citogenética y hallazgos histopatológicos en pacientes adultas, que consultaron a la Unidad de Endocrinología Ginecológica del Hospital Universitario de Caracas con trastornos de la diferenciación sexual. Se reportan cuatro casos clínicos: dos casos con trastorno de la diferenciación sexual 46, XY por alteración en la acción de los andrógenos anteriormente denominado insensibilidad androgénica parcial, una paciente con trastorno de la diferenciación sexual 46, XX y otra con trastorno de la diferenciación sexual 46, XY ovotesticular sin gonadoblastoma por síndrome de Frasier. Es importante realizar un diagnóstico temprano para su tratamiento precoz, por la trascendencia que la definición del sexo tiene para el futuro del individuo. Conclusiones: A pesar de los avances alcanzados a lo largo de los últimos 20 años, algunos casos quedan aún sin diagnóstico etiológico definido, sea por falta de estudio molecular o genes aún no conocidos. Su abordaje diagnóstico y terapéutico es complejo, requiere de un equipo multidiscplinario integrado por ginecólogos, endocrinólogos, psiquiatras, urólogos, cirujanos plásticos.

The aim of this paper is to present the clinical, cytogenetic and histopathological findings in adult patients who consulted the Gynecological Endocrinology Unit of the University Hospital of Caracas with Disorders of sexual development. Four clinical cases reported: Two with Disorder of sexual development 46, XY due defect in androgen action previously called partial androgen insensitivity, one patient with disorders of sexual development 46, XX and another with disorder of sexual development 46, XY ovotesticular without gonadoblastoma by Frasier syndrome. It is important an early diagnosis and treatment to define the sex for the individual’s future. Conclusion: Despite the progress made over the last 20 years, some cases are still without etiologic diagnosis, either through lack of molecular study or yet unknown genes. Its diagnostic and therapeutic approach is complex, requiring a team of gynecologists, endocrinologists, psychiatrists, urologists, plastic surgeons.

Annual advance of the research on gonadal disorders from August 2014 to July 2015 / 中华内分泌代谢杂志

From Aug 2014 to July 2015, researches in the field of gonadal diseases have achieved rapid advances with image technology, the technology of biochemistry, and molecular biotechnology progressing. Considerable literatures concerning the pathogenesis, gene and clinical diagnosis, and treatment of gonadal diseases have been published. We reviewed and analyzed some more instructive literatures for clinical practice, proposed some suggestions, and the work plans for the clinicians.

CLITOROPLASTY FOR GENITAL VIRILIZATION IN GIRLS WITH CONGENITAL ADRENAL HYPERPLASIA / 中国修复重建外科杂志

OBJECTIVE: To investigate the effectiveness of clitoroplasty of reserving the clitoris dorsal neurovascular bundle and the ventral complete urethral plate for genital virilization in girls with congenital adrenal hyperplasia (CAH). METHODS: Between June 2000 and October 2015, 27 girls with genital virilization were treated with clitoroplasty of reserving the clitoris dorsal neurovascular bundle and the ventral complete urethral plate. The chromosomal karyotype was 46, XX in all patients, whose age ranged from 3 to 11 years (mean, 3.9 years). According to Parder's virilization scale, 5 cases were classified as stage Ⅱ, 18 cases as stage Ⅲ, and 4 cases as stage Ⅳ. The hormone tests showed decreased cortisol level and increased testosterone and 17-hydroxyprogesterone levels. They were diagnosed with non-salt-wasting CAH. RESULTS: All of the patients underwent clitoroplasty successfully. The mean operation time was 74 minutes (range, 58-95 minutes). Incision healed primarily. The patients were followed up 6 months to 10 years (median, 19 months). The external genitalia had good appearance, without necrosis of flap and the glans clitoris, abnormal sensation of the glans clitoris, or clitorism recurrence. Five girls had breast development and normal menstrual cycle during adolescence, and 1 patient who was followed up for 10 years gave birth to a son. CONCLUSIONS: Clitoroplasty of reserving the clitoris dorsal neurovascular bundle and the ventral complete urethral plate is a relatively ideal method for treating genital virilization in girls. It has less complications, good aesthetic and functional results. There are satisfactory outcomes when combining with the endocrine treatment.

Approach to the patients with ovotestis / 中华内分泌代谢杂志

Ovotestis is a rare disorder of sexual differentiation in which the gonads have both ovarian and testicular elements. The patients always present with ambiguous external genitalia, and there are usually with serious disorder between chromosomal sex, gonadal sex, social sex, and psychological sex. The definite diagnosis and gender confirmation, appropriate surgery in internal genitalia and orthomorphia in external genitalia, as well as psychological support are essential for a multidisciplinary medical group in managing this disease. The medical data of two children with ovotestis who were reared as boy or girl respectively were analyzed.