Advance in mutations of steroidogenic factor-1 and the related clinical phenotype / 中华内分泌代谢杂志

Steroidogenic factor-1 (SF-1, NR5A1) is a transcription factor that plays a key role in the development of gonad and adrenal gland. NR5A1 gene mutation is one of the common causes of disorders of sex development(DSD). Heterozygous mutations of NR5A1 gene accounts for the majority of reported cases with various phenotyre. Early reported cases manifested with varying degrees of 46, XY gonadal dysplasia, whereas NR5A1 mutation was revealed to be related with the phenotypes of azoospermia in men and premature ovarian insufficiency in women recently. Adrenocortical insufficiency is absent in most cases. The heterogeneity of the clinical phenotype is considered resulting from the functional impact of different gene mutations on transcriptional activity, dose effect of downstream target gene(such as SOX9)and the genetic background of oligogenic mutation, etc. The process and regulation of gonadal development might be understood comprehensively by investigating the genotype and related phenotype of NR5A1.

Approach to the patient with female phenotype 46, XY disorders of sex development / 中华内分泌代谢杂志

The etiology of 46, XY disorders of sex development is complex and the clinical manifestations are various. Patients with a female phenotype often present with primary amenorrhea during adolescence, which is difficult to find. We analyze the clinical features of 3 cases of female phenotype diagnosed by gene sequencing. The pathogenesis, clinical manifestations, diagnosis, and treatment were reviewed.

Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing / 亚洲男科学杂志(英文版)

46,XY disorders of sex development (DSD) is characterized by incomplete masculinization genitalia, with gonadal dysplasia and with/without the presence of Müllerian structures. At least 30 genes related to 46,XY DSD have been found. However, the clinical phenotypes of patients with different gene mutations overlap, and accurate diagnosis relies on gene sequencing technology. Therefore, this study aims to determine the prevalence of pathogenic mutations in a Chinese cohort with 46,XY DSD by the targeted next-generation sequencing (NGS) technology. Eighty-seven 46,XY DSD patients were enrolled from the Peking Union Medical College Hospital (Beijing, China). A total of fifty-four rare variants were identified in 60 patients with 46,XY DSD. The incidence of these rare variants was approximately 69.0% (60/87). Twenty-five novel variants and 29 reported variants were identified. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, thirty-three variants were classified as pathogenic or likely pathogenic variants and 21 variants were assessed as variants of uncertain significance. The overall diagnostic rate was about 42.5% based on the pathogenic and likely pathogenic variants. Androgen receptor (AR), steroid 5-alpha-reductase 2 (SRD5A2) and nuclear receptor subfamily 5 Group A member 1 (NR5A1) gene variants were identified in 21, 13 and 13 patients, respectively. The incidence of these three gene variants was about 78.3% (47/60) in patients with rare variants. It is concluded that targeted NGS is an effective method to detect pathogenic mutations in 46,XY DSD patients and AR, SRD5A2, and NR5A1 genes were the most common pathogenic genes in our cohort.

Clinical features and molecular genetic analysis of congenital lipoid adrenal hyperplasia caused by steroidogenic acute regulatory protein gene mutation / 中华围产医学杂志

Objective@#To investigate the clinical and molecular genetic features of neonatal congenital lipoid adrenal hyperplasia (CLAH) caused by mutations in steroidogenic acute regulatory protein (StAR) encoding gene.@*Methods@#This study retrospectively analyzed the clinical data of a CLAH neonate admitted to Fujian Provincial Maternity and Children's Hospital, Affiliated Hospital of Fujian Medical University in April 2017. StAR gene was analyzed using high-throughput sequencing and Sanger sequencing. Relevant literature retrieved from databases including China National Knowledge Infrastructure (CNKI), Wanfang and PubMed were reviewed, and the reported cases with relatively complete clinical data and results of serum hormone test and StAR gene mutation analysis were collected.@*Results@#The index patient presented with hyperpigmentation and growth retardation soon after birth. Laboratory tests revealed hyponatremia, hyperkalemia, increased serum adrenocorticotrophic hormone (263.4 pmol/L) and decreased 17-hydroxyprogesterone (0.16 ng/ml), dehydroepiandrosterone (<0.95 μmol/L), androstenedione (<1.0 nmol/L), testosterone (<0.025 ng/ml), progesterone (0.02 ng/ml) and cortisol (1.6 μg/ml). High-throughput sequencing showed that the patient carried a compound heterozygous mutation of p.Thr240fs in exon 6 and p.Gln258X in exon 7, inherited from the father and mother, respectively. Sanger sequencing confirmed the diagnosis of CLAH caused by StAR gene mutation. After steroid replacement therapy, the patient's symptoms resolved and the concentrations of electrolytes returned to normal. The neonate was followed up to two years of age and no abnormality was found in physical or neurological development. Two Chinese and 11 English publications were retrieved and altogether 96 cases of neonatal CLAH, including the index one, were reviewed and 42 of them had detailed clinical data. The most common clinical manifestations were skin pigmentation (85.7%, 36/42). Other manifestations included vomiting (35.7%, 15/42) and growth retardation (14.3%, 6/42). All patients with physical examination records had female external genitalia (100.0%, 35/35). The common laboratory abnormalities included hyponatremia (95.2%, 40/42), hyperkalemia (88.1%, 37/42), elevated serum adrenocorticotrophic hormone (100.0%, 37/37) and decreased 17-hydroxyprogesterone (90.5%, 19/21), cortisol (86.2%, 25/29), testosterone (9/10) and dehydroepiandrosterone (14/14). p.Gln258X was the most common StAR gene mutation in neonates in Eastern Asia, including China. Most cases had a good prognosis after appropriate steroid replacement.@*Conclusions@#CLAH should be considered for neonates with adrenocortical hypofunction, especially with female phenotypes and low 17-hydroxyprogesterone. Karyotyping and StAR gene analysis may be helpful in diagnosis. Timely and appropriate treatment could improve the prognosis.

Clinical features and molecular genetic analysis of congenital lipoid adrenal hyperplasia caused by steroidogenic acute regulatory protein gene mutation / 中华围产医学杂志

Objective To investigate the clinical and molecular genetic features of neonatal congenital lipoid adrenal hyperplasia (CLAH) caused by mutations in steroidogenic acute regulatory protein (StAR) encoding gene.Methods This study retrospectively analyzed the clinical data of a CLAH neonate admitted to Fujian Provincial Matemity and Children's Hospital,Affiliated Hospital of Fujian Medical University in April 2017.StAR gene was analyzed using high-throughput sequencing and Sanger sequencing.Relevant literature retrieved from databases including China National Knowledge Infrastructure (CNKI),Wanfang and PubMed were reviewed,and the reported cases with relatively complete clinical data and results of serum hormone test and StAR gene mutation analysis were collected.Results The index patient presented with hyperpigrnentation and growth retardation soon after birth.Laboratory tests revealed hyponatremia,hyperkalemia,increased serum adrenocorticotrophic hormone (263.4 pmol/L) and decreased 17-hydroxyprogesterone (0.16 ng/ml),dehydroepiandrosterone (＜0.95 μmol/L),androstenedione (＜1.0 nmol/L),testosterone (＜0.025 ng/ml),progesterone (0.02 ng/ml) and cortisol (1.6 μ g/ml).High-throughput sequencing showed that the patient carried a compound heterozygous mutation of p.Thr240fs in exon 6 and p.Gln258X in exon 7,inherited from the father and mother,respectively.Sanger sequencing confirmed the diagnosis of CLAH caused by StAR gene mutation.After steroid replacement therapy,the patient's symptoms resolved and the concentrations of electrolytes returned to normal.The neonate was followed up to two years of age and no abnormality was found in physical or neurological development.Two Chinese and 11 English publications were retrieved and altogether 96 cases of neonatal CLAH,including the index one,were reviewed and 42 of them had detailed clinical data.The most common clinical manifestations were skin pigmentation (85.7％,36/42).Other manifestations included vomiting (35.7％,15/42) and growth retardation (14.3％,6/42).All patients with physical examination records had female external genitalia (100.0％,35/35).The common laboratory abnormalities included hyponatremia (95.2％,40/42),hyperkalemia (88.1％,37/42),elevated serum adrenocorticotrophic hormone (100.0％,37/37) and decreased 17-hydroxyprogesterone (90.5％,19/21),cortisol (86.2％,25/29),testosterone (9/10) and dehydroepiandrosterone (14/14).p.Gln258X was the most common StAR gene mutation in neonates in Eastern Asia,including China.Most cases had a good prognosis after appropriate steroid replacement.Conclusions CLAH should be considered for neonates with adrenocortical hypofunction,especially with female phenotypes and low 17-hydroxyprogesterone.Karyotyping and StAR gene analysis may be helpful in diagnosis.Timely and appropriate treatment could improve the prognosis.

Preliminary investigation of gender assignment in 46,XY disorders of sex development with severe male undermasculinisation / 中华儿科杂志

Objective@#To explore the feasibility of gender assignment in 46,XY disorders of sex development (DSD) with severe undermasculinisation mainly based on molecular diagnosis.@*Methods@#A retrospective study of 45 patients of 46, XY DSD with severe undermasculinisation were admitted between November 2015 and October 2018 at Children′s Hospital, Zhejiang University School of Medicine. The initial social gender were all female, of whom the external genital manifestations were Prader 0 to 2; the degree of masculinity was scored using external masculinisation score (EMS); the position and development of the gonads were examined by ultrasound, cystoscopy and laparoscopy, also including assessing the development of the Wolffian tube and the Müllerian tube. The level and ratio of testosterone to dihydrotestosterone before and after hCG stimulation were evaluated for the function of Leydig cell and 5α-reductase-2. Gender role scales and sandbox games were used to assess gender role behavior. Genital sensitivity to androgen stimulation was assessed; A panel including 163 genes related to gender development were determined by second-generation sequencing in all 45 patients. Finally, a multidisciplinary team (MDT) makes a gender assignment after a comprehensive analysis mainly based on the molecular etiological diagnosis.@*Results@#Thirty-nine out of 45 patients (87%) had an identifiable genetic etiology, and the remaining 6 (13%) were negative for genetic testing. Forty-five patients had EMS less than or equal to 3 points. Sexual psychological assessment was performed in 39 patients, with male dominance in 24 (62%) and female dominance in 15 (38%). The gender assignment was 23 cases (51%) for male and 19 cases (42%) for female, and 3 cases (7%) were not completely determined.@*Conclusions@#Molecular diagnosis provides a strong basis for appropriate gender assignment of 46, XY DSD children with severe undermasculinisation. Based on molecular diagnosis, each DSD should be analyzed by professional MDT to analyze the clinical symptoms/signs, gonadal development, gonad tumor risk, external genital morphology, sexual psychological assessment, potential fertility opportunities, parental views, Social and cultural factors, etc. make appropriate gender assignment.

Assessment and management of 46,XY disorders of sexual development / 中华实用儿科临床杂志

Micropenis is one of clinical manifestations of 46,XY disorders of sex development.Due to the complex etiology,the limitation of diagnostic methods,it is difficult to define the causes in some complicated cases.The abnormality in any part of the hypothalamic pituitary gonadal axis,androgen synthesis and function will influence the development of penis.Based on the statistical data of penis in comparison,trying to find the reference data for clinical application,used in the diagnosis of micropenis.For the patient raise a boy,the treatment including medicine and operation to improve the size of penis.Exogenous androgen and human chorionic gonadotrophin (HCG) treatment are the main methods in present,it can effectively promote the micropenis to increase in size.But it is debatable when to start the treatment,dosage and the duration.The potential side effects are unknown.Operation treatment can improve the hypospadias induced abnormal appearance and reconstruction of urethra.Treatment of gonadotropin can be applied to the patients who want to acquire fertility.For patients reared as female,male gonads must be removed,and estrogen replacement administered after adolescent.