Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Child ; China/epidemiology* ; Cryptorchidism/genetics* ; Disorders of Sex Development/genetics* ; Female ; Genital Diseases, Male ; Genotype ; Humans ; Hypospadias/genetics* ; Male ; Membrane Proteins/genetics* ; Penis/abnormalities* ; Phenotype ; Retrospective Studies ; Steroid 21-Hydroxylase/genetics*

OBJECTIVE: To explore the clinical characteristics and genetic basis of a child with 5α-reductase type 2 deficiency. METHODS: Clinical data of the child was retrospectively analyzed. Targeted capture-next generation sequencing and Sanger sequencing were carried out to detect potential variants. RESULTS: The patient's main features included micropenis and hypospadia. He was found to harbor compound heterozygous c.680G>A (p.R227Q) and c.3G>T (p.M1I) variants of the SRD5A2 gene. Among these, c.680G>A (p.R227Q) was inherited from his father and was a known pathogenic mutation, while c.3G>T (p.M1I) was inherited from his mother and was unreported previously. CONCLUSION The compound heterozygous variants of the SRD5A2 gene probably underlay the disease in this child, who was eventually diagnosed with 5α-reductase 2 deficiency.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Child ; Disorder of Sex Development, 46,XY ; Female ; Humans ; Hypospadias ; Male ; Membrane Proteins/genetics* ; Mutation ; Retrospective Studies ; Steroid Metabolism, Inborn Errors ; Steroids

This article reported the clinical characteristics and SRD5A2 gene mutation pattern of a child with steroid 5-α reductase type 2 deficiency. The 2-month-old boy showed hypospadias and short penis shortly after birth. DNA was extracted from the peripheral blood of the child and his parents. The endocrine disease-related genes were captured and sequenced by high-throughput sequencing technology, and the family DNA samples were verified by Sanger sequencing. The results showed that c.680G>A(p.R227Q) and c.608G>A(p.G203D) compound heterozygous mutations existed in the SRD5A2 gene of the child. The c.680G>A mutation inherited from his father, which was a known pathogenic mutation. The c.608G>A mutation originated from his mother, which was a novel mutation discovered in this study. These results provide molecular evidence for the etiological diagnosis of the child and genetic counseling for the family, as well as extend the mutation spectrum of SRD5A2 gene.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase ; genetics ; Base Sequence ; Child ; Female ; Humans ; Hypospadias ; Infant ; Male ; Membrane Proteins ; genetics ; Mutation

In this study, we investigated the genetics, clinical features, and therapeutic approach of 14 patients with 5α-reductase deficiency in China. Genotyping analysis was performed by direct sequencing of PCR products of the steroid 5α-reductase type 2 gene (SRD5A2). The 5α-reductase activities of three novel mutations were investigated by mutagenesis and an in vitro transfection assay. Most patients presented with a microphallus, variable degrees of hypospadias, and cryptorchidism. Eight of 14 patients (57.1%) were initially reared as females and changed their social gender from female to male after puberty. Nine mutations were identified in the 14 patients. p.G203S, p.Q6X, and p.R227Q were the most prevalent mutations. Three mutations (p.K35N, p.H162P, and p.Y136X) have not been reported previously. The nonsense mutation p.Y136X abolished enzymatic activity, whereas p.K35N and p.H162P retained partial enzymatic activity. Topical administration of dihydrotestosterone during infancy or early childhood combined with hypospadia repair surgery had good therapeutic results. In conclusion, we expand the mutation profile of SRD5A2 in the Chinese population. A rational clinical approach to this disorder requires early and accurate diagnosis, especially genetic diagnosis.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Adolescent ; Adult ; Asian People/genetics* ; Child ; Child, Preschool ; China ; Disorder of Sex Development, 46,XY/genetics* ; Follicle Stimulating Hormone/blood* ; Genitalia, Male/abnormalities* ; Humans ; Hypospadias/genetics* ; Luteinizing Hormone/blood* ; Male ; Membrane Proteins/genetics* ; Mutation/genetics* ; Sequence Alignment ; Steroid Metabolism, Inborn Errors/genetics* ; Testosterone/blood* ; Young Adult

3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Child, Preschool ; DNA Mutational Analysis ; Disorder of Sex Development, 46,XY/genetics* ; Female ; Humans ; Membrane Proteins/genetics* ; Mutation

OBJECTIVETo analyze the karyotypes and SRD5A2 gene mutations in 25 patients with sporadic or familial hypospadias.

METHODSThe patients included 10 adults and 15 children, whose chromosomes were analyzed by G-banded karyotyping, and the SRD5A2 genes were sequenced.

RESULTSTwo patients were found to have an abnormal karyotype, while eight have carried compound heterozygous mutations of the SRD5A2 gene, which included 5 genotypes formed by 6 types of mutations, i.e., p.G203S/p.R227Q, p.R227Q/p.R246Q, p.Q6X/p.Q71X, p.L20P/p.G203S, and p.Q71X/p.R227Q. Mutations of the SRD5A2 gene were present in 32% (8/25) of all patients, 35% (8/23) in those with a normal karyotype, and 44.4% (8/18) in those with proximal type hypospadia. Bioinformatic analysis, literature review and pedigree analysis confirmed that all such mutations are pathogenic.

CONCLUSIONChromosomal anomalies and mutations of the SRD5A2 gene are the main cause of hypospadias. Sequencing of the SRD5A2 gene may explain the etiology of nearly half of the patients with proximal type of hypospadas but a normal karyotype, which can facilitate genetic consulting.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase ; genetics ; metabolism ; Adolescent ; Adult ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Child ; Child, Preschool ; Female ; Humans ; Hypospadias ; enzymology ; genetics ; Infant ; Infant, Newborn ; Karyotyping ; Male ; Membrane Proteins ; genetics ; metabolism ; Mutation ; Young Adult

ObjectiveTo explore the expression of I-5α-reductase (SRD5A1)and its prognostic role in prostate cancer .

METHODSData about SRD5A1 were retrieved from the ONCOMINE database and the role of SRD5A1 in prostate cancer was analyzed.

RESULTSTotally, 992 studies of different types relevant to the expression of SRD5A1 were identified in the ONCOMINE database. The SRD5A1 expression was statistically significant in 239 of the studies, overexpressed in 157 (11 in prostate cancer) and underexpressed in the other 82 (3 in prostate cancer). Eighteen of the studies, with 1 068 samples, addressed the expression of SRD5A1 in prostate cancer and normal tissues, which was significantly higher in the former than in the latter tissue (P<0.05). In 3 of the studies, the SRD5A1 expression was high in primary prostate cancer and increased with its metastasis (P<0.0 5). Two of the studies with prognostic data showed a higher rate of postoperative biochemical recurrence and a higher total mortality rate in the patients with a high than in those with a low expression of SRD5A1 (P<0.05).

CONCLUSIONSSRD5A1 is highly expressed in prostate cancer, especially in metastatic and castration-resistant prostate cancer and its expression is associated with the prognosis of prostate cancer, which may be an important target of medication for prostate cancer.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase ; metabolism ; Data Mining ; Humans ; Male ; Neoplasm Recurrence, Local ; Prognosis ; Prostatic Neoplasms ; enzymology ; mortality ; pathology ; surgery ; Prostatic Neoplasms, Castration-Resistant ; enzymology

PURPOSE: Steroid 5-alpha reductase type 2 (SRD5A2) modifies testosterone to dihydrotestosterone (DHT) in the prostate. Single-nucleotide polymorphisms (SNPs) of the SRD5A2 gene might affect DHT. We sought to understand the relationship of SRD5A2 SNPs to prostate cancer in the Korean population. MATERIALS AND METHODS: Twenty-six common SNPs in the SRD5A2 gene were assessed in 272 prostate cancer cases and 173 controls. Single-locus analyses were conducted by using conditional logistic regression. Additionally, we performed a haplotype analysis for the SRD5A2 SNPs tested. RESULTS: Among the 20 SNPs and 4 haplotypes, there were no statistically significant results in the prostate cancer patients and the controls. In the logistic analysis of SRD5A2 polymorphisms with prostate-specific antigen (PSA) criteria, two SNPs (rs508562, rs11675297) and haplotype 1 displayed significant results (odds ratio [OR], 1.76; p=0.05; OR, 1.88-2.02; p=0.01-0.04; OR, 0.59; p=0.02, respectively). rs508562, rs11675297, rs2208532, and haplotype 1 (OR, 1.49; p=0.05; OR, 2.02; p=0.05; OR, 2.01; p=0.04; OR, 0.56-0.64, p=0.03-0.04, respectively) had significant associations with Gleason score. rs508562, rs11675297, and haplotype 1 (OR, 1.41-2.34; p=0.004-0.05; OR, 1.74-1.82; p=0.03-0.05; OR, 0.42-0.67; p=0.0005-0.03, respectively) were significantly associated with clinical stage. CONCLUSIONS: We conclude that there was no significant association between SRD5A2 SNPs and the risk of prostate cancer in the Korean population. However, we found that some SNPs and 1 haplotype influenced PSA level, Gleason score, and clinical stage.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/*genetics ; Aged ; Case-Control Studies ; Dihydrotestosterone/metabolism ; Genetic Predisposition to Disease ; Genotype ; Haplotypes ; Humans ; Logistic Models ; Male ; Membrane Proteins/*genetics ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Odds Ratio ; Polymorphism, Single Nucleotide ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms/epidemiology/*genetics ; Republic of Korea/epidemiology ; Risk Factors ; Testosterone/genetics

PURPOSE: Type III 5-alpha reductase (SRD5A3; steroid 5-alpha reductase 3) may be associated with the progression of prostate cancer (PCa). The aim of our study was to determine whether the length of AC repeats in the SRD5A3 gene is associated with the risk of PCa and the expression of androgen receptor (AR) protein in Korean men. MATERIALS AND METHODS: We compared the length of AC repeats in the short tandem repeat (STR) region of the SRD5A3 gene in 68 PCa patients and 81 control subjects by genotyping. A total of 55 patients in the PCa group underwent radical prostatectomy. We evaluated the expression of AR protein by using Western blotting and tested the association between the type of AC repeats in the SRD5A3 gene and AR protein expression and clinical and pathologic parameters. RESULTS: The short type of STR had less than 21 copies of AC repeats in the SRD5A3 gene. The SS type (short and short type) of STR of the SRD5A3 gene was 2.2 times as likely to occur in PCa patients as in controls (odds ratio, 2.21; 95% confidence interval, 1.14 to 4.31; p=0.019). However, AC repeats of the SRD5A3 gene were not associated with AR protein expression or clinical or pathologic parameters in PCa samples. CONCLUSIONS: These results suggest that the short AC repeats of SRD5A3 polymorphism are associated with an increased risk of PCa. SRD5A3 polymorphism may contribute to a genetic predisposition for PCa.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase ; Blotting, Western ; Coat Protein Complex I ; Genetic Predisposition to Disease ; Humans ; Microsatellite Repeats ; Oxidoreductases ; Passive Cutaneous Anaphylaxis ; Polymorphism, Genetic ; Prostate ; Prostatectomy ; Prostatic Neoplasms ; Receptors, Androgen

OBJECTIVETo investigate the association of V89L polymorphism of the SRD5A2 gene with the prognostic factors of prostate cancer (PCa).

METHODSWe identified the V89L polymorphic sites of the SRD5A2 gene after Rsa-1 restriction enzyme digestion, observed the distribution of V89L (VV, VL and LL) polymorphism in 112 PCa and 89 benign prostate hyperplasia (BPH) patients, and determined the association of V89L polymorphism with the age, free PSA (fPSA), total PSA (tPSA), fPSA/tPSA ratio, tumor stage and Gleason score of the PCa patients.

RESULTSNo statistically significant differences were found in the V89L polymorphism-induced genetic risk frequencies between the PCa and BPH groups (chi2 = 3. 606, df = 2, P = 0. 165), nor any significant correlation between the genotypes of VV and VL + LL and the differences in the fPSA, tPSA, fPSA/tPSA ratio, tumor stage, Gleason score and age of the PCa patients. VV and VL + LL showed no obvious association with the prognostic factors of PCa.

CONCLUSIONV89L polymorphism is not related with the prognosis of PCa, but may be indirectly associated with its risk.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase ; genetics ; Aged ; Aged, 80 and over ; Genotype ; Humans ; Male ; Membrane Proteins ; genetics ; Middle Aged ; Neoplasm Staging ; Polymorphism, Genetic ; Prognosis ; Prostatic Neoplasms ; diagnosis ; genetics ; pathology