Clinical and genetic features of 5 alpha-reductase type2 deficiency caused by SRD5A2 gene variants / 中华内分泌代谢杂志

Objective:To explore the clinical and genetic characteristics of 5α-reductase 2 deficiency syndrome(5α-RD2).Methods:Retrospective analysis of three cases of 5α-RD2 to summarize clinical data. Genetic testing was conducted using chromosome karyotyping analysis, whole-exome sequencing(WES), Sanger sequencing, and bioinformatics analysis. The effect of the novel variant on the structure of the 5α-reductase was evaluated by studying the homology modeling structure using SWISSMODEL and PyMoL.Results:The patients of all three cases have social gender as female. In Case 1, a 6-year-old patient sought medical attention due to abnormal external genitalia development. In Cases 2 and 3, 15-year-old patients presented with primary amenorrhea, and they showed masculinization of secondary sexual characteristics during puberty. In all three cases, the external genitalia exhibited varying degrees of masculinization, with clitoromegaly resembling a small penis and accompanying cryptorchidism. In Case 2, an hCG stimulation test was performed, and the testosterone/dihydrotestosterone(DHT) ratio was found to be 17.4. The karyotype of all three patients was 46, XY. Whole-exome sequencing(WES) detected SRD5A2 gene variants in all cases, with genotypes being p. Gln6Ter/p.Arg227Gln, p. Gln6Ter/p.Pro250Ala, and p. Arg227Ter/p.His89Tyr, respectively. Parental validation confirmed compound heterozygous mutations in all cases. The novel variant p. Pro250Ala was identified and classified as a likely pathogenic variant according to ACMG guidelines. Protein modeling analysis indicated that this variant may affect the binding of 5α-reductase 2 to NADPH. In Case 1, male gender was chosen, and a laparoscopic bilateral orchiopexy was performed. In Case 2, female gender was chosen, and testectomy and vaginoplasty were performed. The gender selection for Case 3 has not been definitively determined yet.Conclusions:Abnormal external genitalia is a common phenotype of 5α-RD2. After hCG stimulation test, there is a significant increase in the testosterone/dihydrotestosterone(DHT) ratio, which indicates that Sanger sequencing of the SRD5A2 gene can be directly performed. 5α-RD2 exhibits significant clinical heterogeneity, and WES can facilitate the differential diagnosis of 46, XY disorders of sex development. The study also reported a novel variant, p. Pro250Ala, which enriches the SRD5A2 gene variant database.

Clinical phenotype and gene analysis of 86 cases of 5 alpha reductase deficiency / 中华儿科杂志

Objective@#Molecular genetics and clinical phenotypic characteristics of 5 alpha reductase deficiency were analyzed.@*Methods@#The genetic results and clinical features classied as Prader grade of external genitalia of 86 children with SRD5A2 mutation seen from 2007 to 2017 at Department of Endocrinology of Beijing Children′s Hospital were analyzed, and the mutation differences in different were compared regions according to the literatures.@*Results@#Among the 86 children, 15 had were homozygous mutations, accounting for 17%, and 71 cases of compound heterozygous mutations accounted for 83%. Totally 172 alleles mutations in this series. The mutation was mainly located on exon 1 and exon 4, in which the mutation frequency of exon 1 was 23.8% (41/172), and the frequency of exon 4 mutation was 55.8% (96/172). A total of 19 mutation types of the SRD5A2 gene in this group were detected, of which 5 were new mutations (p.A228F, p.E57D, p.V124D, p.A117D, p.E197K); 65 patients had p.R227Q mutation, accounting for 76%, while 31 had p.Q6* mutation, accounting for 36%. Other rare types such as p.R246W, p.R103* and so on were also seen in the present study, there was no significant difference between north China and south China (P>0.05). The clinical phenotypes of p.R227Q variation varied, mainly in Prader 3-4, accounting for 82%, while (Prader 0-1) were less, accounting only 2%. The variation of p.Q6* was mainly manifested in Prader 3, accounting for 50%. p.R246Q mainly presented Prader 3. The variation of p.G203S appeared to have Prader 2 and Prader 4-5, accounting for 20% and 73% respectively. There was no significant difference in clinical phenotype corresponding to each protein type (P>0.05) .@*Conclusion@#Among the 86 children have identified 19 SRD5A2 mutation types, p.R227Q is a hotspot mutation in Chinese. Variations at different types may have different clinical phenotypes, while the same variations may have different clinical features. There was no significance different in the variation types between the north and the south.

Research progress of 5α-reductase 2 deficiency / 国际儿科学杂志

Steroid 5α-reductase type 2 deficiency is caused by mutations in the SRD5A2 gene and is a congenital metabolic defect of autosomal recessive inheritance. The variety of gene mutations causes different levels of enzyme deficiency and results in different clinical phenotype,from the typical male sexual characteris-tics to the complete female sexual characteristics( small penis,perineal scrotal hypospadias and complete female phenotype). In puberty,the child with 5α-reductase 2 deficiency may undergo virilization. The correlation be-tween clinical phenotype and genotype is still under investigation. Steroid 5α-reductase type 2 deficiency and oth-er 46,XY disorders of sex development including androgen insensitivity syndrome have similar clinical charac-teristics,and 5α-reductase type 2 deficiency should be differentiated from other 46,XY disorders of sex develop-ment. The diagnosis of 5α-reductase type 2 deficiency is based on clinical manifestations,imaging examination, hormone detection,urinary steroid analysis and genetic testing,etc. The cutoff value of hormonal diagnosis still needs to be studied and the diagnosis should be further standardized. In most patients,the shift from female to male will occur around puberty,and may cause gender anxiety. The patient may have gender social identity crisis and other ethical controversies. In terms of treatment,gender assignment and gender role management are contro-versial,and surgical procedures need to be further studied. This paper reviews the clinical features,clinical pheno-type and genotype,the differential diagnosis,diagnosis basis and treatment strategy as well as the future challen-ges of 5α-reductase type 2 deficiency,in order to alleviate the sufferings caused by later gender transition in pu-berty and improve the quality of life.

The analysis of gene mutation and diagnosis and treatment of 5α-reductase 2 deficiency in a child / 临床儿科杂志

Objective To explore the clinical feature and gene mutation in steroid 5α-reductase 2 deficiency (SRD5A2). Method The clinical data of SRD5A2 in a child with vulva abnormality as the first manifestation was retrospectively analyzed. Results This was a 29-month-old child, whose social gender was female. The level of her basic luteinizing hormone (LH) was 0.07 mIU/mL, and follicle-stimulating hormone was (FSH) 0.39 mIU/mL. The baseline levels of testosterone (T), dihydrotestosterone (DHT), 17-hydroxyprogesterone (17-OHP) and androstendione (A2) were 0.06 ng/mL, 19.67 pg/mL, 1.20 ng/mL, and 0.07 ng/mL respectively. Those levels were 3.65 ng/mL, 68.25 pg/mL, 51.72 ng/mL, and 14.70 ng/mL respectively after Human chorionic gonadotropin (HCG) stimulation. The levels of her anti-mullerian hormone (AMH) was 22.97 ng/mL, and inhibin B (INH-B) was 274.4 pg/mL. The uterus and ovaries were not detected by Pelvic ultrasound and MRI. The chromosome showed 46, XY. Sex determination (SRY) gene detection showed normal. Androgen receptor (AR) gene detection showed negative. There was pathogenic mutation of 5α-reductase 2 (SRD5A2) gene in peripheral blood of the child and her parents. The penis grows 2 cm after 4 months of treatment with 2.5% DHT gel. Conclusion SRD5A2 is diagnosed mainly based on the increase of T/DHT after HCG stimulation experiment and it can be confirmed by detection of pathogenic SRD5A2 mutation.

The correlation between phenotype and genotype of 5α-reductase 2 deficiency in 5 children / 临床儿科杂志

Objective To explore the correlation between phenotype and genotype of 5α-reductase 2 deficiency. Methods The clinical data of five children with 5α-reductase 2 deficiency were retrospectively analyzed and the relation between their clinical phenotype and genotype were analyzed. Results All of these five children presented small penis and testicular hypoplasia, three of whom had ones similar to the clitoris appearance. The testosterone/dihydrotestosterone (T/DHT) ratio was 10.26-64.99 after human chorionic gonadotropin (hCG) stimulation. Gene detection showed one case had c.680G>A homozygous mutation and the others were compound heterozygous mutations. The mutations were mainly missense mutations, followed by deletion, duplication and nonsense mutations. Conclusion The 5α-reductase 2 deficiency has different degrees of abnormal genital development. Genetic testing contributed to the diagnosis of this disease.

A Novel Mutation of the Steroid 5-Alpha Reductase Type 2 (SRD5A2) Gene in a Korean Newborn with Ambiguous Genitalia / 대한소아내분비학회지

The term "disorders of sex development" (DSD) includes congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. Steroid 5-alpha reductase type 2 deficiency (5alpha-RD2) is an uncommon autosomal recessive disorder of sexual differentiation. It results from impaired conversion of testosterone (T) to dihydrotestosterone (DHT) due to mutations in the steroid 5-alpha reductase type 2 (SRD5A2) gene. It is characterized by a lack of masculinization in XY individuals due to failure to convert testosterone to dihydrotestosterone. More than 40 mutations have been reported in all five exons of the SRD5A2 gene. Here, we report on a 17-day-old Korean newborn who was confirmed to have 5alpha-RD2 by SRD5A2 gene analysis. He manifested micropenis, hypospadia and bilateral cryptorchidism without skin hyperpigmentation. T/DHT ratio after human chorionic gonadotropin (hCG) stimulation was slightly increased and genetic analysis of SRD5A2 revealed compound heterozygous mutations, c.657C > G (p.Phe219Leu) and c.656del (p.Phe219SerfsX60), the former of which is a novel mutation. We report a novel SRD5A2 gene mutation in a Korean newborn with 5alpha-RD2.