Mutations In SRD5A2 Gene Research Articles

Screening for carriers of the SRD5A2 gene mutation 5-alpha-reductase 2 deficiency in Vietnamese pregnant wome

Objective: To describe the percentage of people who carry the SRD5A2 gene mutation causing 5-alpha-reductase 2 deficiency and the characteristics of their mutated variants in Vietnamese pregnant women. Subjects and methods: A cross-sectional descriptive study was conducted on 8,464 pregnant women who visited and agreed to perform a screening test for gene carriers related to recessive genetic conditions at the Institute of DNA Technology and Genetic Analysis. All information about pregnant women including maternal age, gestational age, number of pregnancies and SRD5A2 gene mutation test results were collected. Results: Of 8,464 pregnant women participating in the study, 315 pregnant women (3.72%) carried pathogenic mutations on the SRD5A2gene. The c.680G>A mutation (p.Arg227Gln) is the most common of the SRD5A2 gene mutations detected. Conclusion: The rate of pregnant women carrying SRD5A2 gene mutations is 3.72%, indicating the high prevalence of this gene mutation in Vietnamese pregnant women. In the future, it is necessary to expand and develop SRD5A2 gene mutation screening programs in Vietnamese pregnant women.

Study of 5 Alpha Reductase Enzyme Gene Mutations in a Group of Patients with 46XY Disorders of Sex Development

Background Disorders of sex development (DSD) are a wide range of conditions with diverse features and pathophysiology that most often present in the newborn or the adolescent periods. Affected patients usually present with atypical genitalia like hypospadias, isolated micropenis and undescended testis. These clinical situations can often be difficult to manage, particularly in those cases where the sex rearing is uncertain. Aim of the Work Studying 5alpha reductase enzyme gene mutations (SRD5A2) in patients with 46XY DSD to detect its molecular characteristics. Patients and Methods This cross-sectional study was performed on 25 male patients with clinical, laboratory and genetic molecular analysis of SRD5A2 gene mutation fitting the diagnosis of 46XY DSD. To assess the degree of virilization external masculinization score (EMS) was used where EMS less than 7 is considered ambiguous. All parameters were evaluated at the pediatrics endocrinology clinic and genetics department, Ain Shams University from December 2019 to December 2020. Results Only 12 patients showed laboratory and molecular results compatible with the diagnosis of SRD5A2 gene mutation, The mean age of the patients was 3.64 ± 4.75 years. Results showed EMS of 4.3 denoting the high degree of genital ambiguity in our cases. Scrotum was bifid in 5 patients (41.6%), underdeveloped in 5 patients (41.6%) and fused in 2 patients (16.8%). Cryptorchidism was found in 4 patients only (33.3%). Four patients (33.3%) had normal urethral opening while hypospadias was present in 8 patients being perineal in 1 patient (8.3%), perineoscrotal in 5 patients (41.6%) and scrotal in 2 patients (16.6%). Micropenis was present in 7 patients (58.3%), four patients had 2 openings (33.3%) compared to a single opening in 8 patients (66.7%). Regarding type of SRD5A2 gene mutations 56.2% of mutations were Insertion deletion, 25% were Insertion, 12.5 % were Missense, 6.25% were Deletion. Conclusion This study demonstrated ten novel mutations of SRD5A2 gene were identified in association with 5alpha reductase enzyme deficiency. These mutations were reported among 12 patients with 46 XY DSD from total of 25 patients were fit for this study. No distinct relationships were observed between genotypic and phenotypic characteristics in the participants.

Genotype-Phenotype Correlation Analysis and Identification of a Novel SRD5A2 Mutation in Four Unrelated Chinese Patients with 5α-Reductase Deficiency.

ObjectiveThe 5α-reductase type 2 deficiency is mainly caused by mutations in the SRD5A2 gene. Our study aims to investigate the SRD5A2 gene mutations and their corresponding manifestations.MethodsFour unrelated Chinese patients with 46, XY ambiguous genitalia were studied. Molecular genetic alterations and clinical presentations were analyzed.ResultsFive variants in the SRD5A2 gene were identified, all highly conserved in vertebrate orthologs. The p.P251A was a novel variant, predicted to “Affect protein function” and to be “probably damaging”. Combining patients’ gene mutations with their external genitalia and male sexual characteristics, we found that three variants, p.Q6X, p.N193S, and p.H90Y, were associated with severe undervirilization of external genitalia, and the other two, p.G203S and p.P251A, probably retained part of the enzyme activity.ConclusionMutation analysis of SRD5A2 gene is crucial for differential diagnosis in patients with 5α-reductase type 2 deficiency. Patients’ variable manifestations depend on the mutation type and residual enzyme activity. The novel variant p.P251A enlarges the spectrum of SRD5A2 mutations.

Molecular analysis of SRD5A2 a novel homozygous variant found in a Mexican family

5-alpha-Reductase deficiency is one of the causes involving disorders of sex development 46, XY. Mutations in SRD5A2 gene lead to a wide clinical manifestation, sometimes not giving a clear outlook for a clinical diagnosis, making molecular diagnosis an important diagnostic pillar of these conditions. Here, we show the importance of molecular and pedigree analysis for diagnosis and adequate genetic counseling. Keywords: 46, XY disorder of sex development; ambiguous genitalia; 5-alpha-Reducatse type 2; novel mutation.

SUN-LB041 Clinical and Molecular Characteristics, Genotype-Phenotype Correlation in 113 Chinese Children with SRD5A2 Gene Mutations

Objective: Studies on 5α-reductase type 2 deficiency (5α-RD) are limited and the genotype-phenotype correlation has not been elucidated. The aim of the study was to analyze clinical and molecular characteristics, genotype-phenotype correlation in a large Chinese 5α-RD cohort. Design: Database registration study. Method: We analyzed clinical and genetic data of gene confirmed 5α-RD Children, comparing their phenotypes by using external masculinization score (EMS),the position of urethral meatus and gonads as well as penis length-standard deviation score (PL-SDS). Results: 85.84% of patients presented hypospadias while 14.16% had normal urethral meatus. When the cut-off value of stimulated T/DHT was 10 or 15, 98.48% and 92.42% of patients were diagnosed respectively. 8 patients with isolated micropenis were diagnosed as 5α-RD by higher T/DHT ratio and SRD5A2 gene mutations. There was no significant correlation between T/DHT and phenotypes (p>0.05). We identified 31 different variants including 10 unreported ones. The p.R227Q was the most prevalent variant (38.50%). The phenotypic indicators of patients with p.R227Q were higher than those without the mutation in multiple comparisons (p<0.05). Patients with the homozygous p.R227Q had milder phenotypes and larger standard deviation of phenotypic scores than those with other homozygotes. Conclusions: Subjects with 5α-RD can present isolated micropenis and T/DHT cannot foretell the severity of phenotypes. As a founder mutation in Chinese, the p.R227Q seems to link to relatively milder phenotypes and greater phenotypic variability. Variants can explain, at least partially, the heterogeneity of phenotypes, while other factors may also contribute to the phenotypes. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Molecular investigation of mutations in androgen receptor and 5-alpha-reductase-2 genes in 46,XY Disorders of Sex Development with normal testicular development.

In this study, we aimed to determine androgen receptor (AR) and SRD5A2 gene mutations in 45 patients characterised by 46,XY Disorders of Sex Differentiation (DSD) signs with normal testicular development referred to the Children's Medical Center from February 2015 to September 2017. Karyotype and sex hormone analyses were performed. Cytogenetic investigation showed that seven patients were 46,XX DSD, six patients were chromosomal DSD and 32 patients were 46,XY DSD. Eight exons of the AR gene and five exons of the SRD5A2 gene were amplified. Two cases were affected with androgen insensitivity syndrome (AIS) (missense mutation on exon 7, position c.3637 G>A: p.R841H and position c.3610 G>A: p.R832Q), one case was affected with 5-alpha-reductase deficiency type 2 (missense mutation at c.578A>G: p.N193S on exon 4), and 22 cases (88%) did not demonstrate AIS or 5α-RD2 gene abnormality. Due to the great impact of these disorders on human lifestyle, evaluation of genes involved can improve genetic counselling and therapeutic management. We focused on the AR and SRD5A2 genes in patients with 46,XY DSDs with normal testicular development referred to the Children's Medical Center from all over the country to eventually culminate in a reliable prenatal diagnosis protocol at this major referral centre giving service to a great number of families with consanguineous marriages.

Research progress of 5α-reductase 2 deficiency

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 characteristics 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 between clinical phenotype and genotype is still under investigation.Steroid 5α-reductase type 2 deficiency and other 46, XY disorders of sex development including androgen insensitivity syndrome have similar clinical characteristics, and 5α-reductase type 2 deficiency should be differentiated from other 46, XY disorders of sex development.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 controversial, and surgical procedures need to be further studied.This paper reviews the clinical features, clinical phenotype and genotype, the differential diagnosis, diagnosis basis and treatment strategy as well as the future challenges of 5α-reductase type 2 deficiency, in order to alleviate the sufferings caused by later gender transition in puberty and improve the quality of life. Key words: SRD5A2 gene; 46, XY DSD; androgen receptor; spermatogenesis; steroid 5α-reductase 2 deficiency

Karyotyping and analysis of 5α -reductase-2 gene mutation in 25 patients with hypospadias

To analyze the karyotypes and SRD5A2 gene mutations in 25 patients with sporadic or familial hypospadias. The patients included 10 adults and 15 children, whose chromosomes were analyzed by G-banded karyotyping, and the SRD5A2 genes were sequenced. Two 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. Chromosomal 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.

Association of missense substitution of A49T and V89L in the SRD5A2 gene with prostate cancer in Turkish patients

Abstract Objective To determine the association of missense substitution of alanine 49 threonine (A49T) and valine 89 leucine (V89L) in the steroid-5-alpha-reductase type II (SRD5A2) gene with prostate cancer in Turkish patients. Methods Eighty patients with prostate cancer and 76 healthy control subjects were evaluated for A49T and V89L polymorphisms in the SRD5A2 gene mutations via real time fluorescence PCR and melting curve analysis. Results Patients and controls were similar in terms of allele frequencies for polymorphic markers A49T and V89L in the SRD5A2 gene. Most patients had T2b (51.3%), N0 (96.3%) stage tumors with Gleason Score of ≥6 (82.7%) and surgical margin in 28.8%. While 81.3% had no seminal vesicle invasion, 36.3% had capsular invasion. Carrying the 49T allele was associated with higher likelihood of positive surgical margin status (27.5% in 49A vs. 75.0% in 49T, p=0.038) and Gleason Scores of ≥7 (47.5% in 49A vs. 100.0% in 49T, p=0.032) than 49A allele. Conclusion Our findings revealed no significant difference between patient and control groups in terms of allele frequencies of polymorphic markers in the SRD5A2 gene. T allele was only shown in the patient group. Carrying the 49T allele was associated with higher tumor aggressiveness in A49T polymorphism.

Phenotype and molecular characteristics in 45 Chinese children with 5α-reductase type 2 deficiency from South China.

Affected by steroid 5α-reductase type 2 deficiency (5α-RD2), 46, XY individuals present divergent phenotypes characterized by undervirilization of male external genitalia. To identify the disorder, mutational analysis of 5α-reductase type 2 gene (SRD5A2) is a reliable approach. The genotype-phenotype relationship has not been elucidated. To improve the diagnosis and expand the knowledge of the disease, we collected and analysed relevant data of clinical diagnosis, biological investigation and molecular determination in 45 children with the SRD5A2 gene mutations from South China in our centre. We studied a cohort of 45 Chinese children with SRD5A2 gene mutations. Isolated microphallus (35·6%) and microphallus associated with various degrees of hypospadias (55·6%) were frequent phenotype. Female external genitalia with clitoromegaly (8·9%) were rare. 16 of 18 (88·9%) cases had hCG-stimulated T/DHT ratio above 10. In 45 patients, we identified 15 different mutations. Five have never been described: p.His90ThrfsX31, p.Gly21Arg, p.Gly149Asp, p.Arg145Leu and p.Gly66Arg. The p.Arg227Gln mutation was detected in 41 (91·1%) patients. The p.Leu89Val polymorphism was found in 38 (84·4%) patients. Homozygous mutations were presented in 16 (35·6%) patients, compound heterozygous mutations in 20 (44·4%) patients, compound heterozygous mutations alone with the p.Leu89Val polymorphism in nine (20·0%) patients. Exons 1 and 4 were most affected, and the number of mutant alleles per exon was 78·1% and 12·2%, respectively. The study demonstrated a wide spectrum of phenotypes, biological profiles and genotypes in the children with 5α-RD2 from South China. The heterozygous mutation p.Arg227Gln is presumably a hot spot mutation and suggests a founder effect in the population of South China that may explain a moderate phenotype among our patients. Our report provides new insights into the molecular mechanism of 5α-RD2 and help to the diagnosis and treatment of this disease.

Phenotype and genotype of patients with disorder of sex development due to 5α-reductase deficiency

A rare form of the 46,XY disorders of sex development (DSD), 5α-reductase deficiency was first described in patients with pseudovaginal perineoscrotal hypospadias, microphallus, and cryptorchid testes in 1974 by Imperato. This undervirilization in the male is due to an alteration in the 5α-reductase type 2 gene (SRD5A2), which encodes for 5α- reductase activity. Our registry of 750 patients with DSD showed no definitive diagnosis in 80% of cases with 46,XY DSD. Our aim is to identify mutations in SRD5A2 gene and to describe phenotype of detected mutative cases. Mutation analysis was performed for genomic DNA extracted from WBC of 10 patients with 46,XY DSD using PCR and direct sequencing. We identified mutations of SRD5A2 gene in two cases. The first case presented with isolated micropenis at birth, two palpable testes in the normal scrotum. Pelvic ultrasound showed no ovaries and uterus, karyotype was 46,XY and SRY was positive. Serum FSH level was 2.4 UI/L; LH level was 0.9 UI/L and testosterone level was 0.4 nmol/l at 8 years of age. A homozygous missense mutation (p.R237G) was identified in the SRD5A2 gene. The second case presented with microphaslus, penoscrotal hypospadias, gonad bilateral in labioscrotal folds. No uterus and ovaries were found by pelvic ultrasound. Karyotype was 46,XY and SRY was positive. A novel homozygous missense mutation (c.659C>T; p.S220L) was identified in the SRD5A2 gene. Mutation analysis of SRD5A2 gene helps to make definitive diagnosis for patients with 46,XY DSD.

AR and SRD5A2 gene mutations in a series of 51 Turkish 46,XY DSD children with a clinical diagnosis of androgen insensitivity.

46,XY disorders of sex development (DSD) are caused by disorders of gonadal development, androgen biosynthesis and receptor (AR) defects. Although, clinical/biochemical features help in distinguishing specific aetiologies, there are overlaps which necessitate molecular analyses for the definitive diagnosis. To test precision of our clinical diagnosis of androgen insensitivity (AIS) by analysing AR and then SRD5A2 genes, patients were recruited at Marmara University Hospital and molecular analyses were performed at Vall d'Hebron Research Institute. Among 101 46,XY DSD patients, 46 index and five siblings (nine complete, 42 partial) with clinical/biochemical data suggestive of AIS and stimulated T/DHT ratio <25 were selected. AR and then SRD5A2 genes were sequenced. We detected AR mutations in 11 patients [seven index and four siblings (22% of all and 15% of index patients)] and SRD5A2 mutations in six [five index and one sibling (12% of all and 11% of index)]. AR mutation detection rate was 6/9 in all CAIS and 4/7 in the index (67 and 57% respectively) and 5/42 in all PAIS and 3/40 in the index (12 and 7.5% respectively). The eight mutations detected in the AR gene were as follows: p.Q58L, p.P392S, p.R609K, p.R775H, p.R856H, p.A871A, p.V890M and p.F892L, with p.A871A and p.F892L being novel. Further six patients had SRD5A2 mutations which were as follows: p.L73WfsX59, p.Y91H, p.R171S and p.G196S, the first being novel. Hormonal data in those with AR mutations, SRD5A2 mutations and no mutations were not statistically different. In conclusion, a significant proportion of children with presumptive diagnosis of AIS has a normal AR gene. The less severe the phenotype, the less likely is the chance of demonstrating a mutation. Furthermore, a significant number of children with presumptive diagnosis of AIS have mutations in SRD5A2 gene and are clinically and biochemically indistinguishable from AIS.

Clinical presentations and molecular characterization of Indonesian children with 5 alpha-reductase deficiency

Inactivating mutations in 5 alpha-reductase (SRD5A2) gene lead to steroid 5 alpha-reductase deficiency, a rare autosomal recessive condition affecting 46,XY individuals, who generally present with clinical spectrum ranging from a male phenotype with hypospadia to a female phenotype with normal wolffian structures. More than 50 different mutations responsible for this disorder have been documented. This study is to extend our previous report, which described two siblings with 2 novel mutations of SRD5A2 gene, on Indonesian children with 5 alpha-reductase deficiency. We describe clinical, hormonal, and molecular profiles of 14 children with 46,XY DSD and undervirilization due to 5-alpha reductase deficiency. DNAs extracted from peripheral blood lymphocytes, and the 5 exons of SRD5A2 gene were amplified using specific primers and sequenced. All of the patients (aged 2 months-18 years old) presented with genitalia ambiguity, including variable degree of hypospadia, phallic enlargement, palpable testis in ‘girls’, micropenis, cryptorchidism, virilization during puberty in ‘girls’ (8 out of 12 patients), and dismorphic appearances in 1 case. Twelve of them raised as girls, while eight patients who had entered pubertal age changed their identity to male. The T/DHT ratio were more than 20 in 8 patients with documented hormonal results. Three mutations including p.Gly34Fs, c.699-1 G>T, and p.Glu135Lys, which have not been reported in other populations were detected. The p.Arg227Gln was the most frequent mutations found (in 13/14 patients or 13/28 alleles). The combination of p.Val89Leu and p.Arg227Gln, which rarely reported in other populations, were detected in 6 patients. In our series, who all presented with genitalia ambiguity and mostly raised as girls, three mutations, including p.Gly34Fs, c.699-1 G>T, and p.Glu135Lys, which never been reported in other populations were detected.

Novel nucleotide insertions in two unrelated Indian patients with 5α reductase 2 deficiency leading to premature termination of SRD5A2 enzyme

T is converted to a more potent androgen, DHT by the action of microsomal membrane enzyme 5α reductase 2. Defects in 5α reductase 2 isozyme results in incomplete virilisation of external male genitalia. Mutations in SRD5A2 gene leads to diminished enzyme activity, thus hampering DHT synthesis from T. We describe two unrelated patients from India with 5αRD2 due to novel insertion of nucleotides in the exon 1 of SRD5A2 gene that lead to premature termination of protein. Master S (case 1; III.8) was 3years old at initial evaluation, had perineoscrotal hypospadias, microphallus and both testes were palpable in the inguinal region. Master P (case 2; III.9) was born as normal full term baby. He had primary complaint of microphallus, penoscrotal hypospadias and gonads in the inguinal region. Diagnosis of 5αRD2 was made, as T/DHT ratio in the two cases was 41 and 131.2 respectively. Sequence analysis of SRD5A2 gene showed an insertion of nucleotides TA in exon 1 (c.188_189). This resulted in premature termination of the protein due to stop codon at amino acid position 7. The protein formed is drastically truncated and inadequate protein synthesized explains the phenotypic characteristics of our patients.

SRD5A2 gene mutations and polymorphisms in Spanish 46,XY patients with a disorder of sex differentiation

One hundred and forty-six index patients with 46,XY DSD in whom gonads were confirmed as testes were consecutively studied for a molecular diagnosis during the period 2002-2010. AR gene was analysed in all patients as the first candidate gene, yielding a mutation in 42.5% of cases and SRD5A2 gene was analysed as the second candidate gene, resulting in the characterization of 10 different mutations (p.Y91D, p.G115D, p.Q126R, p.R171S, p.Y188CfsX9, p.N193S, p.A207D, p.F219SfsX60, p.R227Q and p.R246W) in nine index patients (6.2% of the total number of 46,XY DSD patients). One of the mutations (p.Y188CfsX9) has never been reported. In addition, we genotyped SRD5A2 gene p.V89L and c.281+15T>C polymorphisms in 46,XY DSD and in 156 normal adult males and found that patients with SRD5A2 mutations or without a known molecular diagnosis presented a higher frequency of homozygous p.L89, homozygous TT and combined CCTT genotypes compared with controls. This result suggests that 46,XY DSD patient phenotypes may be influenced by SRD5A2 polymorphism genotypes. SRD5A2 gene mutations may not be as infrequent as previously considered in 46,XY DSD patients with variable degrees of external genitalia virilization at birth and normal T production and appears to be the second aetiology in our series.

A Novel SRD5A2 Mutation with Loss of Function Identified in Chinese Patients with Hypospadias

Objective: To investigate the functional change of SRD5A2 gene mutations identified in patients with 5α-reductase type 2 deficiency. Patients and Methods: Three unrelated subjects born with ambiguous genitalia were included. All patients were initially reared as girls, but they gradually exhibited variable degrees of virilization at puberty without breast development, followed by a change of gender role. Sequencing analysis of the SRD5A2 gene was performed and enzymatic activities of 5α-reductase type 2 were assessed. Results: Three compound heterozygous mutations in the SRD5A2 gene were identified: patient 1 with p.G203S/ c.655delT, patient 2 with p.Q6X/p.G203S, and patient 3 with p.G203S/c.755_756insT. Heterozygosity for the p.V89L polymorphism was also found in patients 2 and 3. The c.655delT mutation led to a complete loss of the enzymatic activity, whereas mutants p.G203S and c.755_756insT resulted in a reduction of the enzymatic activities by 60 and 90%, respectively. Conclusion: Two frameshift heterozygous mutations, c.655delT and c.755_756insT, led to a dramatic reduction in 5α-reductase activity, and the latter had not been reported previously. In addition, the heterozygous mutation (p.G203) identified in the 3 patients presumably suggests a founder effect in the Chinese population and may explain the similarity in phenotype among the patients.

Undervirilization in XY newborns may hide a 5α‐reductase deficiency: report of three new SRD5A2 gene mutations

The observation of ambiguous genitalia in the newborn signals a medical, surgical and psychological emergency. The most crucial decision will be the choice of sex assignment. Rapid and precise diagnosis is thus essential. In XY newborns with normal/high plasma testosterone (T), partial androgen insensitivity syndrome (PAIS) is usually the first diagnosis evoked, which implies an androgen receptor (AR) defect. The diagnosis of steroid-5-alpha-reductase deficiency is rarely considered by the paediatrician. We report three new SRD5A2 gene mutations in four newborns from France, Morocco and Turkey. The newborns presented with ambiguous genitalia and normal plasma T values and the initial diagnosis\PAIS. In all four cases, normal sequences of the complete AR gene excluded this diagnosis and raised the hypothesis of 5α-reductase deficiency. The entire coding region (5 exons) of the SRD5A2 gene was assessed by PCR and direct sequencing analysis. For patient 1, we identified a new homozygous 2bp deletion in exon 1 (c.122_123delAG). Patient 2 had a known homozygous mutation, p.G115D, in exon 2. New compound heterozygous mutations in exon 4 (p.A215V) and exon 5 (p.X255Q) were found in patient 3. Patient 4 presented a new substitution in exon 1 (p.S14R) associated with a known polymorphism (p.V89L). Our data confirm our previous experience and clearly demonstrate that a 5-α reductase defect should be considered in all XY newborns with ambiguous genitalia and normal plasma T secretion, whatever their geographic area or ethnic group; moreover, this defect was not linked to specific phenotype. Early molecular diagnosis is indispensable for the crucial decision of the newborn's sex of rearing.

Primary amenorrhea in four adolescents revealed 5α-reductase deficiency confirmed by molecular analysis

To determine the genetic cause of primary amenorrhea. Case series. Pediatric endocrinology, endocrinology, and gynecology departments of academic hospitals. Three adolescents and one young woman 46, XY patients with srd5A2 gene mutations. Genetic analysis of srd5A2. We report four srd5A2 gene mutations in three adolescents and one young woman with 46,XY primary amenorrhea. All presented clitoromegaly and two presented hypospadias; all had been reared as females. Virilization of the external genitalia was noted in the pubertal period in all four patients. Three were maintained in the female sex of rearing by personal choice, and the fourth switched gender. We identified the homozygous substitutions p.L55Q (exon 1), p.Q56R (exon 1), and p.N193S (exon 4), in patients 1, 2, and 3, respectively. Patient 4 had compound heterozygous mutations, a new c.34delG (exon 1) associated with p.R246W (exon 5). All patients had high plasma T levels (ranges, 16.2-23.2 nmol/L; normal female teenage range, 0.35-2 nmol/L). Our data clearly demonstrate that 5α-reductase deficiency should be considered in XY adolescents with primary amenorrhea and no breast development associated with virilization at puberty and high plasma T. Positive parental consanguinity should reinforce the diagnostic orientation.

Five novel mutations of SRD5A2 found in eight Chinese patients with 46,XY disorders of sex development

Individuals with male karyotype (46,XY) affected by 5α-reductase type 2 deficiency, a rare autosomal recessive inherited disorder, can have an almost female phenotype or partially virilized external genitalia. Mutations in the steroid-5-α-reductase (SRD5A2) gene, leading to functional impairment of 5α-reductase type 2, are responsible for this disorder. Our present study analyzed SRD5A2 gene mutations in eight unrelated 46,XY Chinese patients with disorders of sex development. Direct sequencing of genomic DNA for SRD5A2 gene revealed the presence of one homozygous (p.Q6X) and seven compound heterozygous mutations (p.G203S/R227Q, p.L20P/R227Q, p.Q6X/p.A228V, p.C222Ffs232X/p.R246Q, p.W140X/F219Sfs278X, p.Q71X/L185Tfs192X and p.Q6X/p.N193S) in our patients. Among them, p.C222Ffs232X, p.A228V, p.Q71X, L185Tfs192X and p.W140X mutations have not been previously reported. These novel mutations may provide us new insights into the molecular mechanism of 5α-reductase type 2 deficiency. Seven out of eight patients had at least one variant in exon 4, and 8 of 12 (66.7%) mutations were located in exon 4. The expanded mutation database of the SRD5A2 gene should benefit patients in the diagnosis and treatment of this disease.

A novel mutation of 5α-steroid reductase 2 deficiency (CD 65 ALA-PRO) with severe virilization defect in a Turkish family and difficulty in gender assignment

Molecular genetic characterization of mutations in SRD5A2 gene is used as an essential procedure for the final diagnosis of 5alpha-reductase deficiency. Here, we report a novel homozygous point mutation of SRD5A2 gene at codon 65 in exon 1, due to a proline for alanine substitution in a Turkish family whose proband has severe undervirilization. This mutation has not been reported up to date in association with 5alpha-reductase deficiency in various ethnic groups. We discussed some questions about gender assignment in addition to the molecular and clinical characteristics of the disease.