Complete Androgen Insensitivity Syndrome: From Bench to Bed.

Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (AR). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the AR gene have been reported in CAIS. They are distributed throughout the gene with a preponderance located in the ligand-binding domain. CAIS mainly presents as primary amenorrhea in an adolescent female or as a bilateral inguinal/labial hernia containing testes in prepubertal children. Some issues regarding the management of females with CAIS remain poorly standardized (such as the follow-up of intact testes, the timing of gonadal removal and optimal hormone replacement therapy). Basic research will lead to the consideration of new issues to improve long-term well-being (such as bone health, immune and metabolic aspects and cardiovascular risk). An expert multidisciplinary approach is mandatory to increase the long-term quality of life of women with CAIS.

Complete Androgen Insensitivity Syndrome: From the Relevance of an Accurate Genetic Diagnosis to the Challenge of Clinical Management. A Case Report.

Introduction: Androgen insensitivity syndrome (AIS), an X-linked recessive disorder of sex development (DSD), is caused by variants of the androgen receptor (AR) gene, mapping in the long arm of the X chromosome, which cause a complete loss of function of the receptor. Case presentation: We report a patient diagnosed with complete AIS (CAIS) at birth due to swelling in the bilateral inguinal region. Transabdominal ultrasound revealed the absence of the uterus and ovaries and the presence of bilateral testes in the inguinal region. The karyotype was 46,XY. She underwent bilateral orchiectomy at 9 months and was given estrogen substitutive therapy at the age of 11 years. Genetic analysis of the AR gene variants was requested when, at the age of 20, the patient came to our observation. Methods: The genetic testing was performed by next-generation sequence (NGS) analysis. Results: The genetic analysis showed the presence of the c.2242T>A, p.(Phe748Ile) variant in the AR gene. To the best of our knowledge, this variant has not been published so far. Furthermore, the patient has a heterozygous c.317A>G, p.(Gln106Arg) variation of the gonadotropin-releasing hormone receptor (GNRHR) gene, a heterozygous c.2273G>A, p.Arg758His variation of the chromodomain helicase DNA binding protein 7 (CHD7) gene, and compound heterozygous c.875A>G, p.Tyr292Cys, and c.8023A>G, p.Ile2675Val variations of the Dynein Axonemal Heavy Chain 11 (DNAH11) gene. Conclusions: The case herein reported underlines the importance of an accurate genetic analysis that has to include karyotype and AR gene variant analysis. This is useful to confirm a clinical diagnosis and establish the proper management of patients with CAIS. Numerous variants of the AR gene have not yet been identified. Moreover, several pitfalls are still present in the management of these patients. More studies are needed to answer unresolved questions, and common protocols are required for the clinical follow-up of patients with CAIS.

[The incidence of AZF deletions, CFTR mutations and long alleles of the ar CAG repeats during the primary laboratory diagnostics in a heterogeneous group of infertily men].

AIM: microdeletions in the AZF region of Y-chromosome, compound heterozygotes of severe and mild CFTR mutations, and long CAG-repeats in the androgen receptor gene (AR) as marker of predisposition are frequently studied as genetic causes of male infertility. A simultaneously testing of the panel including biochemical, immunological, cyto- and molecular genetic markers is often performed during the complex laboratory diagnostics in infertile men. The aim of our work was to identify molecular genetic alterations, which are advisable for simultaneously testing in a man with currently uncertain form of infertility, to increase the informativeness of laboratory diagnostics. MATERIALS AND METHODS: a retrospective study of 885 infertile men was conducted. AZF deletions were determined by multiplex PCR using 10 STS-markers (sY83, sY84, sY86, sY127, sY134, sY143, sY152, sY157, sY254, sY255) and two control loci SRY and AMEL with detection in polyacrylamide gel. Mutations in the CFTR gene (F508del, CFTRdel2.3(21kb), I507del, 1677delTA, 2143delT, 2184insA, 394delTT, W1282X, G542X, N1303K, R334W and 5T) were detected by PCR and SNaPshot. For determination of length of the AR CAG-repeat a fragment analysis of fluorescently labeled PCR products on the 3500xl capillary sequencer was performed. RESULTS: AZF deletions were detected in 8.2% of cases. The largest number of deletions was found in the AZFc subregion (58.9%), while a frequency of deletion in AZFa, AZFb or combined deletions of two and three subregions was 5.5%, 12.3% and 23.3%, respectively. Heterozygous carriage of severe CFTR mutations was detected in 4.7% patients. The most frequent mutation was F508del (83.3%), followed by CFTRdel21kb (7.1%) and W1282X (4.8%). The frequency of the mild splicing 5T mutation was 5.3%, and its incidence was significantly higher than in the previously published control group (p=0.002). AR genotyping revealed that the most prevailing allele was 21 (CAG) (21.5%). Long alleles with 27 or more CAG-trinucleotides were identified in 7.5% of the tested cases. In addition, 7 CAG heterozygotes with Kleinfelter syndrome were found. CONCLUSION: during primary complex laboratory diagnostics in a heterogeneous group of infertile men, it is advisable to detect AZF deletions and the most frequent CFTR mutations, including F508del, CFTRdel21kb, 1677delTA, 2143delT, W1282X and 5T. The more comprehensive analysis of CFTR mutations is justified only in patients with verified obstructive infertility. Sequencing of panels associated with infertility genes using NGS technology is promising.

Association of arg16gly and gln27glu, b2-adrenergic receptor gene polymorphism with asthma. A systematic review and meta-analysis of case control studies.

The study was planned to assimilate quantitatively the available evidences on association of Arg16Gly and Glu27Gln with asthma and to produce more precise results. All case-control studies conducted on adults were searched on Medline, Embase, PubMed, Wiley online library according to Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. The strength of association was measured by odds ratios with 95% confidence interval. A total of 17 case-control studies were included in the meta-analysis and there was no significant association of asthma with Arg16Gly (odds ratio = 1.19; 95% confidence interval = 0.75-1.50, p=0.459) and Glu27Gln of ADRb2 polymorphism (odds ratio=0.87, 95% confidence interval =0.44-1.71, p=0.683). Moreover, neither Gly16 allele (odds ratio = 0.98; 95% confidence interval = 0.70-1.38, p=0.867) nor Glu27 allele (odds ratio = 0.67, 95% confidence interval = 0.38-1.19, p=0.169) contributed to asthma susceptibility. There was also no significant association between haplotypes of both single nucleotide polymorphisms and asthma (p>0.05). Data indicated that adrenergic receptor b2 did not contribute markedly to susceptibility to asthma (p>0.05).

Prenatal Diagnosis of Twin Fetuses with a Novel AR Gene Mutation in a Chinese Family of Complete Androgen Insensitivity Syndrome.

INTRODUCTION AND AIMS: Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disorder caused by mutations in the androgen receptor (AR) gene. Only a few cases of AIS with AR gene mutations have been diagnosed prenatally. This study aimed to investigate the gene mutation in a Chinese complete androgen insensitivity syndrome family and perform prenatal diagnosis for twin fetuses. CASE REPORT: We evaluated the AR gene of the child proband in a Chinese CAIS family, and detected a novel mutation c.3864T>C (p. Phe917Leu). Amniocentesis was performed when the mother presented to our hospital with a subsequent twin pregnancy. Mutation analysis revealed that both fetuses were hemizygous for this mutation. The aborted fetuses had typical female external genitalia and bilateral testes in abdomen. CONCLUSION: The c.3864T>C AR novel mutation is responsible for complete androgen insensitivity syndrome, and its identification was subsequently used for a subsequent successful prenatal diagnosis.

Detection of Molecular Variations at Androgen Receptor Gene in 46,XY Differences in Sex Development Cases.

Introduction: One of the common causes of 46,XY differences in sex development (DSD) cases is androgen insensitivity syndrome. This X-linked recessive inherited condition is associated with pathological variations of the AR gene, leading to defects in androgen action. Affected 46,XY infants or individuals experience variable degrees of undervirilization and those with severe form will have female-like external genitalia. Therefore, they were more likely assigned and reared as females. The confirmatory molecular test is often needed due to similar clinical manifestations with other conditions causing 46,XY DSD. Since in our country, the molecular test for the AR gene is lacking, the study is conducted as a preliminary study to elaborate on the possibility of developing a molecular test for the AR gene in 46,XY DSD cases. Methods: Archived DNAs of 13 46,XY DSD cases were analyzed using polymerase chain reaction and direct sequencing for molecular defects in the AR gene. Clinical and hormonal data were collected and analyzed. Results: The study successfully amplified and visualized the eight exons of the AR gene and revealed two subjects carrying AR gene variants at exon 7. In the first case, 1.2-year-old boy carried heterozygous p.Gln825Arg, which has never been reported elsewhere, and the second subject, a 2.1-year-old girl with heterozygous p.Arg841His. Both subjects presented with severe undervirilization of external genitalia with external genitalia masculinization scores (EMS) of 1.5 and 3. Conclusion: In this series, two of 13 46,XY DSD cases carried variants at the AR gene, resulting in complete androgen insensitivity syndrome.

Preimplantation Genetic Diagnosis of Androgen Resistance Syndrome Caused by Mutation on the AR Gene in Vietnam.

Background: Androgen resistance syndrome or androgen insensitivity syndrome (AIS - Androgen Insensitivity Syndrome, OMIM 300068) is an X-linked recessive genetic syndrome causing disorders of sexual development in males. This disease is caused by mutations in the AR gene located on the X chromosome, which encodes the protein that structures the androgen receptor, with the role of receiving androgens. Mutation of the AR gene causes complete or partial loss of androgen receptor function, thereby androgen not being obtained and exerting its effect on target organs, resulting in abnormalities of the male reproductive system due to this organ system, differentiating towards feminization under the influence of estrogen. Disease prevention can be achieved by using pre-implantation genetic diagnosis, which enables couples carrying the mutation to have healthy offspring. Aim: To carry out preimplantation genetic diagnosis of androgen resistance syndrome. Methods: Sanger sequencing was used to detect the mutation in the blood samples of the couple, their son, and 01 embryo that were biopsied on the fifth day based on the findings of next-generation sequencing (NGS) of the affected son. We combined Sanger sequencing and linkage analysis using short tandem repeats (STR) to provide diagnostic results. Results: We performed preimplantation genetic diagnosis for AIS on an embryo from a couple who had previously had an affected son. Consequently, one healthy embryo was diagnosed without the variant NM_000044: c.796del (p.Asp266IlefsTer30). Conclusion: We report on a novel variant (NM_000044: c.796del (p.Asp266IlefsTer30)) in the AR gene discovered in Vietnam. The developed protocol was helpful for the preimplantation genetic diagnosis process to help families with the monogenic disease of AIS but wish to have healthy children.

Case Report: Surgery and genetic analysis of a complete androgen insensitivity syndrome family with testicular malignant tumors.

Introduction: Complete androgen insensitivity syndrome (CAIS) is a rare sex development disorder that results from X-linked androgen receptor gene mutations. Malignant transformation of the gonads is the most feared complication in postpubertal patients. Methods: In the current report, primary amenorrhea, infertility, and groin mass were symptoms described by a 58-year-old woman and his younger sister. Their two aunts, who shared the same clinical traits, passed away for an unknown reason. Results: After gonadectomy, both patients were diagnosed with seminoma and an extratesticular benign tumor, and the elder sister suffered from breast cancer about a year after the operation. The diagnosis of CAIS was verified by whole-exome sequencing (WES), in which an uncommon mutation (c.2197G>A) in the AR gene was identified. Discussion: This is the first family report of CAIS with germ cell tumors. The identified AR gene mutation based on WES can expand the understanding of CAIS.

Investigation of the regulatory effects of synthesized antisense oligonucleotides on androgen receptor (AR) exon 3 splicing in prostate cancer cells.

The Androgen Receptor (AR) gene plays a key role in castration-resistant prostate cancer (CRPC). Controlling the progression of CRPC by inhibiting AR gene expression is one of the core directions for prostate cancer (Pca) drug development. A 23-amino acids retention, named exon 3a, into the DNA binding domain of the splice variant AR23 has been shown to prevent AR from entering the nucleus and restore the sensitivity of cancer cells to related therapies. In this study, we conducted a preliminary investigation of the splicing modulation of the AR gene in order to develop a splice-switching therapy for Pca by promoting exon 3a inclusion. Using mutagenesis-coupled RT-PCR with AR minigene and over-expression of certain splicing factors, we found that serine/arginine-rich (SR) proteins are key factors facilitating the recognition of the 3' splice site of exon 3a (L-3' SS), while the deletion or blocking of the polypyrimidine tract (PPT) region of the original 3' splice site of exon 3 (S-3' SS) could strongly enhance exon 3a splicing without affecting the function of any SR protein. Furthermore, we designed a series of antisense oligonucleotides (ASOs) to screen drug candidates, and ASOs targeting S-3' SS and its PPT region or the exonic region of exon 3 turned out to be most effective in rescuing exon 3a splicing. A dose-response test indicated ASO12 as the lead candidate drug significantly promoting the inclusion of exon 3a to more than 85%. MTT assay confirmed that the cell proliferation was significantly inhibited after ASO treatment. Our results provide the first glance to AR splicing regulation. With several promising therapeutic ASO candidates obtained here, further development of ASO drugs to treat CRPC is strongly encouraged.

The relationship between common mutations in CFTR, AR genes, Y chromosome microdeletions and karyotyping abnormalities with very severe oligozoospermia in Iranian men.

BACKGROUND: Male infertility due to very severe oligozoospermia has been associated with some genetic risk factors. OBJECTIVE: To investigate the distribution of the mutations in the CFTR gene, the CAG-repeat expansion of the AR gene, also Y chromosome microdeletions and karyotyping abnormalities in very severe oligozoospermia patients. METHODS: In the present case-control study, 200 patients and 200 fertile males were enrolled. All patients and control group were karyotyped. Microdeletions were evaluated using multiplex PCR. Five common CFTR mutations were genotyped using the ARMS-PCR technique. The CAG-repeat expansion in the AR gene was evaluated for each individual using sequencing. RESULTS: Overall 4% of cases shows a numerical and structural abnormality. 7.5% of patients had a deletion in one of the AZF regions on Yq, and 3.5% had a deletion in two regions. F508del was the most common (4.5%) CFTR gene mutation; G542X, and W1282X were detected with 1.5% and 1% respectively. One patient was found to have AZFa microdeletion and F508del in heterozygote form; one patient had AZFb microdeletion with F508del. F508del was seen as compound heterozygous with G542X in one patient and with W1282X in the other patient. The difference in the mean of the CAG-repeats in the AR gene in patients and control groups was statistically significant (P = 0.04). CONCLUSION: Our study shows the genetic mutations in men with severe oligozoospermia and given the possibility of transmission of these disorders to the next generation by fertilization, counseling and genetic testing are suggested for these couples before considering ICSI.

CAG Repeat Number in the Androgen Receptor Gene and Prostate Cancer.

Prostate cancer (PC) is the second leading cause of cancer deaths in men. The effects of androgens on prostatic tissue are mediated by the androgen receptor (AR) gene. The 5' end of exon 1 of the AR gene includes a polymorphic CAG triplet repeat that numbers between 10 to 36 in the normal population. The length of the CAG repeats is inversely related to the transactivation function of the AR gene. There is controversy over association between short CAG repeat numbers in the AR gene and PC. This retrospective case-control study evaluates the possible effect of short CAG repeats on the AR gene in prostate cancer risk in Macedonian males. A total of 392 male subjects, 134 PC patients, 106 patients with benign prostatic hyperplasia (BPH) and 152 males from the general Macedonian population were enrolled in this study. The CAG repeat length was determined by fluorescent polymerase chain reaction (PCR) amplification of exon1 of the AR gene followed by capillary electrophoresis (CE) on a genetic analyzer. The mean repeat length in PC patients was 21.5 ± 2.65, in controls 22.28 ± 2.86 (p = 0.009) and in BPH patients 22.1 ± 2.52 (p = 0.038). Short CAG repeats (<19) were found in 21.64% of PC patients vs. 9.43% in BPH patients (p = 0.0154). We also found an association of low Gleason score (<7) with short CAG repeat (<19) in PC patients (p = 0.0306), and no association between the age at diagnosis of PC and BPH and CAG repeat length. These results suggest that reduced CAG repeat length may be associated with increased prostate cancer risk in Macedonian men.

The Relationship between Androgen Receptor Gene Polymorphism, Aggression and Social Status in Young Men and Women.

In both sexes, aggression has been described as a critical trait to acquire social status. Still, almost uniquely in men, the link between aggressiveness and the genetic background of testosterone sensitivity measured from the polymorphism in the androgen receptor (AR) gene has been previously investigated. We assessed the relevance of the AR gene to understand aggression and how aggressiveness affects social status in a cross-sectional study of 195 participants, for the first time in both young men and women. We estimated polymorphism sequences from saliva and measured aggression and self-perceived social status. Unfortunately, the results did not support our prediction because we did not find any of the expected relationships. Therefore, the results suggest that the genetic association between aggressive mechanisms and polymorphism of the AR gene is less straightforward than expected, at least in men, and seems to indicate that aggression is not usually used to gain social status in our population.

Investigation of androgen receptor gene CAG repeat length polymorphism in pubertal gynecomastia.

OBJECTIVES: Androgen receptor gene CAG repeat, AR (CAG)n, polymorphism is thought to have an effect on male reproductive functions and a relationship between long AR (CAG)n and decreased androgenic activity has been shown. Therefore, we hypothesized that in adolescents with long AR CAG repeat the prevalence of pubertal gynecomastia (PG) will be higher and we aimed to investigate the association between AR (CAG)n polymorphism and PG in Turkish adolescents. METHODS: Adolescents with PG between 11 and 19 years of age were enrolled as the study group and healthy individuals without a history of PG, who were at least 14 years of age and Tanner 4 or 5 were enrolled as the control group. The AR (CAG)n length was detected by direct DNA sequencing analysis and reproductive hormones were measured by standardized analyses. RESULTS: The mean AR (CAG)n was 22.3 ± 2.6 (mean ± SD) in the PG group (n=101) and 21.9 ± 3.1 (mean ± SD) in the control group (n=88) (p=0.276). The adolescents with short AR (CAG)n had lower body mass index standard deviation scores (BMI SDS) compared to the adolescents with intermediate and long repeat numbers (p=0.029). CONCLUSIONS: The results of this study showed a lack of direct association between AR (CAG)n and PG. However, the significant relationship between the AR (CAG)n quartiles and BMI SDS suggests that long AR (CAG)n might cause PG indirectly. Further studies are needed to better clarify this relationship.

Alpha-2 beta-adrenergic receptor (301-303 I/D) gene polymorphism in hypertension and type 2 diabetes mellitus diseases among Saudi cases in the Qassim region.

The hypertension (HTN) and type 2 diabetes mellitus (T2DM) are a common multifactorial disease due to genetics and environmental factors. The alpha 2B adrenergic receptor (α2B-AR) has relationship with secretion of insulin and mediates the vasoconstriction that elevate blood pressure. This study aimed to determine the association between α2B-AR gene polymorphism with HTN and T2DM in Saudi cases. 200 cases and 100 healthy controls from Saudi population were recruited from the Internal Medicine clinic, Qassim University. The patients were grouped into: 72 HTN without T2DM; 62 HTN with T2DM and 66 T2DM only. Full medical history, examination and biochemical assays were performed for all participants. Genomic DNA was isolated from blood lymphocytes of all subjects for detection of α2B-AR gene polymorphism by using polymerase chain reaction (PCR). The results found a significant association between D carriers genotype and HTN with T2DM cases (p < 0.05) as well as with T2DM-only cases, (p < 0.05) compared to control. Regardless of HTN status, only cases with HTN and T2DM as well as those with T2DM were significantly associated with the recessive model DD versus II+ID (p < 0.05). So, D carriers genotype was significantly associated with total cases of HTN and T2DM (p < 0.05) compared to controls. Our results suggested that there is a relationship between the α2B-AR I/D gene polymorphism and the risk for T2DM with or without HTN, but no such comparable relationship is evident with HTN-only cases among Saudi population in Qassim region.

AR gene rearrangement analysis in liquid biopsies reveals heterogeneity in lethal prostate cancer.

Castration-resistant prostate cancer (CRPC) is driven by AR gene aberrations that arise during androgen receptor (AR)-targeted therapy. AR amplification and mutations have been profiled in circulating tumor cells (CTCs), but whether AR gene rearrangements can be assessed in CTCs is unknown. In this study, we leveraged CRPC cell lines with defined AR gene rearrangements to develop and validate a CTC DNA analysis approach that utilized whole genome amplification and targeted DNA-sequencing of AR and other genes important in CRPC. We tested the utility of this approach by analyzing matched CTC DNA and plasma cell-free DNA (cfDNA) from a case series of ten CRPC patients. One of ten CTC samples and two of ten cfDNA samples were positive for AR gene rearrangements. All AR gene rearrangements were discordant between matched liquid biopsy samples. One patient harbored separate AR gene rearrangements in CTC DNA and cfDNA, but concordant AR amplification and AR T878A mutation. This patient also displayed concordant loss of TP53 and PTEN, but the loss of RB1 in cfDNA only. The overall frequency of discordant alterations in these genes between matched CTC DNA and cfDNA was high. This study establishes the technical feasibility of analyzing structural rearrangements, mutations, and copy number variants in AR and other CRPC genes using two different sources of DNA from a single blood sample. Paired CTC DNA and cfDNA analysis may have utility for capturing the heterogeneity of genetic alterations in CRPC patients.

Androgen Receptor Gene Variants in New Cases of Equine Androgen Insensitivity Syndrome.

In the domestic horse; failure of normal masculinization and virilization due to deficiency of androgenic action leads to a specific disorder of sexual development known as equine androgen insensitivity syndrome (AIS). Affected individuals appear to demonstrate an incoherency between their genetic sex and sexual phenotype; i.e., XY-sex chromosome constitution and female phenotypic appearance. AIS is well documented in humans. Here we report the finding of two novel genetic variants for the AR-gene identified in a Tennessee Walking Horse and a Thoroughbred horse mare; each in individual clinical cases of horse AIS syndrome.

Adolescent Gynecomastia due to Minimal Androgen Resistance Syndrome: A Case Report and Literature Review.

A 14-year-old boy with a 46,XY karyotype and persistent breast-3-stage gynecomastia is reported. The reproductive axis was investigated by standard laboratory methods and the androgen receptor (AR) gene was sequenced. Also, a literature review of phenotypes associated with the AR genetic variant p.Pro392Ser was performed. The boy presented with height in the upper normal range (+1.9 SDS) and normal body mass index (-0,3 SDS); pubertal development was PH5/G4 (mean testicular volume 15 mL; 0 SDS). Laboratory findings were normal for age and sex, except aromatization index (0.09; reference range 0.03-0.07). Analysis of the AR gene showed the single nucleotide variant c.1174C>T (p.Pro392Ser) in exon 1, leading to the diagnosis of minimal androgen insensitivity syndrome (AIS). This genetic variant is reported in other 8 patients with AIS and is associated with variable clinical phenotypes ranging from complete to partial and minimal AIS. To the best of our knowledge, this is the first adolescent in whom the p.Pro392Ser mutation is associated with isolated persistent gynecomastia. The underlying reason of phenotypic variability due to this AR mutation remains unknown. Persistent gynecomastia due to minimal AIS has been reported in few additional males with variable AR mutations. Since fertility troubles may occur in adult men with minimal AIS, early diagnosis can allow optimizing the clinical management.

"Spectrum of 46 XY Disorders of Sex Development": A Hospital-based Cross-sectional Study.

BACKGROUND: Disorders of sex development (DSD) are a wide range of relatively rare conditions having diverse pathophysiology. Identification of an underlying cause can help in treating any coexisting hormone deficiencies and can help with anticipating any other immediate or long-term health concerns. OBJECTIVE: To study the clinical and biochemical profile of patients with 46 XY DSD along with androgen receptor (AR) gene mutation status in selected group of patients. METHODS: A cross-sectional study was conducted after enrolling the eligible DSD patients. Thorough elicitation of history and detailed clinical examination was done. Assays for luteinizing hormone, follicle-stimulating hormone, testosterone, dihydrotestosterone, androstenedione, AMH & Inhibin B (where indicated), and human chorionic gonadotropin stimulation were done as per protocol. RESULTS: In total, 48 patients were included in the study. Ambiguous genitalia (58.3%) followed by hypospadias (33.3%) were common presentation. Androgen biosynthetic defect were the most commonly encountered diagnosis followed by androgen insensitivity syndrome (AIS). Swyer syndrome was diagnosed in 4.2% of cases; partial gonadal dysgenesis, ovotesticular DSD, and vanishing testis syndrome contributed to 2% of cases each. Eight cases (16.7%) who presented with isolated proximal and midshaft hypospadias for whom no diagnosis was found were categorized in the "etiology unclear" group. AR gene mutation analysis designed against specific exons did not yield any results. CONCLUSION: 46 XY DSD is a heterogeneous group of patients with a varying age of presentation and a diverse clinical profile. Most patients are reared as males and maintained the same gender identity except in isolated cases. Diagnosis of AIS remains a clinical challenge as a definite hormonal criterion does not exist and genetic mutations in AR gene may be negative. Flanking region sequencing, whole genome sequencing, and promoter region sequencing may reveal pathogenic variants. Variations in other genes regulating AR pathway may also be candidates to be studied.

Novel Androgen Receptor Gene Variant Containing a Premature Termination Codon in a Patient with Androgen Insensitivity Syndrome.

BACKGROUND: Androgen receptor (AR) mutations, which cause androgen insensitivity syndrome, impair the actions of 5α-dihydrotestosterone and testosterone, resulting in abnormal sexual development. In most cases, genetic aberrations of the AR are caused by substitutions, but also can result from mutations in splicing regions and deletions in the AR gene. CASE: Our present report describes a female patient with 46,XY karyotype and normal female external genitalia. A novel de novo c.1669_1670insC insertion in the AR gene caused androgen insensitivity syndrome. SUMMARY AND CONCLUSION: This report provides a detailed clinical characterization of the patient and a possible pathogenic mechanism leading to androgen insensitivity syndrome and should be particularly useful in genetic counseling.

Novel Variant of the Androgen Receptor Gene in a Patient With Complete Androgen Insensitivity Syndrome and Polyorchidism.

Introduction: Complete androgen insensitivity (CAIS) in 65-95% cases is caused by pathogenic allelic variants (mutations) in the gene encoding androgen receptor (AR gene) and is characterized by female phenotype development with a male karyotype (46, XY). Patients are usually diagnosed during puberty and undergo gonadectomy due to increased testicular germ cell tumor risk. Only a few outcomes have been reported in older individuals with postponed gonadectomy. Case presentation: A 48-year-old CAIS patient presented with polyorchidism (four testes) without gonadal malignancies. Genetic testing identified a novel allelic variant in the AR gene [c.2141T>G (p.Phe805Cys)] causing the clinical symptoms. Conclusion: We have described a unique patient with CAIS and polyorchidism without malignancies in her late 40's bearing a novel likely pathogenic variant in the AR gene.