Androgen receptor post-translational modifications and their implications for pathology.

A major mechanism to modulate the biological activities of the androgen receptor (AR) involves a growing number of post-translational modifications (PTMs). In this review we summarise the current knowledge on the structural and functional impact of PTMs that affect this major transcription factor. Next, we discuss the cross-talk between these different PTMs and the presence of clusters of modified residues in the AR protein. Finally, we discuss the implications of these covalent modifications for the aetiology of diseases such as spinal and bulbar muscular atrophy (Kennedy's disease) and prostate cancer, and the perspectives for pharmacological intervention.

Recommendations for 46,XY Disorders/Differences of Sex Development Across Two Decades: Insights from North American Pediatric Endocrinologists and Urologists.

Clinical decision-making for individuals with 46,XY disorders/differences of sex development (DSD) remains unsettled and controversial. The North American DSD Clinician Survey examines the recommendations of a large group of clinical specialists over the last two decades. Active members of the (Lawson Wilkins) Pediatric Endocrine Society and the Societies for Pediatric Urology were invited to respond to a web-based survey at three different timepoints: 2003-2004 (T1), 2010-2011 (T2), and 2019-2020 (T3). Data from 429 participants in T1, 435 in T2, and 264 in T3 were included in this study. The participants were presented with three XY newborn clinical case scenarios-micropenis, partial androgen insensitivity syndrome, and iatrogenic penile ablation-and asked for clinical management recommendations. The main outcomes assessed included the recommended gender of rearing, surgical decision-maker (parent or patient), timing of genital surgery, and age at which to disclose medical details and surgical history to the patient. For all scenarios, the overwhelming majority recommended rearing as male, including a significant increase across timepoints in those recommending a male gender of rearing for the infant with penile ablation. The proportions recommending female gender of rearing declined significantly across timepoints. In general, most recommended parents (in consultation with the physician) serve as surgical decision-makers, but these proportions declined significantly across timepoints. Recommendations on the timing of surgery varied based on the patient's gender and type of surgery. There has been a shift in recommendations away from the "optimal gender policy" regarding gender of rearing and surgical interventions for patients with XY DSD.

MYRF mutation leads to a single manifestation of sexual development and mimics partial androgen insensitivity syndrome: a case report and literature review.

OBJECTIVE: To highlight the challenges in diagnosing 46, XY disorder of sex development related to MYRF mutation. METHODS: We present an unusual case of a 12-year-old female child came for enlargement of clitoris and initially diagnosed as partial androgen insensitivity syndrome (AIS). RESULTS: On examination, the patient's vulva was found virilized with 3cm-long clitoris. Her peripheral blood karyotype was 46, XY. The ultrasound showed an empty pelvis and hormone results confirmed hyperandrogenism. Therefore, the partial AIS was suspected, but the following whole exon sequencing indicates a pathological missense mutation in MYRF. Further investigation and surgery did not reveal any brain, heart, lung or diaphragm lesions related to MYRF, but only maldeveloped internal genitalia and a persistent urachus. Her serum testosterone dropped to normal after surgical removal of the remaining ipsilateral testis and epididymitis without spermatogenesis as shown by pathology. CONCLUSION: Due to the karyotype, hyperandrogenism, empty pelvis but a virilism after puberty, the patient was initially diagnosed as partial AIS. This misleading clinical diagnose will not be verified as the MYRF mutation if without the whole exon sequencing, particularly in the absence of obvious brain, heart, lung and diaphragm lesions as in this case.

Comprehensive molecular analysis identifies eight novel variants in XY females with disorders of sex development.

Disorders of sex development (DSD) are a group of clinical conditions with variable presentation and genetic background. Females with or without development of secondary sexual characters and presenting with primary amenorrhea (PA) and a 46,XY karyotype are one of the classified groups in DSD. In this study, we aimed to determine the genetic mutations in 25 females with PA and a 46,XY karyotype to show correlations with their phenotypes. Routine Sanger sequencing with candidate genes like SRY, AR, SRD5A2, and SF1, which are mainly responsible for 46,XY DSD in adolescent females, was performed. In a cohort of 25 patients of PA with 46,XY DSD, where routine Sanger sequencing failed to detect the mutations, next-generation sequencing of a targeted gene panel with 81 genes was used for the molecular diagnosis. The targeted sequencing identified a total of 21 mutations including 8 novel variants in 20 out of 25 patients with DSD. The most frequently identified mutations in our series were in AR (36%), followed by SRD5A2 (20%), SF1 (12%), DHX37 (4%), HSD17B3 (4%), and DMRT2 (4%). We could not find any mutation in the DSD-related genes in five (20%) patients due to complex molecular mechanisms in 46,XY DSD, highlighting the possibility of new DSD genes which are yet to be discovered in these disorders. In conclusion, genetic testing, including cytogenetics and molecular genetics, is important for the diagnosis and management of 46,XY DSD cases.

Androgen insensitivity syndrome: a review.

PURPOSE: Androgen insensitivity syndrome (AIS) is a disorder characterized by peripheral androgen resistance due to androgen receptor mutations in subjects with 46 XY karyotype. The severity of hormone resistance (complete, partial or mild) determines the wide spectrum of phenotypes. METHODS: We performed a literature review on Pubmed focusing on etiopathogenesis, molecular alterations, and diagnostic-therapeutic management. RESULTS: AIS is determined by a large variety of X-linked mutations that account for the wide phenotypic spectrum of subjects; it represents one of the most frequent disorders of sexual development (DSD). Clinical suspicion can arise at birth in partial AIS, due to the presence of variable degrees of ambiguity of the external genitalia, and at pubertal age in complete AIS, due to the development of female secondary sex characteristics, primary amenorrhea, and absence of female primary sex characteristics (uterus and ovaries). Laboratory tests showing elevated LH and testosterone levels despite mild or absent virilization may be helpful, but diagnosis can be achieved only after genetic testing (karyotype examination and androgen receptor sequencing). The clinical phenotype and especially the decision on sex assignment of the patient, if the diagnosis is made at birth or in the neonatal period, will guide the following medical, surgical and psychological management. CONCLUSIONS: For the management of AIS, a multidisciplinary team consisting of physicians, surgeons, and psychologists is highly recommended to support the patient and his/her family on gender identity choices and subsequent appropriate therapeutic decisions.

Clinical characteristics, AR gene variants, and functional domains in 64 patients with androgen insensitivity syndrome.

BACKGROUND: Androgen insensitivity syndrome (AIS) is caused by abnormal androgen receptor (AR) genes that show variable genotypes and phenotypes. However, the correlation between genotype and phenotype is unclear. METHODS: We retrospectively evaluated 64 patients with AIS at Shanghai Children's Hospital from 2015 to 2022. We analysed the clinical data of the patients, including hormone levels, AR gene variants, and functional domains. RESULTS: Variants occurred in the 3 major functional domains in 56 patients, including 23 patients with complete androgen insensitivity syndrome (CAIS) and 33 with partial androgen insensitivity syndrome (PAIS). The incidence of nonscrotal fusion (P = 0.019) and proximal urethral opening (P = 0.0002) in the ligand-binding domain (LBD) group was higher than that in the non-LBD group. The phallus length in the LBD group was significantly shorter than that in the non-LBD group (P = 0.009). The external masculinization score (EMS) in the LBD group was significantly lower than that in the non-LBD group (P = 0.013). The levels of inhibin-B (INHB; P = 0.0007), basal luteinizing hormone (LH; P = 0.033), LH peak (P = 0.002), and testosterone (T) after human chorionic gonadotropin (HCG) stimulation (P = 0.001) in the LBD group were higher than those in the non-LBD group. There were 53 variants in 64 patients, including 42 reported and 11 novel AR variants, including p.Met247Arg, p.Asp266Glyfs*39, p.Arg362Serfs*140, p.Ala385Val, p.Glu541Asp, p.Pro613Leu, p.Pro695Leu, p.Asn757Asp, c.1616 + 1dup, c.1886-1G > A and exon 5-7 deletion. CONCLUSIONS: The EMS of patients with AIS in the LBD group was significantly lower than that in the non-LBD group. The phallus length was shorter, and the incidences of proximal urethral opening and nonscrotal fusion were higher, suggesting that the phenotypes in the LBD group were more severe. The levels of INHB, basal LH, peak LH, and T after HCG stimulation in the LBD group were higher than those in the non-LBD group, suggesting that androgen resistance in the LBD group was more severe. We identified 53 variants in 64 patients: 42 reported and 11 novel AR variants. These findings provide new and deeper insight into AIS diagnosis and genetic assessment of AIS.

Androgen Insensitivity Syndrome DUE to Non-Coding Variation in the Androgen Receptor Gene: Review of the Literature and Case Report of a Patient with Mosaic c.-547C>T Variant.

Sexual development (SD) is a complex process with strict spatiotemporal regulation of gene expression. Despite advancements in molecular diagnostics, disorders of sexual development (DSD) have a diagnostic rate of ~50%. Androgen insensitivity syndrome (AIS) represents the most common form of 46,XY DSD, with a spectrum of defects in androgen action. Considering the importance of very strict regulation of the SD, it is reasonable to assume that the genetic cause for proportion of the DSD lies in the non-coding part of the genome that regulates proper gene functioning. Here we present a patient with partial AIS (PAIS) due to a mosaic de novo c.-547C>T pathogenic variant in the 5'UTR of androgen receptor (AR) gene. The same mutation was previously described as inherited, in two unrelated patients with complete AIS (CAIS). Thus, our case further confirms the previous findings that variable gene expressivity could be attributed to mosaicism. Mutations in 5'UTR could create new upstream open reading frames (uORFs) or could disrupt the existing one. A recent systematic genome-wide study identified AR as a member of a subset of genes where modifications of uORFs represents an important disease mechanism. Only a small number of studies are reporting non-coding mutations in the AR gene and our case emphasizes the importance of molecular testing of the entire AR locus in AIS patients. The introduction of new methods for comprehensive molecular testing in routine genetic diagnosis, accompanied with new tools for in sillico analysis could improve the genetic diagnosis of AIS, and DSD in general.

Vaginal Reconstruction in Patients with vaginal agenesis: Options and Outcome: A single-center experience.

Objectives: To assess the postoperative functional, anatomical outcome and complications of various surgical procedures of vaginoplasty performed for patients with vaginal agenesis at our institution. Methods: This was a cross-sectional study of 14 patients (age range 17-40 years), who underwent vaginoplasty at the Aga Khan University Hospital, Karachi, Pakistan between January 2008 to December 2018. We aimed to assess the anatomical outcomes in terms of vaginal depth, axis and functional outcome as painless and satisfactory vaginal intercourse. Results: The mean age and mean body mass index (BMI) of the cases were 26.8 ± 8.1 years and 27.7143 ± 4.6 respectively. All were phenotypically female, with only two cases of XY genotype. Two patients were married on presentation. On evaluation, four cases had Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, three had androgen insensitivity syndrome (AIS), one case had congenital adrenal hyperplasia and six cases did not fit into any diagnosis. Associated renal anomalies were diagnosed in 14.3% of cases. The performed procedures were; Singaporean flap vaginoplasty (in four patients), Lee's, modified McIndoe and pull-through vaginoplasty (in three each patients), and Davydov vaginoplasty (in one patient). One patient was complicated by intraoperative bladder injury (p<0.63) and two cases by vaginal stenosis (p<0.43). The mean operative time was 120 minutes and the mean estimated blood loss was 200mls. Postoperatively, the vaginal length varied from 6-10 cm with a normal vaginal axis and satisfactory sexual activity. Conclusions: Vaginal agenesis is associated with several sexual disorders and despite the various surgical options available, the best procedure in terms of fewer complications and best surgical outcome is yet to be determined.

A 10-YEAR STUDY OF CHILDREN WITH GONADAL TUMORS AND DISORDERS OF SEX DIFFERENTIATION, IN ROMANIA.

Context: Children having gonadal tumors and disorder of sex differentiation (DSD) are rare. Objective: To investigate the presentation of DSD children with malignant gonadal tumors. Methods: A retrospective study from 2010-2020, that evaluated 17 children with DSD, including 13 females, eight months to 16 years, with congenital adrenal hyperplasia, 5-alpha reductase deficiency, androgen insensitivity syndrome, Turner, Sywer, and Klinefelter syndromes. Results: Ten children had malignant gonadal tumor; nine had germ cell tumors and one person granulosa cell tumors, while seven children with non-malignant tumor had gonadoblastoma, cystadenoma (five children), and cysts. Systemic malformations, obesity, elevated tumor markers, and psychosocial issues were observed in 90%, 90%, 70%, and 50% of children with malignancy unlike 28.6%, 42.9%, 14.35%, and 57.1% children without malignancy respectively. Most (9/10) children >12 years, had psychosocial issues, unlike 0/7 children ≤12 years. From 8/17 children presenting with symptoms suggestive of tumor, 75% had malignancy, while from 9/17 children with DSD presentation, 44% had malignant tumors. Malignancy was observed in 3/10 children between eight months to age six, while 7/10 children had stage 1-2 tumors. We reported a child, identified as female, aged 13 years, with partial androgen insensivity syndrome (PAIS) 46,XY, and testicular papillary serous cystadenoma with genomic variant AR NM_000044.4:c.2750del. p.(F917Sfs*27) chromosome Xq12, never published in people with PAIS nor population databases (GnomAD). Conclusion: DSD diagnosis raises numerous challenges. People with DSD have increased risk of malignancy, especially when obesity and, systemic malformations are present; also, psychosocial issues in these children are associated with postpubertal age.

Sexual Function in Women With Differences of Sex Development or Premature Loss of Gonadal Function.

BACKGROUND: Previous studies have suggested that sexual function may be compromised in women born with differences of sex development (DSD) or early loss of gonadal function. AIM: To describe sexual function and sexual wellbeing in women with complete androgen insensitivity syndrome (CAIS), complete gonadal dysgenesis (GD) and premature ovarian insufficiency (POI) in relation to gynecological measures and in comparison with unaffected women. METHODS: A cross sectional study including 20 women with CAIS, 8 women with 46,XY GD, 8 women with 46,XX GD, 21 women with POI, and 62 population-derived controls. Study participants underwent gynecological examination for anatomical measurements and evaluation of tactile sensitivity. They responded to the validated Sexual Activity Log (SAL), Profile of Female Sexual Function (PFSF), and the Personal Distress Scale (PDS). RESULTS: The women with CAIS, XY GD, XX GD and POI showed overall satisfying sexual function in comparison to unaffected age-matched population female controls with a median of 1 to 2 satisfying sexual episodes per week among both the patients and the controls depending on available partner. Women with CAIS had shorter vagina and smaller clitoris and women with XY GD had a significantly shallower vagina in comparison to controls. Clitoral width was also significantly smaller among women with XX GD compared to controls. However, results showed overall good genital touch sensitivity with no significant differences between groups. CLINICAL IMPLICATIONS: Women with DSD or POI can be informed on overall satisfactory sexual function and normal genital touch sensitivity. STRENGTHS & LIMITATIONS: The strength is the use of age-matched population-based controls to these rare conditions of DSD and POI. Limitations are the nonresponder rate of recruited controls, as well as the small groups of women with DSD. CONCLUSION: Women with differences of sex development or early loss of gonadal function show overall good sexual well-being, however clinicians have to make efforts to optimize caretaking and treatment to ensure good sexual quality of life for all patients. Engberg H, Strandqvist A, Berg E, et al., Sexual Function in Women With Differences of Sex Development or Premature Loss of Gonadal Function. J Sex Med 2022;19:249-256.

Gender Incongruity in a Person with 46,XY and Complete Androgen Insensitivity Syndrome Raised as a Female.

We present the case of a patient with female sex assignment at birth whose parents consulted with a pediatrician when the child was 12 years old, indicating that despite female sex assignment, she felt that she (henceforth "he") had a male gender identity and was gynephilic. Medical examination revealed a 46XY karyotype, a primary amenorrhea and an appropriate testosterone increase after HCG stimulation test. The patient was diagnosed then with a 46,XY disorder of sex development with androgen insensitivity syndrome, but then he missed subsequent appointments. At the age of 24, he resumed medical follow-up to reaffirm his male gender identity through sex reassignment surgery. His physical examination showed a Tanner stage III-IV breast development, vulva, clitoris, normal-sized vagina, absence of uterus and ovaries on transvaginal ultrasound, bilateral cryptorchidism on abdominal-pelvic MRI and osteoporosis on bone densitometry. The results of the blood tests were LH 24.5 mIU/mL [normal range, 1.7-8.6 mIU/mL for men] and testosterone 8.8 nmol/L [8.7-33 nmol/L]; conversely, FSH, estradiol, progesterone, and prolactin levels were normal. The molecular genetic analysis revealed an androgen receptor gene mutation associated with complete androgen insensitivity syndrome. At present, the patient has undergone bilateral orchiectomy and has initiated treatment with topical testosterone and bisphosphonates. We have yet to evaluate the effects and decide the best therapy taking into account that he has a male gender identity but complete androgen insensitivity syndrome.

Mild Androgen Insensitivity Syndrome: The Current Landscape.

OBJECTIVE: Mild androgen insensitivity syndrome (MAIS) belongs to the androgen insensitivity syndrome (AIS) spectrum, an X-linked genetic disease that is the most common cause of differences in sex development. Unfortunately, AIS studies mainly focus on the partial and complete phenotypes, and the mild phenotype (MAIS) has been barely reported. Our purpose is to explore the MAIS facets, clinical features, and molecular aspects. METHODS: We collected all reported MAIS cases in the medical literature and presented them based on the phenotype and molecular diagnosis. RESULTS: We identified 49 different androgen receptor (AR) mutations in 69 individuals in the literature. We compared the AR mutations presented in individuals with MAIS with AR mutations previously reported in other AIS phenotypes (partial and complete) regarding the type, location, genotype-phenotype correlation, and functional studies. CONCLUSION: This review provides a landscape of the mild phenotype of AIS. Most patients with MAIS present with male factor infertility. Therefore, AR gene sequencing should be considered during male factor infertility investigation, even in males with typically male external genitalia. In addition, MAIS can be part of other medical conditions, such as X-linked spinal and bulbar muscular atrophy (Kennedy disease).

Androgen insensitivity syndrome: Can cytology help?

Androgen insensitivity syndrome (AIS) is described as a patient's clinical (phenotypical) presentation as a female with male karyotyping. Classically, patients are normal looking females with complaints of primary amenorrhea. The gonads may be found as extra-genital swellings; rarely, the testes may undergo malignant transformation. Thus, gonadectomy is indicated in these patients on attaining puberty. A rare and interesting case of clinically unsuspected AIS in a young female who presented with primary amenorrhea and inguinal swelling is reported. The initial diagnosis was suggested on fine needle aspiration cytology (FNAC) from the inguinal swelling that showed the presence of Sertoli cells. Further family history revealed two similar siblings; karyotyping and histopathology confirmed the diagnosis of AIS in the patient. This case highlights the importance of FNAC in early diagnosis and a multidisciplinary approach to confirm the diagnosis and help in appropriate management.

The radiologist's role in assessing differences of sex development.

When infants are identified with a difference of sex development (DSD), a thoughtful approach to imaging is essential to appropriate clinical management. This review provides a comprehensive guide for radiologists who are tasked with performing this critical assignment. We review the embryologic basis of DSDs, with attention to the imaging findings that can indicate specific diagnoses. We also discuss techniques for optimal imaging, including strategies for identifying the gonads by US, tactics for performing genitograms with fluoroscopy and contrast-enhanced US, and the appropriate utilization of MRI. Finally, we review the clinical data and imaging findings that characterize some of the most common DSDs, including congenital adrenal hyperplasia, complete androgen insensitivity syndrome and gonadal dysgenesis.

Ventral clitoroplasty preserves dorsal nerves in case of partial androgen insensitivity syndrome: 4 years follow-up.

Androgen insensitivity syndrome (AIS) causes feminization of the external genitalia, in 46XY individuals. We report a notable case of partial AIS (PAIS), which was treated with ventral clitoroplasty and vaginal dilatation. The patient is a 17-year-old phenotypically female, presented with primary amenorrhea, infantile vagina, clitoromegaly, and presence of testes. Feminizing genitoplasty was done in form of ventral clitoroplasty with gonadectomy and was put on hormone replacement therapy and advised regular use of vaginal dilators to improve vaginal length. In ventral approach, the erectile tissues are excised without disturbing the neurovascular structure. Vibratory threshold perception of clitoris assessed by biothesiometer was normal 4 years after the surgery. Vaginal corrective surgery is not required when presentation is at later stage and has some vaginal depth to work out with vaginal dilators. Regular psychiatric consultations and support are needed in patients with PAIS to develop their confidence in gender identity and sexual orientation.

Novel androgen receptor gene variant containing a frameshift mutation in a patient with complete androgen insensitivity syndrome.

A variety of mutations in the androgen receptor (AR) gene are linked to androgen insensitivity syndrome (AIS). AIS is the most common specific cause of 46, XY disorder in sex development. Here, we reported a patient which presented as a female with 46, XY karyotype and normal female external genitalia. The patient was diagnosed with complete AIS caused by a novel mutation (NM_000044, c.2678-2726del, p. Pro893Leufs*35) in the AR gene. Targeted exome sequencing was used to detect the patient's androgen receptor gene mutations. Sanger sequencing was used to validate the mutation. This study showed that a novel mutation of the AR gene can cause complete AIS; the study also broadened the AR mutation spectrum and indicated that targeted exome sequencing could help facilitate the diagnosis of complicated disorders in sexual development.

Complete androgen insensitivity syndrome - rare case of malignancy of dysgenetic gonads.

OBJECTIVE: A case report of a young patient with primary amenorrhea who was diagnosed with agenesis of the uterus and was genetically confirmed for complete androgen insensitivity syndrome with already developed malignancy of dysgenetic gonads. CASE REPORT: The 17-year-old patient visited a gynecological clinic for primary amenorrhea. Both ultrasound and vaginal examination revealed suspicion of uterine agenesis, which was subsequently verified during diagnostic laparoscopy. Genetic testing showed karyotype 46,XY, and a rare diagnosis - complete androgen insensitivity syndrome. A secondary finding from a left gonadal biopsy was a Sertoli-Leydig cell tumor. The patient underwent bilateral gonadectomy and was given estrogen replacement therapy. She is now regularly examined by a pediatric oncologist. CONCLUSION: Complete androgen insensitivity syndrome is a rare genetic disease characterized by varying degrees of feminization in individuals with a male karyotype. It should not be neglected, especially in the differential diagnostic work-up of primary amenorrhea. Genetic testing of the karyotype should be performed whenever uterine agenesis is suspected.

Challenges in the Diagnosis of XY Differences of Sexual Development.

Background: We report the clinical case of female patient with 46,XY difference of sexual development (DSD) and discuss the challenges in the differential diagnosis between complete gonadal dysgenesis (also called Swyer syndrome) and complete androgen insensitivity syndrome. Case Presentation: The patient's with primary amenorrhea gynaecological examination and magnetic resonance imaging (MRI) revealed the absence of the uterus and a very short vagina. Two sclerotic structures, similar to ovaries, were recognised bilaterally in the iliac regions. Hormonal assay tests revealed hypergonadotropic hypogonadism and the testosterone level was above normal. The karyotype was 46,XY and a diagnosis of Swyer syndrome was made. At the age of 41, the patient underwent a gynaecological review and after evaluating her tests and medical history, the previous diagnosis was questioned. Therefore, a molecular analysis of sex-determining region Y (SRY) and androgen receptor (AR) genes was made and the results instead led to a definite diagnosis of complete androgen insensitivity syndrome. Conclusions: The presented case illustrates that differentiating between complete gonadal dysgenesis and complete androgen insensitivity can be challenging. A well-established diagnosis is crucial because the risk of malignancy is different in those two syndromes, as well as the timing and importance of gonadectomy.

[Timing of gonadectomy in patients with complete androgen insensitivity syndrome]. / Quand proposer une gonadectomie chez les patientes présentant une insensibilité complète aux androgènes ?

Complete androgen insensitivity syndrome is the most frequent cause of disorder of sexual development in 46 XY patients. It is caused by mutations of the AR gene coding for the androgen receptor. Transmission is X-linked and mutations are most of the time inherited. It leads to a complete lack of response to androgen resulting in the presence of female external genitalia in 46 XY patients, normal but undescended testes and lack of female internal genitalia due to the secretion of anti-Müllerian hormone by male gonads. Traditionally, gonadectomy was proposed before puberty to decrease the risk of gonadal malignancy. However, more recent studies underlined the benefits of postponing gonadectomy until after pubertal development. Benefits of deferred gonadectomy are spontaneous pubertal development through peripheral aromatization of testosterone into oestrogens and the chance for the patient to have an active role in the decision-making process. After gonadectomy, hormone replacement therapy is required in order to prevent complications due to hypogonadism such as osteoporosis, cardiovascular diseases and a reduction of life expectancy.

L'insensibilité aux androgènes est l'étiologie principale des troubles du développement sexuel chez des patientes 46 XY. Elle est due à des mutations du gène AR qui code pour le récepteur des androgènes. Le mode de transmission est lié à l'X et les mutations sont le plus souvent héritées. Il en résulte une absence d'action des androgènes sur leurs récepteurs entraînant la présence d'organes génitaux externes féminins chez des patientes 46 XY, de testicules normalement développés en position abdominale ou inguinale et en l'absence d'organes génitaux internes féminins due à la sécrétion d'hormone anti-müllérienne par les gonades masculines. La gonadectomie était auparavant effectuée en période pré-pubertaire en raison du risque suspecté de développement de néoplasie maligne. Des données récentes suggèrent la possibilité de postposer cette intervention après le développement pubertaire. Le risque de transformation maligne pré-pubertaire des gonades est faible, et différer la gonadectomie permet un développement pubertaire naturel grâce à l'aromatisation périphérique de la testostérone en œstradiol. Ce délai permet d'impliquer activement la patiente dans la prise en charge de sa pathologie. Après la gonadectomie, un traitement hormonal substitutif par œstrogènes est indiqué pour prévenir les complications dues à l'hypogonadisme telles que l'ostéoporose, les maladies cardio-vasculaires et la réduction de l'espérance de vie.

[Androgen Insensitivity Syndrome with Bilateral Cryptorchidism and Seminoma in Tibet:Report of One Case].

Androgen insensitivity syndrome(AIS)with bilateral testicular malignant transformation is very rare,and its diagnosis should be based on clinical manifestations,physical examination,serological findings,karyotype analysis,and pathological findings.This study reported a case of complete androgen insensitivity syndrome among Tibetan in Tibet.It took 17 years from the discovery of congenital absence of uterus to bilateral pelvic mass resection.Pathological examination confirmed that bilateral pelvic space occupying lesions were dysplastic testicular tissue with seminoma and sertoli cell adenoma-like nodules.This study summarized the clinicopathological features to deepen the understanding of the disease.