A novel androgen resistance gene mutation (p.G590W) in complete androgen insensitivity syndrome: Emphasizing the need for early gonadectomy and integrated patient care

Abstract

Complete androgen insensitivity syndrome is a rare 46,XY disorder of sex development caused by mutations in the androgen receptor gene, resulting in androgen resistance despite a normal male karyotype. Individuals with complete androgen insensitivity syndrome typically present with female external genitalia, primary amenorrhea, and a heightened risk of gonadal germ cell tumors. Herein, we report the case of a 30-year-old woman who was diagnosed with complete androgen insensitivity syndrome at 18 years of age during evaluation for primary amenorrhea. Chromosomal analysis revealed a 46,XY karyotype, and imaging confirmed the absence of a uterus and ovaries. Despite medical advice for prophylactic gonadectomy, the patient delayed surgery and later presented with a palpable abdominal mass. Genetic analysis identified a novel hemizygous germline missense mutation, c.1768G>T (p.G590W), in exon 2 of the androgen receptor gene, which was classified as potentially pathogenic based on the American College of Medical Genetics and Genomics criteria. The patient underwent tumor resection followed by four cycles of bleomycin, etoposide, cisplatin chemotherapy regimen for advanced seminoma and has remained disease-free during follow-up. This case underscores the importance of genetic analysis, early prophylactic gonadectomy, and multidisciplinary care in managing complete androgen insensitivity syndrome to mitigate tumor risk and optimize outcomes.

Background

Complete androgen insensitivity syndrome (CAIS) is a rare 46,XY disorder of sex development (DSD) caused by mutations in the androgen receptor (AR) gene.^1–3 The AR gene encodes a nuclear receptor that is critical for mediating androgen signaling. ⁴ Mutations in the AR gene are associated with a spectrum of AR dysfunctions, manifesting clinically as CAIS, partial androgen insensitivity syndrome (PAIS), or mild androgen insensitivity syndrome (MAIS), depending on the severity.^5–7 CAIS results from mutations causing complete receptor dysfunction, characterized by female external genitalia despite a 46,XY karyotype. In contrast, PAIS and MAIS involve partial receptor impairment, leading to a range of phenotypes from ambiguous genitalia (PAIS) to mild undervirilization and infertility (MAIS). Individuals with CAIS typically present with primary amenorrhea, absent or rudimentary Müllerian structures, female external genitalia, and a short blind-ending vagina, with gonads frequently located intra-abdominally or in the inguinal region.^8,9

Mutations in the AR gene associated with CAIS are highly heterogeneous, encompassing missense, nonsense, and frameshift mutations as well as and splice-site alterations. ¹⁰ Clinical phenotypes vary considerably depending on the mutation type, with frameshift and nonsense mutations typically associated with more severe androgen insensitivity phenotypes due to complete loss of receptor function, while missense mutations may produce a spectrum of phenotypic outcomes dependent on the specific location and functional domain affected. To date, hundreds of such mutations have been documented in the Androgen Receptor Mutation Database (http://androgendb.mcgill.ca/), many of which are linked to severe androgen insensitivity phenotypes. However, novel pathogenic variants continue to be identified, underscoring the complexity of the genotype–phenotype relationships in CAIS. Characterizing these novel variants is essential for advancing our understanding of the molecular mechanisms underlying AR dysfunction and for developing improved diagnostic, prognostic, and therapeutic strategies.

A significant clinical challenge in managing CAIS is the heightened risk of gonadal germ cell tumors, ¹¹ particularly seminomas, arising due to undescended or dysgenetic gonads. Recent systematic reviews suggest malignancy risks ranging from 15% to as high as 30% in patients with CAIS, underscoring the importance of timely prophylactic gonadectomy to prevent tumor development and progression. ¹² The optimal timing of prophylactic gonadectomy remains a subject of clinical debate, requiring careful consideration of the balance between the prevention of malignancy and preservation of endogenous hormone production and secondary sexual characteristics. Although performing gonadectomy prior to puberty eliminates the risk of malignancy at an early stage, delaying the procedure until after puberty allows for spontaneous breast development and secondary sexual maturation, potentially reducing lifelong reliance on hormone replacement therapy. However, many patients delay or decline surgery due to psychosocial concerns, body image issues, or lack of consistent follow-up care. Delayed intervention increases the likelihood of advanced germ cell tumor development, complicating treatment and worsening prognosis. ¹³ In this context, exploring novel pathogenic variants while documenting clinical outcomes is critical to enhancing our understanding of CAIS and improving patient care. This study presents a unique case of CAIS associated with a novel AR gene mutation, p.G590W, which has not been previously reported in the Androgen Receptor Mutation Database. The mutation was identified through next-generation sequencing (NGS) and is predicted to be pathogenic based on functional analyses.

Through comprehensive genetic and clinical evaluation, this investigation provides valuable insights into the molecular etiology of androgen insensitivity and highlights the critical role of early intervention in reducing germ cell tumor risks. This report contributes to the expanding body of knowledge on AR mutations, offering new perspectives on the genetic basis of CAIS and its clinical management.

Case presentation

This report describes the case of a 30-year-old unmarried woman diagnosed with CAIS at the age of 18 years during an evaluation for primary amenorrhea. Prior to this age, the patient and her family attributed the delayed menarche as individual variation and did not seek medical consultation, resulting in delayed diagnosis. Consequently, this represented a missed opportunity for earlier intervention, highlighting the need for improved patient and public awareness regarding amenorrhea and related conditions. The patient had no notable medical or surgical history. Chromosomal analysis confirmed a 46,XY karyotype. Notably, she exhibited typical external female genitalia. Ultrasound imaging confirmed the absence of a uterus and ovaries. Based on clinical evaluations, a diagnosis of 46,XY DSD was established. Given the markedly increased risk of gonadal germ cell tumors in this patient, prophylactic bilateral gonadectomy was strongly recommended. Despite comprehensive counseling and informed consent, the patient was reluctant to undergo gonadectomy and failed to attend regular follow-up care until a palpable abdominal mass was detected 6 months before the current evaluation.

Physical examination showed that the patient’s height was 170 cm, her weight was 65 kg, and she exhibited Tanner stage IV breast development. Abdominal examination revealed a large, firm, non-tender mass measuring approximately 18 cm in the lower abdomen, with limited mobility. Examination of the urinary and reproductive systems revealed normal female external genitalia, the absence of a uterus and cervix, and a vaginal length of 4 cm. No clitoromegaly or masses were observed in the external genitalia or inguinal region. The patient exhibited female secondary sexual characteristics and lacked facial, axillary, or pubic hair. Baseline hormonal assays at diagnosis (age of 18 years) revealed significantly elevated levels of luteinizing hormone (32.5 IU/L, normal female range: 2.4–12.6 IU/L) and follicle-stimulating hormone (54.2 IU/L, normal female range: 3.5–12.5 IU/L), along with elevated serum testosterone levels (15.8 nmol/L, normal female range: 0.3–2.4 nmol/L), consistent with the features of androgen insensitivity. Gynecologic ultrasonography and contrast-enhanced computed tomography of the abdomen and pelvis identified a cystic lesion measuring 8.6 cm × 5.0 cm × 4.2 cm at the lower pole of the right kidney (Figure 1(a) and (c)) and a solid mass measuring 16.7 cm ×15.0 cm × 11.4 cm in the abdominopelvic region (Figure 1(b) and (d)).

Figure 1.

Gynecologic ultrasound and enhanced computed tomography of the abdomen and pelvis showed a cystic mass measuring 8.6 cm × 5.0 cm × 4.2 cm at the lower pole level of the right kidney (a, c) and a solid mass measuring 16.7 cm × 15.0 cm × 11.4 cm in the abdominal pelvic region (b, d) (yellow arrow).

The patient was admitted for evaluation and treatment at the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China, in September 2022. During the same month, she underwent an exploratory laparotomy. Intraoperatively, examination of the pelvis confirmed the absence of a uterus. In the right adnexal region, a solid mass measuring approximately 17 cm × 15 cm × 12 cm was identified. Additionally, in the retroperitoneal space, a solid mass measuring approximately 8 cm × 5 cm × 5 cm was palpated anterior to the abdominal aorta and inferior vena cava. The surgical procedure included resection of the tumor in the right adnexal region, adnexectomy on the left side, resection of the retroperitoneal mass, and repair of the duodenum and inferior vena cava (Figure 2). Postoperative pathological analysis confirmed that the pelvic mass was a primary germ cell tumor consistent with seminoma, with no evidence of normal gonadal structures. The retroperitoneal mass demonstrated features consistent with necrotic seminoma, confirming the diagnosis of seminoma. Genetic analysis using NGS was conducted on genomic DNA extracted from the patient’s peripheral blood leukocytes. The analysis identified a hemizygous germline missense mutation (COSM8940007) in exon 2 of the AR gene, resulting in a p.G590W amino acid substitution. Variant analysis and nomenclature followed the Human Genome Variation Society (HGVS) guidelines, using the AR gene reference sequence NM_000044.6. The identified variant, c.1768G>T (p.G590W), was annotated according to the AR transcript reference NM_000044.6. This mutation results in a nucleotide change at position 1768 from G to T, leading to an amino acid substitution at position 590 from glycine to tryptophan. The p.G590W variant identified in this patient has not been documented in the Androgen Receptor Mutation Database (http://androgendb.mcgill.ca/). The identified AR variant, c.1768G>T (p.G590W), was classified according to the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology guidelines. Specifically, the following ACMG criteria were applied: PM2 (absence in population databases), PP3 (computational pathogenicity predictions), and PP4 (phenotype-genotype correlation). Based on the ACMG framework, the c.1768G>T (p.G590W) variant was classified as likely pathogenic, supported by PM1, PM2, PP3, and PP4 criteria, which cumulatively amount to 6 points. Functional prediction analyses using computational tools, including PolyPhen-2, SIFT, and MutationTaster, suggest that this variant is likely pathogenic, although direct functional studies for this specific variant have not yet been performed. In addition, splicing analyses were conducted using SpliceAI and MaxEntScan to evaluate the potential impact of the c.1768G>T variant on splicing. Both tools predict that this variant likely disrupts normal exon 2 splicing, providing further evidence in support of its pathogenicity. To the best of our knowledge, the hemizygous missense mutation p.G590W in the AR gene represents a novel variant. The reporting of this study conforms to the Case Report (CARE) guidelines. ¹⁴ The c.1768G>T variant is located in the ligand-binding domain (LBD) of the AR gene, a critical functional domain, satisfying the PM1 criterion of the ACMG guidelines. Splicing prediction analyses indicate that the c.1768G>T variant likely disrupts exon 2 splicing, potentially leading to an out-of-frame deletion. The novel AR variant identified has been submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/) under submission ID: SUB15253315, with the classification updated to likely pathogenic based on the cumulative ACMG criteria.

Figure 2.

(a) The intraoperative findings revealed a solid mass in the right adnexal area, measuring approximately 17 cm × 15 cm × 12 cm in size (yellow arrow). (b) A solid mass measuring approximately 8 cm × 5 cm × 5 cm was observed at the inferior pole of the right retroperitoneal kidney (yellow arrow) and (c) the image illustrates the surgical procedure wherein the retroperitoneal mass was resected and the inferior vena cava was repaired (yellow arrow). IVC: inferior vena cava; RK: right kidney.

The patient’s pathological stage was classified as seminoma IIIC, and she underwent four cycles of bleomycin, etoposide, cisplatin chemotherapy (BEP) chemotherapy following surgery. The BEP regimen consisted of bleomycin (30 IU) administered via intramuscular injection on days 1, 8, and 15; etoposide (100 mg/m²/day) delivered as an intravenous infusion on days 1 through 5; and cisplatin (20 mg/m²/day) administered as an intravenous infusion on days 1 through 5. Each cycle was repeated every 3 weeks, and the treatment was completed on 16 December 2022. Following chemotherapy, the patient was monitored with regular monthly follow-up visits. As of 28 February 2025, the patient’s tumor marker levels were within the normal range. Written informed consent for all treatments and procedures described was obtained from the patient.

Discussion

This case highlights the complex challenges of managing CAIS, particularly in the context of delayed prophylactic gonadectomy and subsequent development of advanced seminoma. Although CAIS is rare, the clinical implications of undescended gonads in 46,XY individuals are profound, necessitating a careful balance between timely intervention, patient autonomy, and long-term follow-up. This discussion contextualizes the findings of this study within the broader body of literature, exploring key clinical, surgical, and psychosocial considerations.

Importance of early prophylactic gonadectomy

Prophylactic gonadectomy in postpubertal CAIS patients remains the cornerstone of management to prevent malignant transformation of dysgenetic gonads,^3,15–18 which carry a high malignancy risk. The risk of gonadal germ cell tumors, particularly seminomas, is estimated to reach up to 30% in undescended testes. ¹⁹ Despite comprehensive counseling, patients may refuse gonadectomy due to personal, cultural, or psychological factors.^15,20,21 This case underscores the serious consequences of such delays, as the patient presented with advanced seminoma requiring extensive surgical resection followed by systemic chemotherapy. These findings reinforce the need for enhanced patient education strategies that emphasize the oncologic risks of retained gonads while addressing psychosocial barriers to improve compliance.

Challenges in delayed diagnosis and management

The delayed diagnosis of seminoma in this case underscores the importance of regular follow-up care for patients with CAIS. Regular imaging and tumor marker surveillance are imperative for detecting early signs of malignancy in patients who defer gonadectomy. ²² In this case, the lack of regular monitoring resulted in the development of a large abdominal mass, necessitating invasive surgery and systemic chemotherapy. This outcome highlights the necessity of structured follow-up protocols and multidisciplinary care involving gynecologists, endocrinologists, oncologists, and mental health professionals to ensure comprehensive management.

Surgical and oncologic considerations

The surgical management of advanced seminomas in CAIS presents distinct challenges due to the anatomical variations inherent to the condition. In this case, the absence of a uterus and ovaries facilitated tumor resection; however, careful dissection of retroperitoneal structures was necessary for minimizing complications. Postoperative histopathological analysis confirmed seminoma, consistent with the known spectrum of gonadal tumors in CAIS. The administration of four cycles of BEP chemotherapy produced favorable oncologic outcomes, with tumor markers remaining within normal limits at the 28-month follow-up.

Broader implications for 46,XY DSD management

This case highlights broader issues in managing 46,XY DSD, particularly the tension between medical recommendations and patient autonomy. Cultural, societal, and psychological factors often influence patients’ decisions regarding surgery, requiring clinicians to adopt a patient-centered approach. Additionally, this case contributes to the limited body of evidence on the long-term outcomes of seminoma in CAIS, providing valuable insights that can inform clinical practice and future research. It also underscores the need for robust patient education frameworks that address the medical, psychological, and social dimensions of living with CAIS.

Limitations and future directions

While this case provides valuable insights, it is important to acknowledge its limitations. The cumulative evaluation of the PM1, PM2, PP3, and PP4 criteria results in a total of 6 points according to the ACMG guidelines, supporting the classification of the p.G590W variant as potentially pathogenic. This updated classification has implications for genetic counseling, risk assessment, and clinical management of patients with CAIS. As a single case study, the findings may not be generalizable to all patients with CAIS. Further research is needed to explore the long-term outcomes of seminoma in CAIS, particularly in patients who defer gonadectomy. Prospective studies examining patient decision-making, adherence to follow-up care, and psychosocial impact of CAIS are also warranted. The PM1 criterion was applied due to the location of the variant within the LBD, which is a mutational hotspot. Further functional studies are required to confirm the pathogenicity of the variant and its impact on splicing. Advances in genetic testing and molecular profiling may offer new opportunities to stratify malignancy risk and personalize management strategies for CAIS patients.

Conclusion

This case underscores the importance of early prophylactic gonadectomy and regular follow-up care in patients with CAIS to mitigate the risk of gonadal germ cell tumors. The successful treatment of advanced seminoma via surgical resection and BEP chemotherapy highlights the efficacy of multidisciplinary approaches in managing late-stage malignancies. Importantly, this study emphasizes the need for patient-centered care that integrates medical, psychological, and social considerations to optimize outcomes in individuals with 46,XY DSD. By bridging gaps in knowledge and practice, this discussion contributes to the evolving understanding of CAIS-associated malignancies and their management.