Pure 46, XY gonadal dysgenesis and 46, XY complete androgen insensitivity syndrome: A case report.

BACKGROUND: Disorders of sex development (DSD) are congenital conditions characterized by atypical development of chromosomal, gonadal, and phenotypic sex. 46, XY DSD can result from disorders of testicular development or androgen synthesis. METHODS: We present 2 rare cases of 46, XY DSD, specifically XY pure gonadal dysgenesis and complete androgen insensitivity syndrome. RESULTS: Both cases underwent prophylactic gonadectomy due to the elevated risk of gonadal malignancy. Bilateral gonadoblastoma and dysgerminoma were diagnosed on one side, while Leydig cell hyperplasia and only Sertoli cells were diagnosed in the seminiferous tubules on both sides. The normal menstruation for the pure gonadal dysgenesis patient only as CAIS patients never menstruate. Estrogen replacement therapy was administered periodically to promote the development of secondary sexual characteristics and menstruation in pure gonadal dysgenesis case, as well as to prevent osteoporosis. Follow-up examinations revealed no tumor recurrence, and the patient with Swyer syndrome had regular menstrual cycles. CONCLUSION: Laparoscopic bilateral prophylactic gonadectomy and long-term hormone therapy with patient counseling and support are recommended.

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.

A case of mild partial androgen insensitivity syndrome in a juvenile boy.

Androgen insensitivity syndrome (AIS) is a rare disorder with X-linked recessive inheritance in 46 XY patients. The clinical manifestations vary between patients, especially regarding external genitalia development. Herein, the case of AIS in a 13-year-old male, who was born with hypospadias and presented to the hospital with gynaecomastia that had developed from 8 years of age, is reported. No micropenis, cryptorchidism or bifid scrotum were found. Testis volume was 12 ml on both sides. His testosterone and luteinizing hormone levels were normal compared with sex- and age-adjusted reference range. His bone age was approximately 13 years according to Greulich-Pyle assessment. Sequence analysis of the androgen receptor (AR) gene revealed a mutation (c.2041A>G) in exon 4, a novel mutation site in the AR gene. Prediction analysis suggested this to be a disease-causing variant. A milder clinical presentation and normal hormone levels in cases of partial AIS might differ from the usually reported signs and symptoms. A diagnosis of AIS should not be ignored in teenage patients who present with gynaecomastia and hypospadias, but normal hormone levels.

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.

Case Report of Male Pseudohermaphroditism (Androgen Insensitivity Syndrome): Congenital Disorder of Sexual Differentiation.

INTRODUCTION: A broad spectrum of anomalies of sexual differentiation may exist at birth, which can be unreported until adolescence. A 17-year-old patent with female phenotype came with complaints of primary amenorrhea. On imaging (ultrasound and MRI) uterus and bilateral ovaries were absent. Small blind-ending vaginal pouch was noted along with features suggesting bilateral cryptorchidism. No definite male external genitalia/scrotal sac was seen except for subtle rudimentary bulbo-cavernous muscles. Karyotyping confirmed 46 XY consistent with Male Pseudohermaphroditism. MATERIALS: Male pseudohermaphroditism refers to a condition that affects 46, XY individuals with differentiated testes who exhibit varying degrees of feminization. In these cases there is a spectrum of external genitalia; some individuals are completely phenotypically female. Androgen insensitivity syndrome (AIS), also known as the testicular feminization syndrome, results from end-organ resistance to androgens, particularly testosterone. As the appearance of the external genitalia often is not distinctive enough to make a specific diagnosis, this must be accomplished by clinical findings along with a combination of imaging, cytogenetic and biochemical studies. Ultrasound and MRI studies are extremely useful to diagnose such conditions at the earliest as these patients have an increased incidence of malignancy in the undescended testes. The treatment is influenced by genital tissue responsiveness to androgens and reconstructive surgical procedures. There is a need for counselling regarding pubertal development, sexual performance and fertility. RESULT: A 17year old patent came with complaints of primary amenorrhea. On examination patient has normal external female genitalia, with developed breast. On laboratory correlation, it shows high testosterone level: 881 ng/dL and Normal progesterone level: 0.182 ng/mL. On karyotyping, it shows 46XY karyotype. On USG: Uterus is not well appreciated. There is iso-echogenic oval shaped soft tissue seen in bilateral inguinal regions with vascularity within-likely to be gonads. On MRI: Absence of uterus and bilateral ovaries are confirmed with evidence of symmetrical oval-shaped soft tissue lesions identified within bilateral inguinal canals - consistent with bilateral cryptorchidism. Male pseudohermaphroditism refers to a condition that affects 46, XY individuals with differentiated testes who exhibit varying degrees of feminization. CONCLUSION: In cases of male pseudohermaphroditism, there is a spectrum of external genitalia; some individuals are completely phenotypically female, whereas others appear to be normal males with varying spermatogenesis and/or pubertal virilization. As the appearance of the external genitalia often is not distinctive enough to make a specific diagnosis, this must be accomplished by clinical findings along with a combination of cytogenetic, biochemical, and radiologic studies. Sonographic and radiographic studies are often used initially to evaluate such conditions. Male pseudohermaphrodites all possess testes yet exhibit incomplete virilization of the genital ducts and/or external genitalia. The findings depend on the underlying defect. Complete androgen insensitivity (testicular feminization) is an X-linked recessive disorder in which the absence of cytoplasmic testosterone receptors prevents specific gene activation and subsequent differentiation of the external genitalia. In this disorder, the external genitalia are completely feminized, while in the other forms of male pseudohermaphroditism various degrees of virilization occur. The absence of internal female genital tract structures reflects the synthesis of active Mullerian regression factor by the testes, which may be maldescended. Multiplanar MR images will confirm the absence of a uterus and demonstrate intraabdominal or inguinal testes. Integrated imaging in the form of ultrasound, genitography and MRI is important in demonstrating the anatomy, classification, possible effects or congenital malformations in other organs, warning patients of any risk of neoplasia and guiding the clinician to plan other investigations, hormonal replacement or reconstruction surgery if required. References Tanaka YO, Mesaki N, Kurosaki Y, et al. Testicular feminization: role of MRI in diagnosing this rare male pseudohermaphroditism. J Comput Assist Tomogr 1998;22(6):884-888. Nakhal RS, Hall-Craggs M, Freeman A, et al. Evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome. Radiology 2013;268(1):153-160.

Complete androgen insensitivity syndrome: a case report and literature review.

Complete androgen insensitivity syndrome (CAIS) is a rare disease that can be easily misdiagnosed. Before puberty, this condition is easily misdiagnosed as an inguinal hernia. This case report describes a 31-year-old phenotypically female patient with CAIS who was misdiagnosed twice previously with an inguinal hernia. Her karyotype analysis showed that she was 46, XY. She underwent a bilateral gonadectomy and long-term hormone replacement therapy. A Leydig cell tumour of the right testis was diagnosed postoperatively. This report also reviews the current understanding of the diagnosis and treatment of CAIS.

An Early Case of Complete Androgen Insensitivity Syndrome.

Inguinal hernias are rare in female infants, and when present, there is an increased incidence of androgen insensitivity in these infants. We present a case of bilateral inguinal hernias in a 26-day-old full-term phenotypic female. On physical exam, the patient was found to have bilateral palpable inguinal masses which were suspected to be testicular tissue on ultrasound. Patient also had bilateral inguinal hernias, but otherwise there were no other concerning symptoms, and the remaining physical examination was overall unremarkable. Initial workup included a pelvic ultrasound that did not visualize a uterus or ovaries. In addition, genetic testing confirmed normal male genotype with 100% 46, on fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (CGH) was negative and did not reveal any copy number changes. Molecular testing was consistent with a diagnosis of androgen insensitivity syndrome with hemizygous pathogenic variant in the androgen receptor (AR) gene (deletion of Exon 2 of AR gene Xq12). This case highlights the importance of a high clinical suspicion of complete androgen insensitivity syndrome (CAIS) in a phenotypic female infant with inguinal hernias. To our knowledge, this is one of the earliest diagnoses of CAIS in a phenotypically female infant.

Characterization of a novel androgen receptor gene variant identified in an Iranian family with complete androgen insensitivity syndrome (CAIS): a molecular dynamics simulation study.

Androgen insensitivity syndrome (AIS) is a common form of 46, XY disorder in sex development disease (DSD). It is due to the androgen receptor (AR) gene mutations and includes clinical subgroups of complete AIS (CAIS) and partial AIS (PAIS), along with a vast area of clinical heterogeneity of completely normal female external genitalia to male infertility. In this study, the Whole Exome Sequencing (WES) was utilized to detect the cause of DSD in a consanguineous Iranian family with two female patients with normal external genitalia and 46, XY karyotype. Sanger sequencing was applied to validate the candidate variant. Next, we predicted the structural alteration induced by the variant on AR protein using bioinformatics analysis such as molecular dynamic (MD) and molecular docking simulations. WES results identified a novel hemizygous p.L763V variant in the AR gene in the proband that was compatible with the X-linked recessive pattern of inheritance. Bioinformatics studies confirmed the loss of AR function. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, it was categorized as pathogenic. This study broadens the AR mutation spectrum and introduces the novel p.L763V missense pathogenic variant leading to AR failure to bind to its ligand, and the resulting CAIS clinical subgroup. This study presents a prosperous application of WES and bioinformatics analysis to recognize the underlying cause of DSD in Iran, necessary for its clinical/psychological management.Communicated by Ramaswamy H. Sarma.

[Complete androgen insensitivity syndrome: diagnosis and multidisciplinary management]. / Síndrome de insensibilidad completa a los andrógenos: diagnóstico y manejo multidisciplinario.

Background: Complete androgen insensitivity syndrome (CAIS) is a sexual differentiation disorder, caused by a defect in the androgen receptor gene (AR; OMIM# 313700). It is characterized by the resistance of target tissues to the action of testosterone, which prevents normal male genital development. The objective is to describe a family case of CAIS and highlight the importance of multidisciplinary medical management and early diagnosis of this syndrome. Clinical case: We present two cases of SICA in a Mexican family. Case 1: 18-year-old female patient with primary amenorrhea and a history of surgery at an early age, without performing gonadectomy. Case 2: 11-year-old female patient who, due to the history of her sister, underwent surgery at that age. In both patients, absence of uterus and ovaries, hypoplastic vagina and male gonads is reported. The 46,XY karyotype was detected with the GTG and CBG band technique and fluorescent in situ hybridization with the presence of the Y chromosome in 100% of the cells analyzed. Although both patients were identified with their assigned sex, they were referred to the institution's psychiatric clinic. Conclusions: The importance of multidisciplinary management for the diagnosis of SICA at an early age is discussed, in order to make decisions regarding the treatment and management of patients, avoiding malignant transformation of the male gonads.

Introducción: el síndrome de insensibilidad completa a los andrógenos (SICA) es un desorden de la diferenciación sexual, causado por un defecto en el gen receptor de andrógenos (AR; OMIM# 313700). Se caracteriza por la resistencia de los tejidos diana a la acción de la testosterona, lo que impide el desarrollo genital masculino de manera normal. El objetivo es describir un caso familiar de SICA y destacar la importancia del manejo médico multidisciplinario y el diagnóstico temprano de este síndrome. Caso clínico: presentamos dos casos de SICA en una familia mexicana. Caso 1: paciente de 18 años con amenorrea primaria y antecedente de intervención quirúrgica a edad temprana, sin realizarle gonadectomía. Caso 2: paciente de 11 años que debido al antecedente de su hermana fue intervenida quirúrgicamente a esa edad. En ambas pacientes, se reporta ausencia de útero y ovarios, vagina hipoplásica y gónadas masculinas. El cariotipo 46,XY fue detectado con técnica de bandas GTG y CBG e hibridación in situ fluorescente con presencia del cromosoma Y en el 100% de las células analizadas. Aunque ambas se identificaban con su sexo de asignación, fueron referidas a consulta de psiquiatría de la institución. Conclusiones: se discute la importancia del manejo multidisciplinario para el diagnóstico de SICA a edades tempranas con la finalidad de tomar decisiones respecto al tratamiento y manejo de las pacientes y evitar la malignización de las gónadas masculinas.

Four novel mutations in the androgen receptor gene from Vietnamese patients with androgen insensitivity syndrome.

BACKGROUND: Androgens and androgen receptor (AR) are critical regulators of the masculinization process in male sexual development. The absence of a functioning AR results in the development of the androgen insensitivity syndrome (AIS), a rare disorder of sexual development (DSD) characterized by the external genitalia feminization, gynecomastia, and impaired spermatogenesis. OBJECTIVE: To determine the AR gene mutations associated with male DSD in four unrelated Vietnamese patients. METHODS: To detect the disease-causing mutations, whole exome sequencing (WES) was performed on four patients diagnosed with AIS. Sanger sequencing was then used for validation of the identified mutations. Finally, 12 web-based tools, three-dimensional protein modeling software, and the guidelines issued by the American College of Medical Genetics and Genomics were used to assess the potential pathogenicity of these mutations. RESULTS: Four distinct novel mutations, namely c.1834T > A (p.Cys612Ser), c.2122 C > G (p.Leu708Val), c.2630T > G (p.Phe877Cys), and c.2641 C > A (p.Leu881Met) in the AR gene, were identified in four AIS patients using WES. The in silico analysis results revealed that the Cys612, Leu708, Phe877, and Leu881 sites are important for an appropriate response to androgens of the AR, and mutation at these sites can have adverse effects on the AR functions, androgen-AR interaction, and AR signaling pathway. CONCLUSIONS: WES and in silico analyses strongly suggested that four novel AR mutations are pathogenic and have led to the development of AIS in the four Vietnamese patients under consideration.

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.

Cohort profile: pathways to care among people with disorders of sex development (DSD).

PURPOSE: The 'DSD Pathways' study was initiated to assess health status and patterns of care among people enrolled in large integrated healthcare systems and diagnosed with conditions comprising the broad category of disorders (differences) of sex development (DSD). The objectives of this communication are to describe methods of cohort ascertainment for two specific DSD conditions-classic congenital adrenal hyperplasia with 46,XX karyotype (46,XX CAH) and complete androgen insensitivity syndrome (CAIS). PARTICIPANTS: Using electronic health records we developed an algorithm that combined diagnostic codes, clinical notes, laboratory data and pharmacy records to assign each cohort candidate a 'strength-of-evidence' score supporting the diagnosis of interest. A sample of cohort candidates underwent a review of the full medical record to determine the score cutoffs for final cohort validation. FINDINGS TO DATE: Among 5404 classic 46,XX CAH cohort candidates the strength-of-evidence scores ranged between 0 and 10. Based on sample validation, the eligibility cut-off for full review was set at the strength-of-evidence score of ≥7 among children under the age of 8 years and ≥8 among older cohort candidates. The final validation of all cohort candidates who met the cut-off criteria identified 115 persons with classic 46,XX CAH. The strength-of-evidence scores among 648 CAIS cohort candidates ranged from 2 to 10. There were no confirmed CAIS cases among cohort candidates with scores <6. The in-depth medical record review for candidates with scores ≥6 identified 61 confirmed cases of CAIS. FUTURE PLANS: As the first cohort of this type, the DSD Pathways study is well-positioned to fill existing knowledge gaps related to management and outcomes in this heterogeneous population. Analyses will examine diagnostic and referral patterns, adherence to care recommendations and physical and mental health morbidities examined through comparisons of DSD and reference populations and analyses of health status across DSD categories.

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.

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 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.

Complete androgen insensitivity syndrome caused by a novel mutation in the androgen receptor gene and its mechanism.

Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disease characterized by disorders of sex development, commonly caused by mutations of the androgen receptor (AR) gene. Herein, we identified a novel hemizygous mutation (c.2118T > A, p. Asn706Lys) of AR resulting in complete androgen insensitivity syndrome (CAIS) in twins. This missense mutation contributed to significantly decreased mRNA transcription and protein expression. In addition, structure model analysis showed that Asn706Lys resulted in loss of hydrogen bond with Asp891 and reduced protein stability. Furthermore, the mutant AR failed to bind to ligand due to the loss of hydrogen bond with dihydrotestosterone (DHT). This disrupted the translocation of AR protein from cytoplasm to nucleus after hormone stimulation. Our findings firstly demonstrated the novel mutation of c.2118T > A in AR directly caused CAIS. This contributed to expanding the AR mutational spectrum and revealed the pathogenic mechanism of AIS, as well as facilitating precise diagnosis and genetic counseling.