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.

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.

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.

Androgen receptor deficiency is associated with reduced aromatase expression in the ventromedial hypothalamus of male cichlids.

Social behaviors are regulated by sex steroid hormones, such as androgens and estrogens. However, the specific molecular and neural processes modulated by steroid hormones to generate social behaviors remain to be elucidated. We investigated whether some actions of androgen signaling in the control of social behavior may occur through the regulation of estradiol synthesis in the highly social cichlid fish, Astatotilapia burtoni. Specifically, we examined the expression of cyp19a1, a brain-specific aromatase, in the brains of male A. burtoni lacking a functional ARα gene (ar1), which was recently found to be necessary for aggression in this species. We found that cyp19a1 expression is higher in wild-type males compared to ar1 mutant males in the anterior tuberal nucleus (ATn), the putative fish homolog of the mammalian ventromedial hypothalamus, a brain region that is critical for aggression across taxa. Using in situ hybridization chain reaction, we determined that cyp19a1+ cells coexpress ar1 throughout the brain, including in the ATn. We speculate that ARα may modulate cyp19a1 expression in the ATn to govern aggression in A. burtoni. These studies provide novel insights into the hormonal mechanisms of social behavior in teleosts and lay a foundation for future functional studies.

Spindly reason for a pulmonary embolism.

Pulmonary artery intimal sarcomas (PAISs) are rare, malignant tumours that arise from the intimal or intramural wall of the pulmonary artery and are often mistaken for pulmonary emboli. Diagnosis and treatment of this condition are difficult due to the lack of formal guidelines. Initiating treatment as soon as possible after diagnosis is essential for maximising survival. Here, we present the case of a patient with a PAIS that initially presented similar to pulmonary thromboembolic disease and was treated with a multimodal approach.

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.

Pubertal and Gonadal Outcomes in 46,XY Individuals with Partial Androgen Insensitivity Syndrome Raised as Girls.

INTRODUCTION: Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls. METHODS: The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls. RESULTS: Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement, and 8/11 had attained Tanner stage 4-5 breast development at the last assessment. CONCLUSION: In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumor.

Formin-mediated nuclear actin at androgen receptors promotes transcription.

Steroid hormone receptors are ligand-binding transcription factors essential for mammalian physiology. The androgen receptor (AR) binds androgens mediating gene expression for sexual, somatic and behavioural functions, and is involved in various conditions including androgen insensitivity syndrome and prostate cancer1. Here we identified functional mutations in the formin and actin nucleator DAAM2 in patients with androgen insensitivity syndrome. DAAM2 was enriched in the nucleus, where its localization correlated with that of the AR to form actin-dependent transcriptional droplets in response to dihydrotestosterone. DAAM2 AR droplets ranged from 0.02 to 0.06 µm3 in size and associated with active RNA polymerase II. DAAM2 polymerized actin directly at the AR to promote droplet coalescence in a highly dynamic manner, and nuclear actin polymerization is required for prostate-specific antigen expression in cancer cells. Our data uncover signal-regulated nuclear actin assembly at a steroid hormone receptor necessary for transcription.

Persistence of foetal testicular features in patients with defective androgen signalling.

OBJECTIVE: Congenital defects of androgen synthesis or action in 46,XY individuals can result in impaired virilisation, despite the apparent testicular development. In a recent case, report of a young adult with complete androgen insensitivity syndrome (CAIS), tumourous gonadal tissue was shown to express HSD17B3 in Sertoli cells (SCs) and not in Leydig cells (LCs). This expression pattern differs from the typical adult human testis and resembles a foetal mouse testis, suggesting an underlying testicular development and function defect. Here, we investigate the effect of altered androgen signalling in gonads from five 46,XY individuals with defects in androgen synthesis or action. METHODS: Gonadal tissue sections from four patients with CAIS, one with CYP17A1 deficiency, and one control were immunostained for LC developmental and steroidogenic markers. The expression of some of these markers during development was investigated by reanalysing previously published single-cell RNA sequencing (scRNA-seq) data from normal human testicular tissues. RESULTS: All gonadal tissues from the patients show an exclusive expression of HSD17B3 in SCs and an expression of the foetal/immature LC marker DLK1 in a subset of LCs, suggesting an androgen-dependent differentiation defect of adult SCs and LCs. Furthermore, reanalysis of scRNA-seq data reveals an expression of HSD17B3 in foetal and neonatal SCs that is downregulated in adult SCs. CONCLUSIONS: Androgen signalling may affect the differentiation of adults, but possibly not foetal SCs or LCs, and may induce a shift of testosterone production from the tubular compartment in the foetal phase to the interstitial compartment in the adult phase.

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.

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.

[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.

Abdominal Mass in a Phenotypic Female with 46,XY Differences in Sex Development.

We present a case of a large intra-abdominal mass found to be localized pure seminoma within a retained gonad of a 53-year-old phenotypic female with 46,XY differences in sex development (DSD) and androgen insensitivity syndrome (AIS). Our management included extirpation of the mass with contralateral gonadectomy. Historically, patients with AIS would undergo gonadectomy to mitigate the lifetime risk of testicular germ cell tumor development; however, growing evidence suggests safety in retention and surveillance of these gonads into adulthood. This case highlights the importance of lifetime surveillance of patients with 46,XY DSD who elect to retain their gonads.

[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.

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.

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.

Síndrome de insensibilidad completa a andrógenos / Complete androgen insensitivity syndrome

El síndrome de insensibilidad a los andrógenos (SIA), conocido también como un síndrome de feminización testicular, incluye un grupo variado de mutaciones que se relacionan con la disfunción de los receptores de andrógenos y la resistencia de los tejidos diana a la acción de las hormonas masculinas. Es causado por alteraciones genéticas localizadas en la secuencia de codificación de los receptores de andrógenos ligada al cromosoma Xq11 - 12, el gen que codifica al receptor de los andrógenos, de un individuo genéticamente masculino (46 XY). Las formas clínicas moderada, parcial o completa, dependen del grado de insensibilidad androgénica. Los avances en las causas genéticas han permitido que estas condiciones congénitas de desarrollo del sexo cromosómico, gonadal o anatómico atípico sean denominados trastornos de diferenciación sexual

Androgen insensitivity syndrome (AIS), also known as testicular feminization syndrome, includes a diverse group of mutations that are related to androgen receptor dysfunction and resistance of target tissues to the action of hormones masculine. It is caused by localized genetic alterations in the androgen receptor coding sequence linked to chromosome Xq11-12, the gene encoding the androgen receptor, of a genetically male (46 XY) individual. Moderate, partial, or complete clinical forms depend on the degree of androgen insensitivity. Advances in genetic causes have allowed these congenital conditions of atypical chromosomal, gonadal, or anatomical sex development to be called disorders of sexual differentiation