[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.

Síndrome de insensibilidad a andrógenos: revisión bibliográfica a propósito de 5 casos / Androgen insensitivity syndrome: literature review about 5 cases

El síndrome de insensibilidad a andrógenos (AIS en la sigla inglesa) es una entidad muy poco frecuente en endocrinología. Se caracteriza por la mutación del receptor de andrógenos de magnitud variable, por medio del cual individuos 46,XY no se virilizan normalmente, a pesar de conservar sus testículos y tener concentraciones de testosterona en rango masculino. El cuadro clínico es variable y depende la profundidad de la alteración del receptor. En un extremo, hay casos de insensibilidad androgénica completa (CAIS) con fenotipo femenino. En el otro extremo hay insensibilidad parcial (PAIS) que se extiende desde el fenotipo femenino, con o sin ambigüedad genital, hasta los casos de hombres infértiles o con subvirilización, que presentan insensibilidad androgénica más leve. En los fenotipos femeninos, los testículos suelen estar en posición ectópica y aquellos ubicados dentro del abdomen tienen riesgo de malignizarse, por lo que suelen extirparse. Estos son los casos de más difícil manejo, pues aparte de la necesidad de gonadectomía seguida de terapia hormonal femenina, existe una vagina estrecha y en fondo de saco ciego y que suele requerir corrección quirúrgica para permitir la actividad sexual. En este trabajo presentamos 5 casos de AIS vistos recientemente en 2 centros clínicos de Santiago y que ilustran la heterogeneidad de presentación. Además, hacemos una revisión actualizada de los criterios diagnósticos, los tratamientos más adecuados y el manejo global de esta condición.

The Androgen insensitivity syndrome (AIS, in its English acronym) is a very rare entity in endocrinology. It is characterized by a variable magnitude androgen receptor mutation, whereby 46, XY individuals are not normally virilized, despite retaining their testicles and having testosterone concentrations in the male range. The clinical picture is variable and depends on the depth of the receptor alteration. At one extreme, there are cases of complete androgenic insensitivity (CAIS) with a female phenotype. At the other extreme, there is partial insensitivity (PAIS) that extends from the female phenotype, with or without genital ambiguity, to cases of infertile or undervirilized men, who have milder androgenic insensitivity. In female phenotypes, the testes are usually in an ectopic position and those located within the abdomen are at risk of malignancy, and therefore are usually removed. These are the most difficult cases to manage because apart from the need for gonadectomy followed by female hormonal therapy, there is a narrow vagina and a deep blind pouch that usually requires surgical correction to allow sexual activity. In this work, we present 5 cases of AIS recently seen in 2 clinical centers in Santiago and that illustrate the heterogeneity of presentation. In addition, we make an updated review of the diagnostic criteria, the most appropriate treatments, and the overall management of this condition.

Conservative Management of Vaginal Hypoplasia

In patients with Mayer-Rokitansky-Küster-Hauser syndrome and complete androgen insensitivity syndrome (CAIS), management of vaginal hypoplasia includes non-surgical or surgical vaginal elongation techniques. For these patients, primary vaginal dilation is considered a first-line option to avoid the risks of having surgery and complications that may occur due to these procedures. Non-surgical dilation is a highly successful treatment if treatment is initiated when the patient is emotionally mature and ready. Here, we present a case of CAIS with vaginal hypoplasia managed successfully with non-surgical dilation therapy.

A shared decision-making tool for individuals living with complete androgen insensitivity syndrome.

Reports exist regarding a gradual approach to the care of patients with differences of sexual development. Each patient and family have different values and styles of learning that have to be taken into account. The goals of care should include education about the condition, counseling of the patient and family, and a complete outlining of treatment options. Motivated by a call from the 2010 Health Reform Law for the use of shared decision-making tools and the emphasis placed on these issues by the DSD Consensus Statement, we sought to develop and implement such tools for the DSD population.1-3 Thus, we developed an organized checklist for providers to share with a patients and families affected by CAIS, beginning with the initial visit. The development of the document enlisted input from physicians, clinical coordinator, advocacy groups and affected individuals. It allows providers to explain the process of care and develop a plan for delivery of that care over multiple visits spanning six months or more. The checklist is divided into five sections: 1) An overview addressing how much information is desired and in what manner the patient prefers to obtain information; 2) A preferred words list so that the patient can choose nomenclature that is most comfortable; 3) A list of topics to review over the course of multiple visits; 4) A list of questions to be answered by the providers or other resources over time, and; 5) A list of concerns to be addressed before surgical intervention is considered. An organized approach to long-term delivery of compassionate care and accurate information can be facilitated for patients with CAIS by the use of a shared decision-making checklist. Documentation of the care delivery process can stimulate referral to peer support and promote fully informed consent for treatment decisions. The use of the checklist should encourage trust in the provider, as well as aid in identifying and addressing stressors for the patient and family. The checklist will be updated and revised as new treatments and advanced technology emerges.

Primary gonadal failure.

The term primary gonadal failure encompasses not only testicular insufficiency in 46,XY males and ovarian insufficiency in 46,XX females, but also those disorders of sex development (DSD) which result in gender assignment that is at variance with the genotype and gonadal type. In boys, causes of gonadal failure include Klinefelter and other aneuploidy syndromes, bilateral cryptorchidism, testicular torsion, and forms of 46,XY DSD such as partial androgen insensitivity. Causes in girls include Turner syndrome and other aneuploidies, galactosemia, and autoimmune ovarian failure. Iatrogenic causes in both boys and girls include the late effects of childhood cancer treatment, total body irradiation prior to bone marrow transplantation, and iron overload in transfusion-dependent thalassaemia. In this paper, a brief description of the physiology of testicular and ovarian development is followed by a section on the causes and practical management of gonadal impairment in boys and girls. Protocols for pubertal induction and post-pubertal hormone replacement - intramuscular, oral and transdermal testosterone in boys; oral and transdermal oestrogen in girls - are then given. Finally, current and future strategies for assisted conception and fertility preservation are discussed.

Androgen insensitivity syndrome.

OBJECTIVE: We provide a review of the literature about the Androgen Insensitivity Syndrome (AIS), its onset and associated developmental anomalies and the genetic alterations causing it. MATERIALS AND METHODS: We searched PubMed with a larger emphasis on the physiology, genetics and current management of AIS. RESULTS: AIS is an X-linked recessive Disorder of Sex Development (DSD). It is caused by mutations of the Androgen Receptor, and their large amount and heterogeneity (missense and nonsense mutations, splicing variants, deletions, and insertions) are responsible for the wide spectrum of possible phenotypes of patients, divided into Partial AIS (PAIS) and Complete AIS (CAIS). Once the clinical and laboratory investigations have laid the foundation for a diagnostic hypothesis, it is important to identify the actual karyotype of the individual and search for the mutation in the Androgen Receptor to diagnose with certainty the syndrome. Alternatively, in the absence of such evidence, the diagnosis should more properly be an AIS-like condition, which we describe as well in our report. CONCLUSIONS: The management of this DSD is based on pharmacotherapies, surgery and psychological support: all of them must be directed to facilitate the patient's life, considering his/her sexual identity.

Androgen insensitivity syndrome: a review

ABSTRACT Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). The androgen receptor gene has 8 exons and 3 domains, and allelic variants in this gene occur in all domains and exons, regardless of phenotype, providing a poor genotype - phenotype correlation in this syndrome. Typically, laboratory diagnosis is made through elevated levels of LH and testosterone, with little or no virilization. Treatment depends on the phenotype and social sex of the individual. Open issues in the management of androgen insensitivity syndromes includes decisions on sex assignment, timing of gonadectomy, fertility, physcological outcomes and genetic counseling.

Androgen Insensitivity Syndrome: Management Considerations from Infancy to Adulthood.

Androgen insensitivity syndrome (AIS) is an undervirilization syndrome in individuals with 46, XY karyotype. The undervirilization can be complete feminization or incomplete virilization with grades of ambiguity. AIS is caused by mutations in the androgen receptor, resulting in resistance to the physiologic activities of androgens. Differing degrees of resistance lead to three phenotypes: a complete form with female-appearing external genitalia, a partial form with a wide range of virilization, and a mild form with only minor undervirilization. AIS presents different challenges depending on whether resistance is complete or partial. Challenges include sex assignment, which impacts other medical decisions such as gonadectomy, hormonal replacement, and other surgical interventions. This review describes medical, psychosocial, and ethical concerns for each stage of development in complete and partial AIS, from the neonatal period to adulthood. These aspects of care should be addressed within an ethical framework by a multidisciplinary team, with the patients and families being the stakeholders in the decision-making process. We use the GRADE system when appropriate to appraise the existing evidence and provide recommendations and guidelines for management of AIS and appropriate transition of patients from pediatric to adult care.

Complete androgen insensitivity syndrome in juveniles and adults with female phenotypes.

AIM: To report on six cases of the diagnosis and treatment of patients with complete androgen insensitivity syndrome (CAIS) and a review of the relevant published work. METHODS: A retrospective analysis was performed on the clinical features, diagnosis and treatment of a total of six patients with CAIS who were admitted to our hospital between September 1985 and June 2012. All surgical patients were examined for sex chromosomes and sex hormone levels pre- and postoperatively, respectively, and underwent lower abdominal B ultrasounds and pathological examinations among other tests. RESULTS: Five of the patients were treated with castration, one patient aged 5 years was treated conservatively Tissue from surgical resections showed normal testicular tissue that comprised Leydig cells and Sertoli cells, and pathological examinations showed no sign of testicular cancer. Following corrective operations, postoperative complications, such as female secondary sexual characteristics, stagnation and osteoporosis, have not developed. Sex hormone level ratio changed significantly after being treated with castration compared with preoperative levels; mainly testosterone and estrogen decreased significantly (P < 0.05), while luteinizing hormone and follicle-stimulating hormone significantly increased (P < 0.05). However, prolactin did not change significantly (P > 0.05). CONCLUSION: The study show that removal of the testes in CAIS patients after puberty is safe and reliable. Meanwhile, it is essential to provide a hormone drug after being treated with castration. Further studies are needed to evaluate the safety and the quality of life for CAIS patients.

[Androgen insensitivity syndrome - case report]. / Syndrom úplné androgenní insenzitivity - kazuistika.

OBJECTIVE: Presentation of a familiar incidence of complete androgen insensitivity syndrome. DESIGN: Case report with literature review. SETTING: Department of Gynecology and Obstetrics, Department of Pediatrics, Medical Faculty and University Hospital in Pilsen, Charles University in Prague. CONCLUSION: Androgen insensitivity syndrome is the most common male-hermaphroditism. Affected individuals have a male karyotype, but owing to the unresponsiveness of the cells to androgens a disruption in sexual development occurs. Clinical picture of the syndrome is very variable. Our case-report deals with a familiar incidence of complete androgen insensitivity syndrome, formerly incorrectly called "testicular feminization syndrome". The karyotype of these individuals is 46, XY. They have female external genitalia, male gonads, the uterus and fallopian tubes are missing and vagina is shorter. In this case, the complete androgen insensitivity syndrome was diagnosed in two sisters in childhood as a part of reduced growth investigation. The same syndrome was also detected in their mothers sister. Both girls already underwent laparoscopic gonadectomy. The older one started at the age of 11 with estrogen replacement therapy.

Diagnostic pitfalls in the evaluation and management of amenorrhea in adolescents.

Amenorrhea is a common menstrual problem seen in adolescents. Amenorrhea has been shown to have a negative impact on adolescents' quality of life. In this paper we discuss the various causes and investigations of amenorrhea in adolescents and address management dilemmas for specific conditions. Specific approaches in dealing with adolescents using the HEADSS (Home, Education, Activity, Drugs, Sexual activity, Suicidal) approach are discussed.

Risks of reproducing with a genetic disorder.

Male-factor infertility is the cause of reproductive issues in many couples. For approximately 15% of these men, the origin of the infertility is genetic. These causes include both chromosomal and single-gene disorders frequently impacting spermatogenesis. By identifying the genetic mechanism behind the infertility, we determine the ability of the couple to use assisted reproduction technologies. Use of these methods has ignited a new spectrum of concerns for the genetic competence of the offspring. By knowing what specific genetic risks exist for the offspring of men with these particular disorders, we are able to use preimplantation genetic diagnosis to detect these problems.

Psychosexual outcomes in three siblings with partial androgen insensitivity syndrome: impact of nature versus nurture.

There are few reports of adults with disorders of sexual development (DSD). Here we describe the clinical profile and results of psychological assessment of three siblings with 46, XY DSD caused by partial androgen insensitivity syndrome (PAIS). The elder sibling (aged 22 years) was reared as female, while the middle and youngest siblings (17 and 18 years of age), were reared as males. The gender identity was concordant with the sex of rearing. There was no gender dysphoria. The psychological distress that our patients experienced was due to the limitations placed on them by their medical condition. It did not permit them to experience various facets of being either male or female completely. The younger siblings reared as males had additional problems of gynecomastia and lack of male secondary sexual development.

Clinical and molecular aspects of androgen insensitivity.

Androgen insensitivity describes the inability of cells to respond adequately to androgens. The clinical aspects are well characterized and described in the androgen insensitivity syndrome, where underandrogenization occurs despite normal to high levels of androgens. In 46,XY individuals, this is associated with a variable phenotype ranging from completely female to ambiguous genitalia and infertility in males with gynecomastia. Androgen action is facilitated by a single androgen receptor (AR), whose gene is localized on the X chromosome. However, the identification of mutations in the AR gene in patients with androgen insensitivity is variable, and chances are lower the more subtle the phenotype is. Therefore, other currently unknown mechanisms must be hypothesized to lead to the respective phenotype. The AR is a nuclear transcription factor, acting in concert with an array of only partly known cofactors serving as modulators of target gene transcription. The induced transcription pattern is highly tissue and cell specific, and in some tissues may lead to lasting changes of cell programming. Only one regulated gene APOD has currently been identified to serve as a clinical tool for the diagnosis of androgen insensitivity.

Androgen insensitivity syndrome.

The androgen insensitivity syndromes (AIS) fall within the generic category of 46,XY DSD (disorder of sex development) and present as phenotypes associated with complete or partial resistance to the action of androgens. Three categories are recognized: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), mild androgen insensitivity syndrome (MAIS). The androgen receptor (AR) is encoded by an 8 exon gene on the X chromosome long arm. More than 800 mutations in the AR gene have been reported in AIS patients (www.androgendb.mcgill.ca/). They are distributed throughout the gene with a preponderance located in the ligand binding domain. The most severe mutations are generally associated with a CAIS phenotype, but the correlation is less defined in PAIS. CAIS presents typically as primary amenorrhoea in an adolescent female and less commonly in infancy with bilateral inguinal/labial swellings due to testes. The differential diagnosis in CAIS is limited, whereas in PAIS, numerous other causes of DSD can also produce the typical phenotype of micropenis, severe hypospadias and bifid scrotum. Management issues in CAIS involve timing of gonadectomy, appropriate hormone replacement therapy and assessment of the need for vaginal dilation or rarely, vaginal surgery. The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood. Expert psychological counseling is mandatory to manage the disconnect between chromosomal, gonadal and phenotypic sex and to choreograph the evolving process of disclosure from late childhood through to maturity. It is implicit that management in AIS requires a multidisciplinary team and engagement with patient advocacy groups.

The in vivo role of androgen receptor SUMOylation as revealed by androgen insensitivity syndrome and prostate cancer mutations targeting the proline/glycine residues of synergy control motifs.

The androgen receptor (AR) mediates the effects of male sexual hormones on development and physiology. Alterations in AR function are central to reproductive disorders, prostate cancer, and Kennedy disease. AR activity is influenced by post-translational modifications, but their role in AR-based diseases is poorly understood. Conjugation by small ubiquitin-like modifier (SUMO) proteins at two synergy control (SC) motifs in AR exerts a promoter context-dependent inhibitory role. SC motifs are composed of a four-amino acid core that is often preceded and/or followed by nearby proline or glycine residues. The function of these flanking residues, however, has not been examined directly. Remarkably, several AR mutations associated with oligospermia and androgen insensitivity syndrome map to Pro-390, the conserved proline downstream of the first SC motif in AR. Similarly, mutations at Gly-524, downstream of the second SC motif, were recovered in recurrent prostate cancer samples. We now provide evidence that these clinically isolated substitutions lead to a partial loss of SC motif function and AR SUMOylation that affects multiple endogenous genes. Consistent with a structural role as terminators of secondary structure elements, substitution of Pro-390 by Gly fully supports both SC motif function and SUMOylation. As predicted from the functional properties of SC motifs, the clinically isolated mutations preferentially enhance transcription driven by genomic regions harboring multiple AR binding sites. The data support the view that alterations in AR SUMOylation play significant roles in AR-based diseases and offer novel SUMO-based therapeutic opportunities.

Androgen insensitivity syndrome.

Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor--a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.

Disorders of sex development among Sudanese children: 5-year experience of a pediatric endocrinology clinic.

BACKGROUND: The birth of a child with disorders of sex development (DSDs) is considered a medical and psychosocial emergency. Management of these cases requires facilities and a multidisciplinary team. In developing countries, this is made difficult by the lack of facilities in addition to sociocultural and religious factors that can affect management. This is the first experience to be published from Sudan. OBJECTIVE: The aim of this study was to see the prevalence, etiological factors, management, and problems faced in handling these cases. METHODS: This is a retrospective descriptive study reviewing the records of all cases referred to a pediatric endocrinology clinic over a 5-year period. Cases were managed by a multidisciplinary team. RESULTS: One hundred fifty-six cases were seen, of which 122 were included in the study. A total of 79 (64.8%) were born at home, whereas 59 (52.2%) of the cases were not observed at birth by health-care providers. The average cost of investigating a case was $250-300. The investigations showed that 69 had XX DSD and 45 had XY DSD. The most common cause of XX DSD was congenital adrenal hyperplasia and that of XY DSD was androgen insensitivity syndrome. Twenty-three (19%) needed sex reassignment. There was a preference for the male sex. CONCLUSION: DSDs are not uncommon in Sudan. Because of lack of awareness and sociocultural reasons cases are referred late. Investigating these cases is expensive and has to be supported, and more multidisciplinary teams have to be trained to make services accessible and affordable.

Enhancement balloon vaginoplasty for treatment of blind vagina due to androgen insensitivity syndrome.

OBJECTIVE: To evaluate the safety and feasibility of enhancement balloon vaginoplasty (EBV) in cases with blind vagina due to androgen insensitivity syndrome. DESIGN: Case series with description of the technique. SETTING: Women's Health Center, Assiut University, and Sohage Teaching Hospital, Sohage University. PATIENT(S): Three X,Y females (two cases presenting with apareunia and the third presenting with severe dyspareunia). INTERVENTION(S): Laparoscopy-assisted EBV. MAIN OUTCOME MEASURE(S): Operative time, complications, depth and width of neovagina, and functional status. RESULT(S): Our cases were currently married phenotypical females and had 46,X,Y karyotypes. They had well developed secondary sexual characters, but they presented with failure of intravaginal intercourse. EBV was performed successfully for three X,Y females. The total operative time was 38-45 minutes. No operative complications were reported, and there were no reported postoperative complications as a result of moving the direction of traction. The resultant neovagina's depths were 10, 11, and 12 cm, respectively. Sexual intercourse was set off on the day of discharge. Penetration and satisfaction scores increased up to 90 points for both partners. CONCLUSION(S): It was feasible and safe to move centrally the direction of traction and to move the point of catheter exit up with apparently better outcomes than conventional balloon vaginoplasty for treatment of blind vagina due to androgen insensitivity syndrome.

Care of women with XY karyotype: a clinical practice guideline.

OBJECTIVE: To provide an evidence-based guideline for professionals working with XY women. DESIGN: Review including patient cases from a Danish fertility clinic. SETTING: University-associated scientific unit and fertility clinic. PATIENT(S): Three selected cases. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Evaluation of etiology, diagnosis, treatment, and associated disorders in XY women. RESULT(S): Many gene mutations can cause abnormal fetal development leading to androgen insensitivity syndrome or gonadal dysgenesis disorders. Females with these disorders have an XY karyotype but look like girls. They are mostly diagnosed at puberty, and the condition will often lead to serious psychological problems. Increased risk of malignancies and problems with pregnancy and infertility are other aspects that should be considered. This guideline will aid doctors in caring for XY females. CONCLUSION(S): A precise diagnosis is important, because the treatment possibilities (e.g., use of allogenic oocytes) depend on the subgroup to which the XY female belongs.