Case Of Complete Androgen Insensitivity Syndrome Research Articles

FRI445 A Late Diagnosis Of Complete Androgen Insensitivity Syndrome

Abstract Disclosure: J. Muuse: None. R.J. Shah: None. P.A. Belany: None. Introduction: Complete Androgen Insensitivity Syndrome (CAIS) is a rare disorder of hormone resistance characterized by a female phenotype in an individual with an XY karyotype. Individuals with CAIS are born unambiguously female without any apparent abnormalities. They develop a short blind ending vaginal canal, with absence of Wolffian duct derived structures (vas deferens, seminal vesicles). Breast development advances regularly at puberty, while there is absent pubic and axillary hair, both due to peripheral conversion of testosterone to estrogen. Testes remain undescended in the abdominal cavity. Case: A 28 year old female with a past medical history of bipolar disorder presented to her primary care physician’s office with a chief complaint of fatigue. Blood work revealed an elevated testosterone level of 686, at which time she was referred to endocrinology for further work up. On further history gathering, she endorsed a life long history of amenorrhea. She saw an OB-GYN at 19 years old and was told she had a short vaginal canal. A pelvic ultrasound revealed no uterus and one left ovary. She was not given a diagnosis other than congenital absence of a uterus. She was lost to follow up until 28 years of age when she sought medical help for her fatigue. Physical exam was pertinent for a tall female with no signs of hirsuitism. Additional blood work revealed normal LH, FSH, and DHEA-S. A chromosomal analysis revealed XY. She was referred to gynecology for further management and assessment for orchiectomy. Discussion: This was an unusual case of CAIS, as this was diagnosed far past menarche. Most cases are diagnosed during puberty- which aids in an early approach towards the psychological and social well being of the individual as well as close follow up for evaluation of orchiectomy. Orchiectomy is recommended due to the increased risk of gonadal malignancy following puberty. The risk of developing malignancy increases with age, and has been reported to be between 15-22%. Thus it is important to identify this syndrome early in life to ensure this is addressed. It is followed by long term hormonal therapy with estrogen to maintain normal breast and bone development. This case highlights the importance of maintaining a high clinical suspicion of CAIS in females presenting with short vaginal canal and absence of a uterus in order to prevent malignancy and provide optimal psychological support to the individual. Presentation: Friday, June 16, 2023

Clinical characteristics and molecular genetics of complete androgen insensitivity syndrome patients: a series study of 30 cases from a Chinese tertiary medical center

To study the clinical characteristics and genetic basis of complete androgen insensitivity syndrome (CAIS) in patients from the People's Republic of China. CAIS patients with 46 XY karyotype produce male levels of androgens but present with female external genitalia and secondary sex characteristics. The majority of affected individuals have androgen receptor (AR) gene mutations. This case series explored clinical and molecular characteristics of CAIS patients from the People's Republic of China. Genomic DNA from peripheral blood of clinically diagnosed CAIS patients was sequenced for mutation in the androgen receptor (AR) gene and steroid 5α-reductase type 2 gene (SRD5A2). Participants were recruited from Peking Union Medical College Hospital when they came in for consultation. Thirty patients from unrelated families were recruited. Data from medical documents recording diagnosis and treatment of these patients were retrospectively collected. Patient genotypes were determined by sequencing the AR and SRD5A2 genes. Their clinical characteristics were summarized based on symptoms, hormone profiles, operative findings, and pathological results. Twenty-one patients diagnosed with CAIS had mutations in AR exons. Analysis of AR exons revealed the presence of seven novel mutations (c.58C>T, c.645_652delGGGGGCTC, c.910G>T, c.1078C>T, c.1786T>A, c.2230G>T, and c.2522G>C); of these mutations, 47.6% (10/21) were located in the ligand-binding domain. Gonadal insufficiency was found in one case of CAIS. Among the remaining nine patients, three had SRD5A2 mutations and therefore a steroid 5α-reductase deficiency. No AR or SRD5A2 mutations were detected in the other six patients. This study broadens the spectrum of known AR gene mutations responsible for CAIS, and implies that there can be more complex underlying causes of CAIS.

Two Korean girls with complete androgen insensitivity syndrome diagnosed in infancy.

Androgen insensitivity syndrome (AIS) is a rare genetic disease caused by various abnormalities in the androgen receptor (AR). The AR is an essential steroid hormone receptor that plays a critical role in male sexual differentiation and development and preservation of the male phenotype. Mutations in the AR gene on the X chromosome cause malfunction of the AR so that a 46,XY karyotype male has some physical characteristics of a woman or a full female phenotype. Depending on the phenotype, AIS can be classified as complete, partial or mild. Here, we report 2 cases of complete AIS in young children who showed complete sex reversal from male to female as a result of AR mutations. They had palpable inguinal masses and normal female external genitalia, a blind-end vagina and absent Müllerian duct derivatives. They were both 46,XY karyotype and AR gene analysis demonstrated pathologic mutations in both. Because AIS is inherited in an X-linked recessive manner, we performed genetic analysis of the female family members of each patient and found the same mutation in the mothers of both patients and in the female sibling of case 2. Gonadectomy was performed in both patients to avoid the risk of malignancy in the undescended testicles, and estrogen replacement therapy is planned for their adolescence. Individuals with complete AIS are usually raised as females and need appropriate care.

A rare case of bilateral sertoli cell adenoma in gonads associated with unilateral serous cyst in a patient with complete androgen insensitivity syndrome

Complete androgen insensitivity syndrome (CAIS) is an extremely infrequent disease. The patients exhibit female phenotype because of insensitivity to the androgen receptor and may develop tumors, especially in their undescended gonads. We present here a case of CAIS with bilateral Sertoli cell adenoma along with unilateral serous cyst in a 16-year-old patient.

Giant Inguinal Hernia Repair Leading To the Diagnosis of Complete Androgen Insensitivity Syndrome in an Elderly Lady

Complete androgen insensitivity syndrome (CAIS) is an X linked disorder characterized by lack of mullerian derivatives, absent uterus, normal breast development and sparse or absent axillary and pubic hairs. Mutation in the androgen receptor is the cause for this rare disorder. Classically diagnosis is made when evaluating for primary amenorrhea in a young girl. These patients are at higher risk for development of gonadal malignancy the risk of which increases with increasing age. Bilateral gonadectomy after puberty is recommended. We are presenting a case of CAIS who was diagnosed at the age of 60 years during surgery for giant inguinal hernia.

1590 Inguinal Hernia in “Girls” Rarely Reveals Complete Androgen Insensitivity Syndrome

Background AimAccording to literature, the incidence of complete androgen insensitivity syndrome (CAIS) revealed by inguinal hernia in “girls” is variable due to the clinical heterogeneity of the series. The aim...

Laparoscopic Gonadectomy for Complete Androgen Insensitivity Syndrome

Introduction: Androgen insensitivity syndrome is a form of malepseudohermaphrodite where the phenotype female has malegonads and is genotypically male.Case report: We report a case of complete androgeninsensitivity syndrome in a 22-year-old who underwentlaparoscopic gonadectomy.Discussion: Androgen insensitivity syndrome is the mostcommon cause of male pseudohermaphroditism and third mostcommon cause of primary amenorrhea.Conclusion: Laparoscopy is an effective method in androgeninsensitivity syndrome treatment, mainly due to the increasedrisk of malignant transformation of the testes. Psychosexualneeds should be addressed along with low-dose hormonaltherapy to maximize long-term success.

Gonadal structures in a fetus with complete androgen insensitivity syndrome and persistent Müllerian derivatives: comparison with normal fetal development

To report a case of complete androgen insensitivity syndrome (CAIS) with Müllerian duct persistence. Case report. Academic hospital. A case of CAIS at 20 weeks' gestational age, and three male and one female 20-week-old fetuses for comparison. DNA screening for androgen receptor (AR), antimüllerian hormone (AMH), and AMH receptor type 2 (AMHR2) gene mutations, and morphologic examination of Wolffian and Müllerian derivatives and immunohistochemistry for AMH, AMHR2, and bone morphogenetic protein receptor type 1A (BMPR1A) in aborted fetuses. Histopathologic, genetic, and immunohistochemical studies. A novel mutation of AR (D767V) was identified in the index fetus. The CAIS case showed Wolffian duct degeneration, Leydig cell hyperplasia, and normally developed Sertoli cells. No AMH and AMHR2 gene sequence alterations were observed in the CAIS case, and the uterus and vagina were developed to a similar extent as found in the normal female 20-week-old fetus. The CAIS testes expressed more abundant AMH and showed fewer AMHR2-positive peritubular mesenchymal cells than the normal male testes, but BMPR1A stained similarly. Our study indicates that testes differentiation and development as well as the expression patterns of AMH, AMHR2, and BMPR1A are independent from AR function, at least up to the second trimester. The mechanisms by which the lack of functional androgen interferes with AMH action and Müllerian duct regression remain undefined.

Familial complete androgen insensitivity syndrome with prostatic tissue and seminal vesicles

Complete androgen insensitivity syndrome (CAIS) is a rare androgen receptor function disorder where phenotypic female has a male genotype. They mostly present as bilateral inguinal hernias containing testes. Uterus and cervix are absent. The authors present a case of CAIS in a 22-year-old female where the presence of testes, prostatic tissue and seminal vesicles was confirmed by ultrasonography, hormonal analysis, operative findings and histopathological study. She was second of the two sisters and her elder sister was also diagnosed with CAIS. High levels of testosterone seen in CAIS can stimulate Wolffian duct development/differentiation. Gonadectomy is advisable in such patients to avoid future neoplastic changes.

Gender Outcome in 46,XY Complete Androgen Insensitivity Syndrome: Comment on T’Sjoen et al. (2010)

The case report by T’Sjoen et al. (2010) constitutes the third published case of an originally female-assigned individual with 46,XY complete androgen insensitivity syndrome (CAIS) who appeared to have developed a male gender identity. Of the three individuals, this third one underwent the most sophisticated genetic work-up, and the social history makes a contribution of social coercion to the identity development least likely. Therefore, this report raises challenging diagnostic, phenomenologic, and etiologic questions. T’Sjoen et al. ‘‘believe this patient qualifies as female-tomale transsexual.’’ Their diagnosis was predated by the psychotherapist’s diagnosis of ‘‘childhood-onset gender identity disorder’’ made in the course of 5 years of psychotherapy that had started at age 23 years, i.e., 2 years before the initiation of androgen treatment and 4 years before mastectomy. The psychiatric nomenclature used in this case from Belgium was presumably that of the International Classification of Diseases, 10th revision (ICD-10; World Health Organization, 1992). In this context, the use of the diagnosis of F64.0 Transsexualism for a case of CAIS is puzzling, because the respective guidelines text clearly states that the ‘‘transsexual identity...must not be...associated with any intersex, genetic, or sex chromosome abnormality’’ (World Health Organization, 1992, p. 215; website p. 168). Perhaps the choice of diagnosis was influenced by the fact that this exclusion criterium has not been listed specifically for F64.2 Gender identity disorder of [prepubertal] childhood (World Health Organization, 1992, pp. 215–217; website pp. 168–170). In the Diagnostic and Statistical Manual ofMentalDisorders (DSM-IV-TR) of the American Psychiatric Association (2000), a ‘‘concurrent...physical intersex condition’’ is an exclusion criterium for Gender Identity Disorder regardless of pubertal stage. I have presented detailed arguments why the DSM-IV-TR diagnostic category of Gender Identity Disorder, as defined for persons without physical intersexuality (recently re-named ‘‘disorders of sex development’’ [DSD; Hughes et al., 2006]), should not be applied to persons with gender-identity problems in the context of a DSD (MeyerBahlburg, 1994, 2009). As T’Sjoen et al. did not discuss this issue in their report, it is unclear whether the transsexualism diagnosis was just an oversight on their part, or whether they assumed that, in this particular case, the patient-initiated gender change was distinctly different from that found in other cases of intersexuality and really more comparable to that of non-DSD transsexualism. The case history, as presented retrospectively, is much in line with what one sees clinically in many cases of DSD with patient-initiated gender change. Although assigned female at birth and undiagnosed until age 17 years, this child showed substantial cross-gender behavior since the age of 3 years, with verbal expressions of the wish to be of the other gender. However, this patient must have agreed to a short course of estrogen treatment at age 18, which was soon stopped again because of the patient’s aversive reaction to body feminization. Yet, subsequently, it took another 5 years and a revisit of her medical records for the patient to realize the potential implications of her 46,XY karyotype, which ‘‘supported the desire to make her body congruent with a long-standing male gender identity,’’ but even then there was substantial ‘‘hesitation’’ about her presentation, and another 2 years of psychotherapy before beginning androgen treatment, etc. Transient periods of gender uncertainty are experienced by many patients with DSD (Meyer-Bahlburg et al., 2004b), and the slow gradual procession to gender change in later adolescence and adulthood also appears more common among H. F. L. Meyer-Bahlburg (&) New York State Psychiatric Institute and Department of Psychiatry, Columbia University, 1051 Riverside Drive, Unit 15, New York, NY 10032, USA e-mail: meyerb@childpsych.columbia.edu

Male Gender Identity in Complete Androgen Insensitivity Syndrome

Purpose In XY individuals with complete androgen insensitivity syndrome (CAIS), the external genitalia are unremarkable (normal female) at birth. That is why CAIS patients are invariably assigned and reared as girls. In spite of the presence of a Y chromosome, and concordant with the absent androgenization of the brain, CAIS girls and women have a female-typical core gender identity, and female-typical gender role behavior in adulthood, usually choose a male partner and do not appear to suffer from gender identity disorder. There is no documented case of gender change in individuals with CAIS. Material and Methods In 1995, our patient was diagnosed with CAIS at age 17 following investigations for primary amenorrhoea. The diagnosis was based on an unambiguously female phenotype, a 46,XY karyotype and an androgen receptor gene mutation. Bilateral gonadectomy and hernia repair was performed in 1996. A short time of oestrogen treatment induced a negative emotional reaction and treatment was stopped.Since the age of three, childhood-onset cross gender behavior had been noticed. After a period of psychotherapy, started in 2001, persisting male gender identity was confirmed. Hormonal therapy with Testosterone enanthate 200 mg intramuscularly every 2 weeks was started in 2003, however without inducing any of the desired secondary male characteristics. A subcutaneous mastectomy was performed in 2005 and this was a relief for the patient. Results We saw this individual at age 28 with clear male gender role and presentation, mastectomyscars, and female external genitalia without clitoral hypertrophy. The patient received in 2008 phalloplasty by left forearm free flap to the perineal region and scrotoplasty. Even without virilization, testosterone treatment was continued and bone density remained normal. Conclusions To our knowledge, this is the first case of CAIS who chose gender reassigment to male.

Testicular development in the complete androgen insensitivity syndrome

The complete androgen insensitivity syndrome (CAIS), caused by mutations in the androgen receptor (AR) gene, is associated with abnormal testicular development and an increased risk of germ cell malignancy. Previous histological studies in CAIS have selected patients purely on the basis of clinical diagnosis and were mostly based on small numbers, many of whom were post-pubertal. Here, we present 44 cases of CAIS, each with molecular pathological confirmation of an AR mutation. The median age at gonadectomy was 5.5 years (5.5; IQR 1-13). We have been able, therefore, to investigate testicular development in infancy, childhood and puberty, and estimate the incidence of premalignant change in this series. In addition, we have investigated whether the presence of epididymides and/or vasa deferentia in CAIS, previously shown to be associated with residual activity of mutant ARs, is related to a particular testicular phenotype. Epididymides/vasa deferentia were present in 36% of cases and these patients showed varying degrees of seminiferous tubule maturation at puberty above those without epididymides/vasa deferentia (p = 0.003). There were no other histological differences between these patient groups. In both groups, features of testicular degeneration and dysgenesis were present and germ cell development was delayed, with prolonged expression of the gonocyte markers, placental-like alkaline phosphatase and activator protein-2gamma. Germ cell numbers rapidly declined after the first year of life (R(2) = 0.42). Only two cases of carcinoma in situ were identified in our study and both patients were postpubertal (17 and 53 years). From these results and the literature, we conclude that the risk of premalignant change in germ cells is low before and during puberty. Patients can be advised, therefore, that gonadectomy can be delayed to allow for a natural puberty, with low risk of malignant transformation. Our study only included one patient over 18 years, so we cannot comment on the risk of malignant transformation in later life.

Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is the most common single entity that results in male under-masculinization, but large cohort studies of AIS have rarely been performed. Over the last decade, nationwide cooperation between pediatric endocrinologists in the United Kingdom has allowed the creation of a database of cases of intersex and ambiguous genitalia where detailed clinical information on every notified case has been collected via a questionnaire. Among the 816 entries recorded by January 1999, there were 105 clinically diagnosed cases of complete AIS (CAIS) and 173 cases of partial AIS (PAIS). A masculinization score was devised by scoring the external phenotype, and a score of 12 represented normal masculinization. Androgen receptor (AR) binding was determined by studying binding capacity (Bmax) and receptor affinity (K(d)), and cases were classified as either zero, abnormal, or normal binding. Mutation screening of all eight exons of the AR gene was performed by single-strand conformational polymorphism analysis, followed by direct DNA sequencing. All cases of PAIS presented within the first month of birth. The median age at presentation of children with CAIS was 1 yr (P10,P90: 0.1,10.4). The testes were palpable in the labioscrotal folds or the inguinal region in 77% and 41% of cases of CAIS and PAIS, respectively. There was marked overlap between the masculinization score of those children with PAIS reared as girls [2.5(P10,P90:1, 6)] and those reared as boys [3(P10,P90:2, 7.5)]. Gonadectomy was performed prepubertally in 66% and postpubertally in 29% of the cases of CAIS. The median age of the latter group was older at 14 yr (P10,P90:0.1,18). No cases of malignancy or carcinoma in situ were reported in the 121 cases of AIS where histology results were available. Biochemical endocrine investigations were reported to have been performed in a greater number of cases of PAIS than CAIS (98% vs. 48%). AR binding was abnormal in 44 of 51 (86%) and 40 of 113 (35%) cases of CAIS and PAIS, respectively. Zero binding was encountered in 29 of 43 (67%) and 1 of 55 (2%) cases of CAIS and PAIS, respectively. Mutational analysis of the AR gene, performed in 102 index cases was positive in 57 of 69 (83%) cases of CAIS and 12 of 43 (28%) cases of PAIS. In 24 of these cases, the mutation identified was novel. The mutations in PAIS cases were all missense, whereas in CAIS the mutations were more diverse. AR binding was only normal in 3 of 69 mutation-positive cases. In the PAIS group, mutation-positive cases had a significantly higher Kd and Bmax compared to the mutation negative cases. The clinical diagnosis of AIS can be confirmed in a significant number of cases by a combination of androgen-binding studies and mutational analysis. There is some correlation between the phenotypic features and the abnormalities discovered on mutational analysis of the AR gene, but there is a need to improve this further by developing optimal bioassays of AR function. The phenotypic heterogeneity among clinically diagnosed cases of AIS emphasizes the need for appropriate comprehensive evaluation of male under-masculinization.

Genetic counselling in complete androgen insensitivity syndrome: trinucleotide repeat polymorphisms, single-strand conformation polymorphism and direct detection of two novel mutations in the androgen receptor gene.

Androgen insensitivity syndrome is a disorder of male sexual development which results in varying degrees of undervirilization in 46XY individuals with functional testes. In the most severe form, complete androgen insensitivity syndrome (CAIS), patients have a normal female appearance. Although CAIS is not life-threatening, affected individuals are infertile and require counselling, gonadectomy, hormone therapy, and sometimes vaginoplasty. Many families therefore request genetic counselling. Defects in the androgen receptor gene account for most if not all cases of CAIS. The purpose of this study was to evaluate the use of the polyglutamine and polyglycine trinucleotide repeat polymorphisms in the first exon of the androgen receptor gene for carrier status determination in three CAIS families. In two of these families novel mutations in the androgen receptor gene were subsequently identified which allowed confirmation of carrier status and also a prenatal diagnosis to be made in one family. Three CAIS families were studied. The index cases all presented with a clinical phenotype typical of CAIS. Family members were typed initially for the polyglutamine repeat. In one family this was not informative and the polyglycine repeat was therefore studied. In this and one further family, the androgen receptor gene was sequenced to identify the mutation causing the CAIS. On the basis of information from trinucleotide repeat analysis carrier status could be assessed in each family. In one family, evidence for somatic instability of the polyglutamine repeat was found. In the same family, a novel mutation in the androgen receptor gene, which substituted valine for leucine 881, was identified. Other family members were subsequently typed for the mutation and a prenatal diagnosis was performed. A novel mutation was also identified in a second family substituting the glycine codon at position 371 with a stop codon. Other family members were typed for this mutation. Both the polyglutamine and polyglycine repeat polymorphisms are useful for the genetic counselling of complete androgen insensitivity syndrome families. In some cases, however, where the family history is limited, more precise information can be provided only once the androgen receptor mutation causing the complete androgen insensitivity syndrome has been identified.