Complete Androgen Insensitivity Syndrome Patients Research Articles

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.

Clinical, hormonal and genetic characteristics of androgen insensitivity syndrome in 39 Chinese patients

BackgroundAbnormal androgen receptor (AR) genes can cause androgen insensitivity syndrome (AIS), and AIS can be classified into complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS) and mild AIS. We investigated the characteristics of clinical manifestations, serum sex hormone levels and AR gene mutations of 39 AIS patients, which provided deeper insight into this disease.MethodsWe prospectively evaluated 39 patients with 46, XY disorders of sex development (46, XY DSD) who were diagnosed with AIS at the Department of Endocrinology of Shanghai Children’s Hospital from 2014 to 2019. We analysed clinical data from the patients including hormone levels and AR gene sequences. Furthermore, we screened the AR gene sequences of the 39 AIS patients to identify probable mutations.ResultsThe 39 AIS patients came from 37 different families; 19 of the patients presented CAIS, and 20 of them presented PAIS. The CAIS patients exhibited a higher cryptorchidism rate than the PAIS (100 and 55%, P = 0.001). There were no significant difference between the CAIS and PAIS groups regarding the levels of inhibin B (INHB), sex hormone-binding globulin (SHBG), basal luteinizing hormone (LH), testosterone (T), or basal dihydrotestosterone (DHT), the T:DHT ratio, DHT levels after human chorionic gonadotropin (HCG) stimulation or T levels after HCG stimulation. However, the hormone levels of AMH (P = 0.010), peak LH (P = 0.033), basal FSH (P = 0.009) and peak FSH (P = 0.033) showed significant differences between the CAIS group and the PAIS group. Twenty-one reported pathogenic and 9 novel AR mutations were identified. Spontaneous AR mutations were found in 5 AIS patients, and 21 patients inherited mutations from their mothers, who carried heterozygous mutations.ConclusionsForty-six XY DSD patients with cryptorchidism and female phenotypes were highly suspected of having AIS. We demonstrated that CAIS patients could not be distinguished by their hormone levels alone. Compared with PAIS patients, CAIS patients exhibited higher basal FSH, peak FSH, and peak LH hormone levels but lower AMH expression. We identified 21 reported pathogenic AR mutations and 9 novel AR mutations that led to different types of AIS. Missense mutations were the major cause of AIS and mostly occurred in exon 7 of the AR gene. These findings provided deeper insight into the diagnosis and classification of AIS and will even contributed to its clinical assessment.

Sex assignment practice in disorders of sexual differentiation: survey results from paediatric endocrinologists in the Arab region.

Background Sex assignment is a major issue in disorders of sexual differentiation (DSD). Not all conditions of DSD have clear recommendations on assignment and timing of surgery. Reports about sex assignment practice and the influence of culture and religion in the Arab region are scarce. Methods A survey questionnaire was distributed to participants in a paediatric endocrinology conference. Four DSD cases were presented. Participants were asked to fill in their answers on sex assignment choice, reasons for the particular assignment, strength of own recommendation and timing of surgery based on their practice. The cases presented were severely virilised XX congenital adrenal hyperplasia (CAH), complete androgen insensitivity syndrome (CAIS), severely undervirilised 5α reductase deficiency (5α RD) and XX ovotesticular case. Results Eighty-five endocrinologists participated in the study. Eighty (97.5%) chose a female sex to assign for the XX CAH. For the CAIS, 64 (78%) chose a female sex. Seventy-one (86.5%) voted for a male sex for the XY case of 5α RD. Forty-seven (57%) and 35 (43%) chose a female and a male sex for the ovotesticular case, respectively. The majority indicated that their advice for sex assignment is based on strong recommendations for the CAH, CAIS and 5α RD patients but they were open to the parents' cultural and religious beliefs in their decision of the assignment for the ovotesticular case. Conclusions Practice in the Arab region appears to be in line with the international guidelines in the majority of DSD sex assignment and timing of surgery issues. However, culture and religious beliefs influence the practice in certain circumstances.

Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis

Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder of sex development (DSD) where affected individuals are phenotypically female, but have an XY karyotype and testes. The risk of gonadal tumour development in CAIS may increase with age; incidence rates have been reported to be 0.8-22% in patients who have retained their gonads into adulthood. Consequently, gonadectomy has been recommended either during childhood or after puberty is complete, although there is no consensus on the optimal timing for this procedure. To establish the frequency of histological abnormalities in CAIS in relation to the age at gonadectomy. Data were collected from the Cambridge DSD database on patients with CAIS (n=225; age range 3-88 years) who had undergone gonadectomy, and their age of gonadectomy, gonadal histology and immunohistochemistry. Evaluable data were obtained from 133 patients. Median age at gonadectomy was 14.0 years (range: 18 days-68 years). Pubertal status was: prepuberty, n=62; postpuberty, n=68. Thirteen cases were aged >20years at gonadectomy. The pattern of histology is summarised in the Summary table. In this large case series of CAIS patients who had undergone gonadectomy, while the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings confirm the low occurrence of gonadal malignancy in CAIS, with a frequency of 1.5%. The two cases of malignancy were postpubertal. Germ cell neoplasia in situ (GCNIS) was observed in six cases, of which one occurred prepuberty and five postpuberty. The study highlighted difficulties in diagnosis of GCNIS and the need for histological analysis in expert centres. The results support the current recommendation that gonads in CAIS can be retained until early adulthood. The small number of individuals with gonadectomy after age 20 years do not allow firm conclusion regarding later adulthood. Therefore, it is recommended that the option of gonadectomy be discussed in adulthood. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal.

Vaginal Agenesis and Psychosexual Functioning: Long Term Outcome of a Vaginal Substitution Treatment

Purpose In congenital vaginal hypo- or aplasia, seen in Complete Androgen Insensitivity Syndrome (CAIS) or Mayer Rokitansky Syndrome (MRS), an absent or blind ending vagina makes sexual intercourse impossible. Operative vaginoplasty and vaginal dilation are both valid vaginal substitution treatments. The ACOG recommends vaginal dilation as a first choice treatment, because of its less invasive character and high success rate. Although a functional vagina has been created, it is estimated that the majority of women experience sexual problems of unknown cause in either treatment group. Only few studies compare the psychosexual functioning after vaginoplasty to that after vaginal dilation. Material and Methods Psychosexual functioning and quality of life (QoL) of 26 women after vaginal dilation (11 CAIS patients) and after vaginoplasty (8 MRS, 7 CAIS patients) was investigated. Questionnaires (FSFI, FSDS-R, TNO/AZL QoL) and a semi-structured interview were used. A gynecological examination was performed. Results No difference in QoL was observed between both treatment groups. After vaginoplasty, patients reported significantly more problems with desire and lubrication than after vaginal dilation. 66.7% had an acceptable vaginal depth after either treatment. In general 59% of the patients had (a) sexual dysfunction(s), mostly on the domains of lubrication and dyspareunia, and experienced sexual distress. Conclusions Both psychological and physical factors are predisposing for sexual difficulties. The clinical management of these women needs to be multidisciplinary and individualy tailored to optimize psychosexual comfort. Vaginal dilatation is a non-invasive, valuable alternative to vaginoplasty, possibly with less side effects and post treatment problems. Further studies are needed to confirm these conclusions.

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.

536 VAGINAL AGENESIS AND PSYCHOSEXUAL FUNCTIONING: LONG TERM OUTCOME OF A VAGINAL SUBSTITUTION TREATMENT

Purpose In congenital vaginal hypo- or aplasia, seen in Complete Androgen Insensitivity Syndrome (CAIS) or Mayer Rokitansky Syndrome (MRS), an absent or blind ending vagina makes sexual intercourse impossible. Operative vaginoplasty and vaginal dilation are both valid vaginal substitution treatments. The ACOG recommends vaginal dilation as a first choice treatment, because of its less invasive character and high success rate. Although a functional vagina has been created, it is estimated that the majority of women experience sexual problems of unknown cause in either treatment group. Only few studies compare the psychosexual functioning after vaginoplasty to that after vaginal dilation. Material and Methods Psychosexual functioning and quality of life (QoL) of 26 women after vaginal dilation (11 CAIS patients) and after vaginoplasty (8 MRS, 7 CAIS patients) was investigated. Questionnaires (FSFI, FSDS-R, TNO/AZL QoL) and a semi-structured interview were used. A gynecological examination was performed. Results No difference in QoL was observed between both treatment groups. After vaginoplasty, patients reported significantly more problems with desire and lubrication than after vaginal dilation. 66.7% had an acceptable vaginal depth after either treatment. In general 59% of the patients had (a) sexual dysfunction(s), mostly on the domains of lubrication and dyspareunia, and experienced sexual distress. Conclusions Both psychological and physical factors are predisposing for sexual difficulties. The clinical management of these women needs to be multidisciplinary and individualy tailored to optimize psychosexual comfort. Vaginal dilatation is a non-invasive, valuable alternative to vaginoplasty, possibly with less side effects and post treatment problems. Further studies are needed to confirm these conclusions.

Complete androgen insensitivity syndrome is frequently due to premature stop codons in exon 1 of the androgen receptor gene: an international collaborative report of 13 new mutations

To confirm the clinical diagnosis of complete androgen insensitivity syndrome (CAIS) by molecular genetic analysis and to determine the prevalence of exon 1 mutations in the androgen receptor (AR) transactivation defects of a large series of CAIS patients. International retrospective study. University Hospital of Montpellier, Department of Hormonology. 105 patients with normal female external genitalia, bilateral intra-abdominal or inguinal testis, normal breast development, absent or sparse pubic hair, normal or high endogenous testosterone production, hypoplastic or absent wolffian structures, and 46,XY karyotype. Sequencing of the AR gene. Prevalence of AR exon 1 mutations. Over a 10-year period (1997 to 2007), we identified 78 AR gene mutations in 105 patients with CAIS; 21 of them were located in exon 1, and 13 of these were new mutations. We report 13 new mutations in the AR gene. All but one were stop codons, and the last was a splicing abnormality. The finding that 27% of the mutations in our cohort were localized in exon 1 versus 15% in previous works justifies the sequencing of this exon in patients with CAIS.

Clinical findings in prepubertal girls with inguinal hernia with special reference to the diagnosis of androgen insensitivity syndrome

Complete androgen insensitivity syndrome (CAIS) is a rare disease. However, there is a higher rate of CAIS in girls with inguinal hernia. The aim of this study was to estimate the incidence of CAIS in girls with inguinal hernia and to find a proper screening test for CAIS in these girls. A total of 109 consecutive girls attending the University Hospitals of Turku and Tampere, Finland, for inguinal hernia repair between January 2003 and December 2007 participated in the study. After induction of anaesthesia, vaginal length was measured with a small, lubricated Hegar dilator. During hernia repair, tension was placed on the round ligament to identify the contents of the hernial sac. The karyotype of all patients was measured, with identification of the Y-chromosome from a buccal mucosa swab sample. Vaginal length measurements were plotted against age and standards for vaginal length in prepuberty were established. Four patients were found to have very short vaginas, with one CAIS patient confirmed as having a 46XY karyotype from the verification of the Y-chromosome from buccal mucosa. The other three patients with abnormal vaginal length were karyotypically normal XX girls and had visible ovaries, fallopian tubes or round ligament, which suggests an error in the measurements. Unlike all the other operated girls, the CAIS patient lacked a round ligament. The incidence of CAIS in girls undergoing hernia repair was 1%. The CAIS patient had a significantly shorter vagina than girls with normal karyotype. Vaginal length is a useful additional clinical tool in screening girls for karyotyping CAIS, especially if abnormalities in the round ligament and contents of the hernial sac are suspected. It is recommended that ovaries and fallopian tubes are searched for if the round ligament is not found to be normal during the hernia operation. If no ovaries or fallopian tubes are found, consent for karyotyping should be sought in cases where the vaginal length is <4 cm in girls older than 4 years and <3 cm in younger girls.

Complete androgen insensitivity syndrome: diagnosis and clinical characteristics

Complete androgen insensitivity syndrome (CAIS) is a genetic disease caused by mutations in the androgen receptor gene. CAIS patients are individuals with a 46, XY karyotype. The phenotype consists in female external genitalia, short vagina, absent mullerian structures, and abdominal, inguinal or intralabial testes. Our aim is to describe a group of CAIS patients in our centre and identify the difficulties in the diagnosis. The amount of patients with inguinal hernia in childhood was remarkable (83%). Interestingly, the diagnosis was suspected later when patients presented primary amenorrhea. CAIS must be suspected every time a female child shows inguinal hernia. Early diagnosis is very important for a correct genetic counseling.

Complete androgen insensitivity without Wolffian duct development: the AR‐A form of the androgen receptor is not sufficient for male genital development

The androgen receptor (AR) is essential for the differentiation of male external and internal genitalia. It is normally present in two forms, a full-length form B and an N-terminal truncated form A with still unknown function. Mutations in the AR gene cause androgen insensitivity syndrome (AIS), which is divided into subgroups according to the degree of undermasculinization. Patients with completely female external genitalia are classified as complete AIS (CAIS). However, a recent study has shown that some CAIS patients have signs of internal male genital differentiation due to missense mutations that show some degree of residual function. We aimed to study the expression of the different forms of the AR in two CAIS patients in relation to the development of male internal genital structures. One patient had a mutation (L7fsX33) that affects only the full-length AR-B form of the AR, whereas the other had a nonsense mutation (Q733X) affecting both isoforms. We thoroughly analysed internal genitalia at surgery and by histological examination. No signs of Wolffian duct (WD) development were present in any of the patients. Western blotting of proteins from gonadal and genital skin fibroblasts was performed with AR antibodies directed against different AR epitopes. The N-terminally truncated A form was expressed in normal amounts in the patient with the L7fsX33 mutation while no AR was detected in the other patient. The presence of the AR-A form does not seem to be sufficient for WD maintenance and differentiation.

Androgen Receptor Genotyping in a Large Australasian Cohort with Androgen Insensitivity Syndrom? Identification of Four Novel Mutations

We genotyped the androgen receptor (AR) gene in 31 Australasian patients with androgen insensitivity syndrome (AIS). The entire coding region of AR was examined including analysis of polymorphic CAG and GGN repeats in all patients. AR defects were found in 66.7% (6/9) of patients with complete AIS (CAIS) and 13.6% (3/22) of patients with partial AIS (PAIS). A novel deletion (N858delG) leading to a premature stop codon was found in CAIS patient P1. CAIS patient P2 has a novel deletion (N2676delGAGT) resulting in a stop at codon 787. These mutations would result in inactivation of AR protein. A novel insertion of a cysteine residue in the first zinc finger of the AR DNA-binding domain (N2045_2047dupCTG) was found in CAIS patient P3. PAIS patient P4 has a novel amino acid substitution (Arg760Ser) in the AR ligand binding domain, which may impair ligand binding. Five patients were found to have previously reported AR mutations and no mutations were identified in the remaining patients.

Primary amenorrhea in a young Polish woman with complete androgen insensitivity syndrome and Sertoli–Leydig cell tumor: Identification of a new androgen receptor gene mutation and evidence of aromatase hyperactivity and apoptosis dysregulation within the tumor

Primary amenorrhea in 46,XY females can be due to complete androgen insensitivity syndrome (CAIS), pure gonadal dysgenesis, 17β-hydroxysteroid dehydrogenase deficiency, or mixed gonadal dysgenesis. The present paper describes a new de novo non-sense mutation in exon 1 (K141Z) of the androgen receptor gene (AR) and the expression in CAIS testis of aromatase, estrogen receptors, as well as proliferation- and apoptosis-associated proteins. CAIS is a rare disease characterized by absent virilization in 46,XY individuals and the development of a female phenotype despite normal or even elevated androgen levels. CAIS is usually caused by a mutation in AR, which leads to organ resistance to androgens. Testicular tumors such as Sertoli–Leydig cell tumor often develop in patients with CAIS. The immunohistochemical findings in the testes of our CAIS patient suggest that the high expression of aromatase and other molecular changes in the testis may be responsible for pubertal breast development and the increased risk of testicular tumor.

Conjunctival mucin deficiency in complete androgen insensitivity syndrome (CAIS)

Sex steroid hormones are essential for a healthy ocular surface and the androgen receptor impairment found in patients with complete androgen insensitivity syndrome (CAIS) has been described to cause meibomian gland dysfunction and functional dry eye for lipid tear film layer instability. However, it has not been reported if the mucous layer is also affected. A 37-year-old CAIS patient with persistent symptoms of dry eye underwent ophthalmological examination and was evaluated for qualitative and quantitative tear function tests and conjunctival cytology. Samples obtained from the conjunctival epithelium were stained for histology and immunohistochemistry and compared with three age-matched female controls. Western blot and relative real-time RT-PCR for MUC1 and MUC5AC were also performed on these samples. Immunohistochemistry, Western blot and relative real-time RT-PCR showed a decrease in the expression of MUC1 and MUC5AC in CAIS. Changes in the tear film mucous layer were accompanied by a reduction in the tear film break up time test. This is the first report describing mucous layer alteration associated with androgen receptor impairment. Decreased mucin levels contribute in explaining the tear film instability in CAIS and should be considered an additional cause of dry eye in sex steroid hormone pathology.

Impaired Nuclear Translocation, Nuclear Matrix Targeting, and Intranuclear Mobility of Mutant Androgen Receptors Carrying Amino Acid Substitutions in the Deoxyribonucleic Acid-Binding Domain Derived from Androgen Insensitivity Syndrome Patients

Recent imaging studies revealed that androgen receptor (AR) is ligand-dependently translocated from the cytoplasm into the nucleus and forms intranuclear fine foci. In this study, we examined whether intracellular dynamics of mutant ARs detected in two androgen insensitivity syndrome (AIS) patients was impaired. ARs with mutations in the DNA-binding domain were functionally characterized and compared with the wild-type AR. In a complete AIS patient (subject 1), cysteine residue 579 in the first zinc finger motif of AR was substituted for phenylalanine (AR-C579F). Another mutation (AR-F582Y) was found in a partial AIS patient (subject 2). AR-F582Y retained less than 10% of the transactivation activity of the wild-type AR, whereas no ligand-dependent transactivation was detected for AR-C579F. Image analyses of the receptors fused to green fluorescent protein showed that the wild-type AR was ligand-dependently translocated into the nucleus in which it formed fine subnuclear foci. Surprisingly, after the addition of dihydrotestosterone, the two mutant ARs initially formed large cytoplasmic dots, many of which were found to be close to mitochondria by electron microscopy. Subsequently, a part of the ligand-bound mutant ARs gradually entered the nucleus to form a smaller number of larger dots, compared with the wild-type AR. Fluorescence recovery after photobleaching analysis revealed that the intranuclear mobility of the mutant ARs decreased, compared with that of the wild-type AR. These results suggest that the abnormal translocation, localization, and mobility of the mutant ARs may be the cause of AIS in these subjects.

Novel and Recurrent Mutations in Patients with Androgen Insensitivity Syndromes

Background/Aims: Androgen insensitivity syndrome (AIS) caused by mutations within the androgen receptor gene represents a variety of phenotypes from females with 46,XY karyotype over individuals with ambiguous genitalia to infertile males. Methods: We studied 24 patients with AIS by sequencing androgen receptor gene. 19 of the investigated patients were affected by complete androgen insensitivity syndrome (CAIS) and 5 suffered from partial androgen insensitivity syndrome (PAIS). Results: So far we have detected 12 unreported mutations as well as 9 recurrent mutations (3 recurrent mutations were detected twice) in exons 2–8 of the androgen receptor gene. Three of the novel mutations cause a frameshift with subsequent premature termination and were found in patients with CAIS. These frameshifts were induced by single nucleotide deletion or insertion, or in one case by a 13-bp deletion, respectively. Another premature stop codon found in a CAIS patient results from an already reported nucleotide substitution in exon 5. Furthermore, in a CAIS patient we found a novel duplication of codon 788. All other mutations caused single base substitutions spread through exons 2–8 and were associated with CAIS or PAIS. Conclusions: We report a broad spectrum of different mutations within the AR gene leading to various manifestations of AIS. Apart from truncating mutations, a reliable genotype/phenotype correlation cannot be established. Therefore, modifying factors must be effective.

Androgen insensitivity with mental retardation: a contiguous gene syndrome?

We present data to suggest the existence of a mental retardation (MR) locus at Xq11.2-q12 between DXS1 and DXS905, identified in two subjects with complete androgen insensitivity syndrome (CAIS) and...