Androgen insensitivity syndrome (AIS) is a common etiology of sexual developmental disorders resulting in varying phenotypes. These disorders of androgen action present as 46 XY disorders or differences of sex development (DSD). The phenotypic spectrum of AIS depends on the residual androgen receptor activity and encompasses individuals with completely female phenotype to male phenotype with infertility /undervirilization . Androgen resistance results in complete androgen insensitivity syndrome (CAIS) characterizing XY sex reversal with normal female phenotype whereas phenotype diversity is variable with residual androgen receptor activity which leads to partial androgen insensitivity syndrome (PAIS). PAIS presents a substantial challenge to the clinician in determining the gender identity at the time of the birth of the child. Therefore, it is crucial for the clinician to have an understanding of the physiology of androgen receptors mechanism to diagnose the condition as CAIS or PAIS accurately and plan the treatment course from birth to adulthood.
Androgen insensitivity syndrome arises from loss-of-function mutations in the coding sequence of the androgen receptors (AR). This X-linked genetic mutation of the androgen receptor gene results in dysfunction of androgen receptors and hormone resistance. These mutations lead to a loss in virilization or infertility in 46XY males in individuals with functional testes and adequate testosterone production. CAIS and PAIS encompass variability in phenotypic expression; however, both these conditions have similar genetic, endocrine, and pathophysiologic mechanisms.
The Office of Rare Diseases (ORD) of the National Institutes of Health (NIH) classifies androgen insensitivity syndrome and its subtypes as “rare disease” which signifies that it affects less than 200000 people in the US population. The prevalence of 46XY phenotypic females is low, which limits the data about the age and clinical presentation at diagnosis for AIS. As per a nationwide study in Denmark, all known females with 46XY karyotype females since 1960 were analyzed via medical record evaluation and found to have a prevalence of 6.4 per 100000 live-born females. Prevalence of AIS was found to be 4.1 per 100000 live-born females. The prevalence of CAIS proven via molecular diagnosis is estimated to range from 1 in 20400 to 1 in 99100 genetic males.
Androgen insensitivity syndrome is the result of profound resistance of the androgen receptor towards the action of androgen. Various studies done in women established the androgen receptor (AR) dysfunction with no detectable androgen receptor binding leading to resistance to virilization effect of the exogenous androgen. The androgen receptor nuclear receptor contains a hormone binding domain and an N-terminal region used for transactivation, and most mutations cause androgen receptor dysfunction to localize specifically in the hormone-binding domain.
Androgen insensitivity syndrome may subclassify in the form of following clinical entities: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), mild androgen insensitivity syndrome (MAIS).
CAIS: There are various forms of presentation of CAIS in different age group, varying from infants to adolescent females. CAIS will present very commonly as primary amenorrhea in adolescent females or incidental finding of testes in females undergoing inguinal hernia repair. Physical examination reveals a female phenotype at birth, which will be a mismatch from the results of prenatal fetal sexing (Y chromosome on DNA analysis). The vagina is blind-ending with no uterus, gonads present in the lower abdomen or inguinal canal. At puberty, with the normal growth spurt, there is breast development secondary to the conversion of androgens to estrogens, and taller female phenotype secondary to the effect of the Y chromosome.
PAIS: PAIS results in a varied phenotype from the residual androgen receptor function. Symptoms vary from severe under-masculinization with female genitalia to male genitalia. The physical examination will be pertinent for hypospadias, bifid scrotum, and micropenis.
MAIS: This usually presents as a normal male phenotype with isolated micropenis. In adulthood, may be associated with gynecomastia and infertility.
The diagnosis of CAIS and PAIS includes assessing clinical and biochemical features, 46 XY karyotype, and exclusion of defects in testosterone synthesis. Furthermore, confirmation is possible with genetic testing.
Exclusion of defects in testosterone synthesis: Studies suggest measuring levels of testosterone, LH, and FSH in the first year of life. The expected postnatal surge in gonadotropins and testosterone is usually present in PAIS, but may not occur in CAIS as the gonadotropins surge is androgen dependent (11788616). However, there is normal Sertoli cell function exhibited by the normal or even elevated levels of Inhibin B or AMH. In children, assessment of testosterone synthesis requires hCG stimulation test with measurement of serum androstenedione, testosterone, and DHT 72 hours afterward. In adults, testing can be via basal hormone measurements.
17-beta-hydroxysteroid dehydrogenase deficiency: CAIS and PAIS individuals have normal testosterone responses after the hCG stimulation test. Low serum testosterone synthesis implies impaired testosterone synthesis secondary to 17-beta-hydroxysteroid dehydrogenase deficiency
-5-alpha-reductase deficiency: differentiation of CAIS and PAIS from 5-alpha-reductase is by analyzing the ratio of testosterone to DHT in serum. In patients with steroid 5-alpha-reductase 2 deficiency, the production of DHT decreases, and the plasma ratio of testosterone to DHT increases. In most girls/ boys with PAIS, the production of DHT, and the ratio of testosterone to DHT is normal. Women with CAIS may have secondary 5-alpha-reductase deficiency due to a decreased mass of the urogenital tract tissues, which normally produces DHT.
Importance of Genetic testing in the evaluation of AIS: In addition to clinical features, biochemical testing may not be adequate to establish the diagnosis of CAIS or PAIS. Therefore, molecular genetic studies become imperative to diagnose CAIS or PAIS. CAIS confirmation is possible with genetic testing locations where the typical loss-of-function mutations in the coding sequence of the androgen receptor exist. The AR gene is on chromosome Xq11-12. It encodes a protein which composes the typical three major functional domains of the nuclear receptor superfamily. In patients with AIS, research has described large structural alterations along with over 1000 mutations. Multiplex ligation-dependent probe amplification (MLPA) analysis is a study available to detect deletions or duplications of exons or the entire gene. The mutational analysis may confirm the diagnosis of androgen insensitivity syndrome, PAIS still poses a substantial amount of challenge towards the clinicians to predict a genotype-phenotype correlation and further clinical prognosis.
Management of androgen insensitivity syndrome involves a holistic approach towards the psychological, physiological, social well being of the individual suffering from this disorder. It is imperative to address the challenges foreseen to the family of the infant who is born with AIS to optimize well being of the infant into adulthood. Given the irreversibility of the development during embryogenesis in AIS, management involves counseling families, appropriate gender assignment, improving functional status with time and timing of gonadectomy to prevent tumorigenesis.
Complete Androgen Insensitivity Syndrome (CAIS): CAIS presents as an incidental finding of gonad at the time of inguinal hernia repair or as primary amenorrhea in females. It is advisable to obtain a biopsy of the gonad at the time of hernia repair and replace it back either subcutaneously or within the abdomen, while further discussion with the parents about the diagnosis and plans for future management are pending.
Parents can choose early gonadectomy to prevent tumorigenesis when complete androgen insensitivity presents in infancy, and the child is unaware of the issues around the diagnosis of CAIS. In this scenario, puberty induction can be done later via estrogen replacement. Also, since women with CAIS do not have a uterus, the risk of estrogen-induced cancer is absent. Alternatively, gonadectomy can be delayed until early adulthood in which scenario, there is a low risk of gonadal tumor in childhood.. However, there is no necessity of puberty induction via external estrogen replacement. Puberty occurs spontaneously manifesting as standard breast development and an appropriately timed growth spurt, however, it is not followed by menarche.
Surgical management in CAIS includes vaginal dilation and rarely vaginoplasty for normal sexual well functioning and well being.
Partial Androgen Insensitivity Syndrome (PAIS): Unlike CAIS, infants with PAIS are usually born with unambiguous genitalia which presents the necessity of accurate diagnosis primarily and decision on sex assignment after a holistic discussion with family and caregiver. After that, the clinician can address early management issues.
In infants assigned as males, medical management includes androgen supplementation at the time of puberty. Surgical management includes correction of hypospadias and undescended testes. These procedures are preferable during the 2/3 year of life. At the time of puberty, gynecomastia may develop, which should be corrected with reduction mammoplasty to prevent tumorigenesis. However, the incidence of breast cancer in men with PAIS.
Management of PAIS in Infants assigned as females includes estrogen supplementation at the time of puberty, along with genitoplasty with gonadectomy before the onset of puberty.
The differentials of CAIS include- Disorders of androgen biosynthesis or Leydig cell dysfunction, Mullerian agenesis, Mixed gonadal dysgenesis, etc.
Disorders in androgen synthesis – Defects in testosterone synthesis can be the result of a defect in any of the enzymes in the pathway of testosterone synthesis or dysfunction of the LH receptor. Women with Leydig cells dysfunction are 46, XY genotype who lack pubertal development and have hypogonadotropic hypogonadism. Mullerian agenesis ( Mayer-Rokitansky-Kuster-Hauser syndrome) is included in the differentials in a female who presents with primary amenorrhea, absent uterus, and blind vaginal pouch. The difference being, women with Mullerian agenesis, a 46 XX karyotype, have a normal ovarian function, serum androgen, and estrogen concentrations and therefore present with normal axillary and pubic hair.
The differentials of PAIS may be extensive given the variable genotypic and phenotypic presentations. Most common differentials to consider are the disorders of androgen synthesis, as mentioned above, along with disorders of gonadal dysgenesis.
46, XY women with a uterus present with gonadal dysgenesis. Mixed gonadal dysgenesis (also termed chromosomal disorder of sex development [DSD]), as the name suggests, is associated with a mosaic 45, X/46, XY karyotype and presence of single descended gonad should raise suspicion of this disorder. It presents with a dysgenetic testis on one side and a streak gonad on the other. Partial gonadal dysgenesis: 46 XY karyotype, and is characterized by the presence of müllerian structures but decreased testosterone and anti-müllerian hormone (AMH) and or inhibin B production. The phenotypic variability of partial gonadal dysgenesis is from genital ambiguity to an under virilized male.
Androgen insensitivity syndrome and individuals with cryptorchid testes have increased risk of tumorigenesis. Cryptorchidism in partial androgen insensitivity syndrome (PAIS) should be corrected surgically soon after diagnosis to maintain testicular function and minimize the risk of malignancy. These tumors may be germ cell tumors gonadoblastomas. They tend to occur in approximately 1.5 to 2 percent of undescended testes and may become malignant. Carcinoma in situ or intra-tubular germ cell neoplasia, unclassified the premalignant precursor from which tumors associated with AIS arise. Carcinoma in situ arises from gonocytes or primordial germ cells and is thought to be the result of a developmental arrest of fetal germ cells. Carcinoma in situ will lead to the development of a gonadoblastoma in more than 50% of cases. The risk of germ-cell tumors is higher in PAIS than in CAIS, and studies suggest an incidence of 15% and even higher if the testes are not scrotal in position. Women with complete androgen insensitivity syndrome are advised strongly to have a gonadectomy because of the tumor risk, which might increase substantially in later adulthood. Monitoring for carcinoma is based primarily on imaging studies.
Untreated or inadequately managed AIS may result in severe psychological distress in infants as they go through puberty into adulthood and their families at the same time. Psychological distress is more frequent in adults with partial androgen insensitivity syndrome than in those with complete androgen insensitivity syndrome, irrespective of whether they were raised as male or female. Bouvattier C et al. conducted a study of men with partial androgen insensitivity syndrome, and they noted that in men with PAIS, all aspects of sexual activity were substantially impaired.
Education of the families with newborns with androgen insensitivity syndrome is vital for optimizing the plan of care of the newborn into adulthood, which is achievable by undertaking a multidisciplinary approach with the help of the clinician, geneticist, along with the support groups to tailor the needs of the individual suffering from this disorder and their families.
It is imperative to follow a multidisciplinary approach when treating patients with androgen insensitivity syndrome. It requires management by an interprofessional team of healthcare professionals including an endocrinologist (pediatric or adult), urology, gynecology, primary medical doctor, clinical psychology, neonatology, clinical genetics, medical ethics, specialty-trained nurses, and social services. This multidisciplinary approach assists inappropriate management of the condition and prepares the child and the family to overcome the challenges with the additional support from patient advocacy groups. Pasterskietal et al. conducted a study to assess clinical management of disorders of sex development (DSD) with the help of an online questionnaire and audit of DSD literature sent to pediatric endocrinologists from 60 medical centers representing 23 European countries. They studied the multidisciplinary team composition, psychological support services, and also the incidence of feminizing clitoroplasty. The study noted that 57% of centers regularly included the multidisciplinary approach utilizing the services of recommended pediatric subspecialists: pediatric endocrinologist, pediatric surgeon/urologist, plastic surgeon, pediatric psychiatrist/psychologist, gynecologist, clinical geneticist, histopathologist and neonatologist.Level V]
The multidisciplinary approach is also beneficial in the education of health-care professionals to interpret diagnostics tests accurately and avoid incorrect diagnosis and treatment of individuals from infancy to adulthood. There is still a vast scope to improve diagnosis and management of all causes of XY disorders of sex development (including complete and particularly partial androgen insensitivity syndromes) requiring multicentre collaboration at national and international levels.
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