An Early Case of Complete Androgen Insensitivity Syndrome

Abstract

Inguinal hernias are rare in female infants, and when present, there is an increased incidence of androgen insensitivity in these infants. We present a case of bilateral inguinal hernias in a 26-day-old full-term phenotypic female. On physical exam, the patient was found to have bilateral palpable inguinal masses which were suspected to be testicular tissue on ultrasound. Patient also had bilateral inguinal hernias, but otherwise there were no other concerning symptoms, and the remaining physical examination was overall unremarkable. Initial workup included a pelvic ultrasound that did not visualize a uterus or ovaries. In addition, genetic testing confirmed normal male genotype with 100% 46, on fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (CGH) was negative and did not reveal any copy number changes. Molecular testing was consistent with a diagnosis of androgen insensitivity syndrome with hemizygous pathogenic variant in the androgen receptor (AR) gene (deletion of Exon 2 of AR gene Xq12). This case highlights the importance of a high clinical suspicion of complete androgen insensitivity syndrome (CAIS) in a phenotypic female infant with inguinal hernias. To our knowledge, this is one of the earliest diagnoses of CAIS in a phenotypically female infant.

Introduction

Androgen insensitivity syndrome (AIS) is an X-linked recessive disorder comprising a variety of phenotypes caused by up to 800 mutations in the androgen receptor (AR) gene.^1,2 AIS can have a spectrum of presentations, ranging from normal phenotypic female to undervirilization and infertility in phenotypic male with gynecomastia. Complete androgen insensitivity syndrome (CAIS) is a disorder of AR resistance characterized by the absence of Mullerian derivative structures and female external genitalia in an individual with an XY karyotype. The testicles produce normal concentrations of androgens; however, due to their defective action, Wollfian structures, including epididymis and vas deferens, are absent. Mutations in the AR gene cause alterations in synthesis of AR, resulting in insensitivity to circulating androgens. ³ Typical presentation of CAIS is primary amenorrhea in an adolescent or an inguinal hernia in an infant. Inguinal hernias are rare in female infants and, when present, the incidence of androgen insensitivity in these infants is 0.8% to 2.4%. ⁴ To our knowledge, this case represents one of the earliest cases of detection of CAIS and serves as an important reminder for pediatricians and urologists who co-manage these patients to consider AIS spectrum, including partial and complete AIS, in the differential diagnosis of palpable gonads in a herniated sac.

Case Presentation

A 26-day-old infant presented to our endocrine clinic as a referral from pediatrician’s office for evaluation of palpable masses in labia observed during bilateral inguinal hernias palpation. The child was born at 39.5 weeks gestation via primary cesarean delivery due to non-reassuring fetal heart tones and had an otherwise unremarkable antenatal and perinatal course. She had been assigned female in utero based on phenotypic appearance on ultrasonography. She was the first-born for her parents and had been growing and developing appropriately for her age.

At 26 days of life, family noted right inguinal swelling prompting a pediatrician’s visit. She underwent an abdominal ultrasound that showed a right inguinal hernia in addition to “bilateral homogeneously echogenic rounded structures within labial regions, possibly representing testes versus ovaries or ovo-testes” and a pelvic ultrasound that did not visualize uterus or ovaries.

Patient’s physical exam revealed a non-syndromic appearing infant with complete phenotypic female genitalia, including normally developed labia, no pubic hair, normal urethral meatus, normal vaginal opening, and normal clitoris. However, there were small palpable firm masses in bilateral labia majora, although the right side was easier to palpate compared to the left side. An abdominal ultrasound was concerning for testicular tissue and a pelvic ultrasound did not visualize uterus or ovaries, further raising concerns for CAIS. Our other differential diagnoses at this point included gonadal dysgenesis, 3-beta-hydroxysteroid dehydrogenase (HSD) deficiency, P450 oxidoreductase deficiency, 17-beta-HSD deficiency, and 5-alpha reductase deficiency.

Labs obtained included a 17-hydroxyprogesterone level at 25 days of life was normal at 34 ng/dL, luteinizing hormone (LH) <0.09 m[iU]/mL (0.00-2.41), follicular stimulating hormone (FSH) 0.07 m[iU]/mL (0.38-10.5), testosterone 4.9 ng/dL (<10), and dihydrotestosterone (DHT) 4.6 ng/dL (<3). Since labs were obtained prior to mini-puberty of infancy, we did not catch the usual increase in gonadotropins that occurs in healthy infants between 4 weeks of age until 6 months of age due to the physiological transient activation of the hypothalamic-pituitary-gonadal (HPG) axis. Furthermore, patient’s total testosterone to DHT ratio is normal, thereby decreasing the suspicion for 5-alpha reductase deficiency. Additional labs were remarkable for Inhibin B 164 pg/mL and anti-mullerian hormone (AMH) 90.7 ng/mL (0.53-7.78). Anti-mullerian hormone is normal for male genotype, which is the case in CAIS, and inhibin B shows normal Sertoli cell function.

Given the concern for CAIS, fluorescence in situ-hybridization (FISH) was obtained to rapidly determine the sex chromosome complement. This returned with a normal XY signal pattern consistent with a male sex chromosome complement. Chromosome analysis then confirmed a normal male genotype of 46, XY. With CAIS remaining on the top of the differential, sequencing and deletion/duplication analysis of the AR gene was then performed, which revealed a maternally inherited pathogenic deletion of exon 2. This confirmed the diagnosis of CAIS.

A diagnosis of CAIS was made based on normal external female genitalia, 46, XY karyotype, absence of uterus and presence of labial testicles on ultrasound, and molecular genetic testing consistent with the diagnosis of AIS.

Management

The infant is currently being managed by a multidisciplinary team, including pediatric endocrinology, genetics, and urology. Due to the opportunity of spontaneous puberty and signs of estrogenization secondary to aromatization of circulating androgens, the decision was made with the team and the patient’s family to defer gonadectomy at this time. At 13 months of age, patient underwent bilateral hernia repair surgery with urology and gonads were repositioned in the abdomen.

Discussion

CAIS is estimated to have an incidence of 1:20,000 to 1:64,000 live male births. ⁴ Individuals with CAIS usually present during adolescence as a phenotypic female with primary amenorrhea. Physical exam will note normal breast development but no secondary sexual characteristics, including axillary and pubic hair. On the other hand, infants and children usually present as a phenotypic female with inguinal hernia or swelling of the labia majora. ³ Moreover, incidence of inguinal hernia is about 1% to 4% in the pediatric population with a 10:1 male to female ratio. Thus, presentation of a female infant with unilateral or bilateral inguinal hernias should prompt a karyotype analysis. ⁵

Testicular differentiation occurs during the sixth week of male fetal development, under the influence of sex-determining region Y (SRY) gene on the Y chromosome. With normal testicular development, Leydig cells produce testosterone, which in turn stabilizes the Wollfian ducts, including epididymis, vas deferens, and seminal vesicles. Sertoli cells secrete AMH, which leads to regression of the Mullerian ducts, including uterus, fallopian tubes, and superior two-thirds of the vagina. As for the external differentiation of the male genitalia, the conversion of testosterone to DHT via 5-alpha reductase enzyme promotes phallic growth, fusion of urethral folds, and development of scrotum and penis. Testosterone and DHT bind to AR to mediate the actions required for normal sexual development expressing the significance of androgen secretion and AR functioning.^1,3 In addition, testicular decent is androgen-dependent. ⁴ Thus, in CAIS, testes are usually found in 1 of 3 locations—abdomen, inguinal canal, or labia majora—presenting as inguinal hernia or labial swelling. ⁶ When there is no testicular development, Mullerian ducts stabilize and develop into uterus, fallopian tubes, and superior two-thirds of the vagina, and Wollfian ducts regress, thus there is no epididymis, vas deferens, or seminal vesicles. ⁷ Genital virilization depends on androgen secretion and AR response; thus, complication with either process will hinder genital virilization.

The X chromosome houses the AR gene on Xq11-12. Mutation in this X-linked AR gene results in androgen insensitivity. Thus, external differentiation does not occur and there is no masculinization of the genitalia due to the AR mutation. Depending on the degree of androgen insensitivity, different genital phenotypes arise, with CAIS suggested by normal female phenotype but male genotype.^3,4 Single nucleotide variants in AR are the most common cause of CAIS. Only a minority of individuals with CAIS are found to have a deletion of one or more exons in AR. A deletion of exon 2 in AR has only been reported in 3 other individuals with CAIS. ⁸ This highlights the importance of obtaining sequencing, in addition to deletion and duplication analysis, of AR whenever there is clinical concern for CAIS.

Biochemical findings in CAIS include elevated LH levels and high or normal basal serum testosterone levels. This is consistent with the androgen insensitivity and reiterating the absence of negative feedback on the pituitary. During mini puberty or in post-pubertal patients, estradiol levels are either normal or elevated for a male, due to the increase in aromatization of testosterone. Follicular stimulating hormone is regulated by inhibin, and is usually normal in AIS. ⁹

While CAIS can present in adolescents or infants, a patient with CAIS with intact gonads will go through a pubertal growth spurt at the appropriate age. Given the normal aromatase levels, patients undergo aromatization of their androgens as expected due to elevated serum levels of testosterone and LH. In effect, patients will have normal onset of breast development but absence of secondary sexual characteristics, including sexual hair. This aspect of spontaneous puberty displays the advantage of leaving gonads intact until puberty, after which the risk of testicular cancer increases. ⁴ The timing of gonadectomy can be challenging because, while spontaneous puberty occurs with intact gonads, there is a theoretical risk of malignant transformation of the intact gonads, particularly testicular germ cell tumors. Complete androgen insensitivity syndrome does have a higher risk of carcinoma-in-situ, seminomas and gonadoblastomas than the general population. ¹⁰ However, prior to adolescence, the tumor risk is considered very low and increases with age. In addition, the possibility of discomfort from enlarging testes should be taken into account, and consideration of repositioning in the abdominal cavity should be discussed. ¹⁰

Conclusion

Proper diagnosis is essential for patients with disorders of sexual development to enable appropriate management and beyond. A multidisciplinary approach is important while caring for patients with CAIS, including pediatric endocrinology, urology, gynecology, and clinical psychology. Discussion about spontaneous puberty, gonadectomy after completion of puberty, hormone replacement afterwards, and future infertility are central aspects of counseling.