The Invisible Man – Androgen Insensitivity Syndrome: Disorders of sexual development
Karthick. M
Physician Assistant, Department of Urology and Renal Transplant, Kauvery hospital, Hosur
Abstract
Disorders of sexual development (DSD) are congenital anomalies due to atypical development of chromosomes, gonads and anatomy. Androgen insensitivity syndrome (AIS) is a rare X-linked recessive androgen receptor (AR) disorder with 46, XY karyotype. A partial AIS Affects 5-7 per 1,00,000 genetically male individual whereas Complete Androgen insensitivity syndrome (CAIS) affect 2-5 per 100,000 genetically male individuals. CAIS is characterized by complete resistance to the action of androgens.
Presentation of case: A 65-years aged patient presented with painful swelling in bilateral inguinal region. Patient also complained of primary amenorrhea and primary infertility. Serum testosterone level was normal. MRI pelvis revealed agenesis of Uterine body, both ovaries and cervix. Bilateral undescended testis was noted in mid part of inguinal canal. Bilateral orchiectomy (B/L Gonadectomy) was done. Histopathology report revealed Germinoma – left testis, Post Gonadectomy tumor markers were normal. Advised observation and follow-up.
Discussion: CAIS is usually diagnosed at puberty, when presenting with primary amenorrhea. Karyotype has to be mapped to differentiate from other genetic disorders. Orchidectomy should be done to avoid malignancy in undescended abdominal testis (3.6% in 25 years and 33% in at 50 years old reported by various studies) Hormonal substitution therapy should be administrated. Comprehensive psychiatric assessment and intervention go a long way in alleviating distress and enhancing quality of life.
Introduction:
Androgen insensitivity syndrome (AIS) is a rare X-linked recessive androgen receptor (AR) disorder. The individual with androgen insensitive syndrome has 46, XY karyotype (phenotypically female). AIS classified as partial and complete, or mild AIS according to the gradation of androgen insensitivity. Complete androgen insensitivity syndrome (CAIS), also known as testicular feminization (TF) is characterized by complete resistance to the action of androgens (a rare DSD disease). The majority of CAIS patients present with female appearance and normal breast development, but with absent uterus and ovaries, bilateral undescended testis and elevated testosterone levels. A complete androgen insensitivity syndrome is a rare disorder affecting 2-5 per 100,000 genetically male individuals while partial AIS Affects 5-7 per 1,000,000 genetically male individuals. AIS patient come to hospitals with the complaint of primary amenorrhea or infertility. CAIS diagnosis should be disclosed in an age-appropriate manner preferably by a mental health professional
Case Presentation
- A 65 years aged patient presented with painful swelling in bilateral inguinal regions and also history of primary amenorrhea. Patient had normal secondary sexual characteristics, with breast development at Tanner stage-4 and pubic and axillary hair development at Tanners stage-1 and feminine facial features. There was hoarseness of voice. Patient was normotensive with height 154 and weight 76 kg, Body mass index 32.1 kg/m2.
- The patient was brought up as a female. Clinical examination revealed a female phenotype: the breasts were normally developed. There was scanty axillary hair (+) and pubic hair. Per vaginal examination revealed a blind ending short vagina ~ 2.5cm. A solitary tender swelling of size ~3×3 cm presented in right superficial inguinal region. Another tender swelling about ~ 5×4 cm Swelling noted in left superficial inguinal region. Both the swellings were soft to firm consistency, freely mobile, non-reducible and cough impulse test was negative.
Local examination
- Per vaginal examination revealed a narrow introitus with blind ending vagina
- Labia – underdeveloped
- Clitoris (+)
- External urethral meatus (+)
- DRE – Tone – Normal, No nodules palpable
Investigations
- Hematological investigation and hormone evaluation revealed serum FSH and LH reports on upper limit, and testosterone level on normal.
- Serum testosterone: 20.51ng/dL,
- Serum LDH: 205 U/L,
- Alpha 1-Feto protein (AFP) :1.891 IU/mL,
- Beta HCG: <2.39 mIU/mL
- Blood sugar level and lipid profile were within normal limit
MRI pelvis
- Revealed agenesis of waserine body, both ovaries and cervix.
- Bilateral undescended testes were noted in mid part of inguinal canal. Right testis was shrunken in size ~2.1 x 1.6 x 3.2cm and left testis was normal in size ~ 4.2 x 3.3 x 4.1cm. Prominent fat content was seen proximal to the testis
Karyotyping
- A peripheral blood sample was taken for karyotyping –Method – 72hrs PHA stimulated culture
- Analysis showed male (46, XY) Karyotype in all the metaphases analyzed.
- Suggestive of Disorder of sexual differentiation
| Banding: GTG | Band resolution: 450 |
|---|---|
| Screened: 30 | Karyotyped: 30 |
| Modal number: 46 | Autosome: Normal |
| Sex Chromosome: XY | Karyotype: 46, XY |
- After counselling the patient and her relatives about the patient’s condition, the patient consented to identify herself as female and underwent B/L Gonadectomy to avoid risk of malignancy.
- Intraoperatively the bilateral testes were found in superficial inguinal ring within the hernia sac. About ~ 3×3 cm, swelling (testes) noted at right inguinal ring within the hernia sac. Another ~5x 4 cm noted at left superficial inguinal ring within the hernia sac.
- The specimen was sent for histopathological evaluation, which revealed Germinoma – Left testis, Extensive stromal hyalinization and smooth muscle proliferation in bilateral testis, Persistent mullerian remnants (fallopian tube).
- Right testis (Orchidectomy specimen ~ 8x4x2 cut surface testis ~ 4×3.5×2.5cms). Epididymis shows extensive stromal hyalinization with periphery showing Leydig cell nodules. Multiple nests of atypical germ cells are seen surrounded by dense lymphoid aggregates and granulomas. Areas resembling ovarian stroma and areas of smooth muscle proliferation are also noted. Multiple structures resembling Fallopian tubes are seen.
- Left testis shows (Orchidectomy specimen ~ 6x2x1.5cms.cut surface testis ~ 0.5×0.5×0.5cms). Epididymis shows extensive stromal hyalinization with few tubules lined by immature Sertoli cells. Periphery shows Leydig cell nodules. Areas resembling Fallopian tube seen.
Fig (1): The development and upbringing of the patient was that of a female and after the recent course of events the patient opted for psychiatric counselling. The patient came for wound review, and She desired to continue as female gender.
Discussion
AIS is an X-linked disorder of sexual development affecting chromosome. It may occur spontaneously without any prior family history. Despite the presence of bilateral testis, there is absence of virilization in males in normal pattern because of mutations in androgen receptors (ARs). To date, more than 500 mutations have been reported to be present in the entire sequence of the gene. Seventy percent of these mutations are maternally inherited while the remaining thirty percent are thought to be de novo. These males have a normal or even higher level of testosterone & dihydrotestosterone (DHT), so the basic anomaly lies within the response to these hormones. Since the action of these androgens is mediated via androgen receptors, and as in AIS, there is mutagenic resistance in androgen receptors of target tissues, it renders these androgens ineffective resulting in a variety of phenotypic changes ranging between complete, partial, and mild female phenotypes.
We report a case of a 65-year-old phenotypically female patient with a history of painful swelling in B/L Inguinal region diagnosed as a case of CAIS.
CAIS is a rare entity that is usually diagnosed at the time of puberty when patients complain of primary amenorrhea but an early diagnosis at the time of birth or even in early childhood can drastically reduce the morbidity & alleviate the psychological burden. These female patients lack fallopian tubes, uterus, and proximal vagina because of AMH secreted by the testis as is the case with our patient. Apart from this, their oestrogen level will also be within the normal limit which is derived from the aromatization of DHT by aromatase enzyme, and results in normal development of breast and female adiposity that is consistent with this particular case. Apart from this, axillary and pubic hair are largely scarce.
Thus, screening can be performed by measuring the vaginal length of female patients, karyotyping, or biopsy of cryptorchid testis in the hernial sac . For further help in diagnosis, Ultrasound & MRI can also be employed which will demonstrate the absent uterus, fallopian tube & blind vagina. In the case of our patient, the LH, FSH, and testosterone levels were also abnormal. Management should be centred around gonadectomy in view of malignancy, counselling the patient & family.
Psychological aspect of androgen insensitive syndrome
The reason for reporting this case of complete androgen insensitive syndrome and its multi-disciplinary management. Most of the patients with androgen insensitivity syndrome are brought up as a girl child. For them the realizing that they are genetically male and have only partial female characteristics and would not bear children can be mentally devastating As for few who are raised as male child can benefit from sex reassignment surgeries.
- Our patient was raised as a girl child from birth. She was tall, had normal breast development and scanty axillary hair. She is married & divorced. The revelation of being genetically male was not very well accepted by her and her family at first and resulted is significant psychological trauma. It also resulted in minor depressive episodes. Our patient achieved satisfactory level of adjustment to assignment of feminine role after in her mind about society acceptance for her condition
- Androgen insensitivity syndrome can be extremely distressful to the individuals concerned. Apart from orchidectomy, Hormone replacement therapies Re-assignment surgery, comprehensive psychiatric assessment and counselling can go a long way in alleviating distress in young ages well as improving quality of life.
Conclusion
Androgen insensitivity syndrome, although rare, is very distressing to individuals and family members. It requires expert and sympathetic handling close collaboration between surgeon, gynecology and psychiatrist. Prenatal screening for ambiguous genitalia should be done as early as possible, followed by imaging of any suspected cases at birth to address future physical and psychiatric issues and is essential for proper management of Complete androgen insensitive syndrome. Due to risk of degeneration of the gonad and malignancy of undescended testis, orchidectomy should be performed. In our case the revelation of being genetically male was not very well accepted by her and her family at first and resulted is significant psychological trauma. It also resulted in minor depressive episodes. Our patient achieved satisfactory level of adjustment to assignment of feminine role after in her mind about society acceptance for her condition.
