Abstract
Complete Androgen Insensitivity Syndrome (CAIS ) is a rare condition with affected patients exhibiting a female phenotype with well developed breasts, axillary hair and pubic hair are absent. External genitalia are small and internal genitalia are absent. Gonads are consistent with cryptorchoid testes. Treatment includes gonadectomy, vaginoplasty, and other genital plastic surgical procedures.

Introduction

CAIS is a rare condition wherein the affected individual is phenotypically female with well developed breasts with rudimentary nipples, under developed external genitalia, absent internal genitalia, absent axillary and pubic hair. The most important finding is the presence of testes which are consistent with the histological diagnosis of cryptorchid testes. We present this case in view of the rarity of the condition and the importance of early diagnosis and management considering the social and personal implications of this condition.

Case Report

A forty year old female patient from Uttar Pradesh presented with complaints of swelling in both the inguinal regions since many years. Swelling was static for many years. During last five to six years patient noticed gradual increase in the size of the swelling. There were no other complaints pertaining to the swelling. The patient had never got her menses and she was married but could not consummate her marriage. On her examination both the inguinal swellings measured 3 x 3 cm, non reducible with no cough impulse. On per vaginal examination the external genitalia were not fully developed with absent pubic hair. The vagina was short (about 2 cm) and ended blindly. Her breasts were normally developed with small rudimentary nipples.

On ultrasound examination, the ovaries, fallopian tubes and uterus were absent. Her hormonal profile revealed elevated testosterone (378 ng/dl) with low FSH and LH.

Excision of both swellings was done intra-operatively; it was found that both the swellings were well formed testes with epididymis. Histopathologically both the testes showed immature seminiferous tubules with absent spermatogenesis. There was no evidence of malignancy. In view of the advanced age of presentation, any vaginoplasty was not considered. Patient has been followed up for the past three months without any evidence of recurrence.

Fig. 1: Patient's pre-op picture	Fig.2 : Intro-operative picture showing testis in swelling
Fig. 3 : Low power view (10X, H & E stain) section shows tubular and interstitial component (increased fibrous tissue element)	Fig. 4 : High power view (40X, H & E stain) section shows increased interstitial fibrous tissue with tubules show presence of spermatogonia and prominence of sertoli cells suggestive of cryptorchild testis.

Discussion

This syndrome was first noted by Morris and assigned the name Testicular Feminization Syndrome.1 The name is now replaced by the less stigmatizing Androgen insensitivity syndrome.²

The classical CAIS will have the following:

1. Female body shape
2. Large breasts with juvenile nipples
3. Absent/scanty axillary and pubic hair
4. No temporal hair recession (balding)
5. Female external genitalia with small labia
6. Blind-ending vagina
7. Absent or rudimentary internal genitalia
8. Gonads consistent histologically with cryptorchid testes
9. Hyperplasia of interstitial cells: adenoma
10. Testes produce androgen and oestrogen
11. Increased gonadotrophins.

Even in CAIS there will be no ovaries, Fallopian tubes or uterus; and the vagina will be blind-ending and possibly short or absent. Female pubertal development occurs but there will be no menstruation and no possibility of conceiving/bearing children.

Some girls with AIS may develop some dark, coarse pubic/underarm hair (AIS Grade 6) but usually this does not develop (Grade 7) because its growth is dependent on the effects of androgens. The nipples usually remain under-developed and pale in colour. The vagina may need to be lengthened or constructed before sexual intercourse is possible.

The undescended testes can result in an inguinal hernia in infancy and this is when AIS may be diagnosed in an apparently female child (approx. 50% of cases). Otherwise CAIS may not be discovered until puberty when there is a failure to menstruate (approx. 50% of cases).

Pubic and axillary hair growth is dependent on androgens. Even if the testes are still in place at puberty, pubic and axillary hair growth is likely to be sparse or absent.

Although androgens are often called “male hormones” and oestrogens are often called “female hormones,” both types of hormones are present in males and females, in different amounts. In normal males the body produces androgens and a smaller amount of oestrogens. In fact, the richest natural source of oestrone (one type of oestrogen) is the testis of the stallion. Similarly, normal females produce male as well as female hormones. In AIS the testicular oestrogen is secreted in a non-cyclical manner and not cyclically as in the menstruating female.³

In AIS, although the body is insensitive to androgens, it is very responsive to oestrogens, and is affected by the small amount of oestradiol (an oestrogen) produced by the testes, by the oestrone produced from testosterone in fat tissue, or by the oestrogen replacement therapy given in the case where the testes have been removed.³

This means that the body not only fails to develop masculinity but develops even further in a feminine direction, causing the body appearance to perfectly simulate an XX female, with female breast development. However, since there is no uterus, and no ovaries, there is no possibility of menstruation. Although a vagina of sorts may be present, as mentioned earlier, it is usually no more than a short blind pocket, and may require lengthening if intercourse is to be possible.

Zachmann et al have studied growth in nine girls with AIS and suggest that girls with AIS may be more sensitive to the effects of oestrogens than normal females, because of their insensitivity to androgens. Unlike the situation in normal girls, the oestrogen effects are unopposed by the effects of the androgens from the adrenal glands and this could account for the very adequate breast development in AIS girls.⁴ A high sensitivity to very low quantities of oestrogens is also indicated by the observation by Sobrinho et al of spontaneous breast development in patients with androgen insensitivity who have had gonadectomies. This increased sensitivity may have a bearing on the management of hormone replacement therapy (HRT) in these patients.⁵ Simpson states that individuals with CAIS are phenotypic females ‘with normal female appearance’ and that their growth in stature and body proportions are normal but there are some observations indicating that they might be taller than normal females.⁶ The review of CAIS and PAIS by Wilson et al mention that AIS patients tend to have a masculine skeleton and that the size of their teeth is closer to that of men than of women. Dewhurst and Spence say that AIS subjects can show a eunuchoid appearance with elongated limbs and large hands and feet.⁷ An average height of 171.5 cm is given for a group of these patients by Varrela et al.⁸ A book chapter by Barlatos and Baramki gives an average height of 5 feet 7 and 1/2 inches.⁹ Zachman et al report the mean adult height in their AIS patients to be 172.3 cm, which was lower than normal men but higher than normal women.⁴

Some researchers in the field have suggested that genes on the Y chromosome have an effect on growth, independently of hormonal changes, as shown by increased growth in boys with an extra Y chromosome. Westphal states that in AIS “the XY karyotype (chromosomes) will result in excessive final height in relation to the female phenotype (body form)”.¹⁰ Varrela et al observed that the body shape (having accounted for size differences) of 46 XY females does not deviate much from that of normal females but that 46 XY females tend to be larger in all body measurements, although with a tendency to a slimmer body. The mean height (171.5 cm) of the 46 XY females was 10.2 cm higher than that of the normal females but was 4.9 cm lower than that of a sample of 40 normal males. They conclude that the Y chromosome has a direct influence on growth but that the greater height in normal males may indicate that an additive or inductive action of androgens is also necessary for the completion of body growth in normal males. They suggest that the body shape in 46 XY females is under the control of oestrogens and is not affected by the Y chromosome.⁸

Orchidectomy (Gonadectomy):

There seems to be a trend in recent years towards removal in early childhood (often at the time when an inguinal hernia is investigated surgically). Some clinicians justify this by claiming to spare the patient the ostensible psychological trauma of ‘knowing too much’ or, where there is a single parent, advising that the possibility of an accident might leave the child to fare for herself not knowing her need for surgery. Others feel that this undermines the rights of the child to know their own medical history, to give informed consent, and in some cases of PAIS, to decide to continue in the gender of rearing. (Note that girls with CAIS cannot be masculinized by hormone administration, because of their complete insensitivity to androgens.)¹¹

Some clinicians recommend that orchidectomy be postponed until after secondary sexual development is completed, due to the low likelihood of tumour development before puberty and the fact that the testes produce enough oestrogen at puberty to stimulate breast development etc. Other clinicians recommend this strategy because of an alleged ‘more natural’ female development via gonadal oestrogens as compared to externally administered hormones (HRT). However, Shah et al state that they have not found this to be true.¹² Clinicians at the Royal Society of Medicine (UK) symposium on Any testicular malignancy in AIS is thought to be preceded by low grade CIS or carcinoma in situ, also called intratubular germ cell neoplasia. Although information about the incidence and spontaneous course of CIS in children is limited, CIS in one 10 year-old boy (not AIS but with bilateral cryptorchidism) was followed by invasive neoplasia 10 years later. Two studies in children and adolescents suggest that CIS is more common in PAIS than CAIS. One of these studies found CIS in 3 of 8 PAIS children (youngest 2 months) but in none of 4 CAIS children, whilst the other study found CIS in 5 of 8 prepubertal PAIS children. In contrast, two other studies found no cases of CIS in a total of 36 children and adolescents with PAIS or CAIS, although it was not clear how the diagnosis was made in the second study. Similarly, no gonadal tumours were found in a series of 14 individuals with AIS. Malignant germ cell tumours (seminomas) have been reported in postpubertal patients, these patients generally being more than 30 years of age. In adult studies, 50% of untreated patients with CIS developed germ cell cancer within five years of diagnosis.
The overall frequency of gonadal neoplasia in AIS is difficult to judge, due to the small size of most series and a variety of sampling biases. An early (1963) study which we mentioned in “Gonadectomy” in ALIAS No. 2 estimated a risk of 22% but this is most likely an overestimate, since many of the cases were referred primarily because of the malignancy. A 1992 Danish study reported tumours in 4 of 21 patients but a 1976 study had found no tumours in 23 patients of their own and only 7 tumours in 82 cases gleaned from the literature (8.5%). The risk of such tumours increases with age, the 1976 study suggesting an age-related risk of 3.6% at age 25 but approaching 33% at age 50. Two reports from one group (1981 and 1991) estimate the overall risk to be 6 to 9%.

Apart from the children with CIS, noted earlier, the youngest age at which a gonadal tumour has been reported is 14 years and all such patients were postpubertal. Other workers estimate an overall rate of malignancy of 5 to 10%.¹³ A 1987 study estimates the prevalence of gonadal carcinoma in AIS to be 2 to 5%, compared to an overall prevalence of CIS and invasive testicular cancer of less than 1% in the general adult male population. A 1993 paper offers a case report and review of the literature. Testicular cancer has recently been reported in a 17 year-old AIS woman by Chen et al.

The 2005 study by Cools et al¹⁴ show promise in developing a methodology for detecting early signs of neoplasia (specifically, differentiating this from delayed maturation of gonadal tissue) and suggests that once larger patient groups have been studied it may be possible to monitor patients via biopsies to evaluate the risk, as an alternative to gonadectomy.

There are two basic approaches to treating vaginal hypoplasia. One is to use plastic surgical techniques to construct a new vagina out of tissue from various donor sites. The other is to expand and enlarge the tissue already present at the vaginal entrance by applying pressure (pressure dilation) over an extended period of time.

Dilation should always be the first intervention tried, with surgery resorted to only after dilation has been ruled out. Dilation is also required following most surgical methods of vaginoplasty, and this postoperative dilation can be more painful than dilation without operation. While performing dilation will not adversely affect the potential success of a subsequent surgical vaginoplasty, creation of a vagina by dilation is generally successful only if plastic surgical vaginoplasty has not been previously attempted.¹⁵

Plastic Surgical Techniques

All of these procedures are best deferred until after puberty so that dilation can be tried first, and because vaginoplasty in childhood usually has poor results.
Abbe-McIndoe Method

This is the most common surgical technique used. A newly created (neovaginal) cavity lined with split-thickness skin graft held in place with mold (stent). The main problem is the strong tendency of the graft to contract, thus closing up the cavity, prevention of which requires conscientious use of dilators postoperatively.
McIndoe Method Variants

The neovagina is lined with full-thickness skin grafts (which tend to contract less than split-thickness grafts), or with amnion or non-biological materials, which become gradually replaced by vaginal epithelium (cells that form the vaginal lining) during a somewhat prolonged convalescence.

Davydov Technique
This method uses peritoneum (the membrane lining of the abdominal cavity) to line a newly excavated vagina.

Baldwin Intestinal Transposition and Variants
A vagina is formed from a transplanted length of patient’s colon (gut), tied at one end and moved down to new position with blood supply intact (also known as colovaginoplasty). This is possibly the most invasive of the techniques used. Afterwards, there may be a problem with prolonged mucous discharge. Claimed advantages include less contracture than with the McIndoe procedure.

Williams Vulvo-Vaginoplasty
The outer edges of the labia minora (if they are large enough) are stitched together forming an outward, rather than an inward, extension to the vagina. The axis of this extension is angled slightly differently from that of the normal vagina (less so in more modern variants), but Muram et al report a case in which it was possible to reverse the operation after some time, once the procedure had enabled a deepening of the original short vagina via intercourse.¹⁶

References

*Associate Professor; **Lecturer Dept. of Anaesthesiology; ***Lecturer; ****Resident, Dept. of ENT, Seth G.S. Medical College and King Edward the VII Memorial University Hospital, Acharya Donde Marg, Parel, Mumbai- 400 012.