Background
Disorders of sex development (DSD) is an umbrella term encompassing those diagnoses where there is some discordance between expected and observed findings in terms of genetic sex, gonadal development, or appearance of the genitalia. This could include a female with 46XY karyotype, a female with testes, or a baby born with atypical genitalia representing either an over-virilized female or an under-virilized male. Such conditions were previously referred to as intersex, but terminology has changed following a consensus meeting between clinicians and patient groups [1]. Historical terms such as “pseudohermaphrodite” are technically inaccurate, widely disliked by patients and families and should not be used. Conditions are now referred to by their clinical descriptions. While the terminology has not been universally popular, there is no doubt that it has been widely accepted by the medical community and many patient groups [2].
Historically, the diagnosis of DSD was often cloaked in secrecy and shame, with the medical profession colluding in this [3]. Patients were not informed of their underlying diagnosis and alternative explanations were often offered, such as “diseased ovaries.” While such strategies were often offered with good intentions, this practice is no longer acceptable, and clear openness with parents and ultimately individuals with DSD is a mandatory part of offering care. The model of caregiving has also changed with time, with the recognition that services need to be provided by a multidisciplinary team in a center of clinical expertise [4].
Embryology
To understand the spectrum of complex conditions that comprise DSDs, some knowledge of embryological development is required. The reproductive tract in the developing embryo consists of three main areas: the gonad, the internal genital tract, and the external genital and urinary opening.
The Gonad
Genetic sex in humans is determined at the point of conception to be either XX or XY. This leads to the formation of the gonadal ridge with an undifferentiated gonad that has the capacity to develop into either an ovary or a testis. Primordial germ cells migrate to the ridge and initiate sex differentiation. Sertoli cells (XY) or granulosa cells (XX) lead to the production of the sex steroids that is itself triggered by the presence (or not) of the sex-determining region of the Y chromosome – the SRY gene. The SRY initiates a series of genetic switches that promote cell differentiation. It is a highly complex process that ultimately leads to the expression of anti-Mullerian hormone (AMH), which regulates the development of the internal genital tract.
The Internal Genital Tract
The genital duct system consists of the Mullerian duct (MD) and the Woolfian duct (WD) systems that are a set of paired tubes that meet in the midline and continue caudally to the genital opening. The usual developmental pathway would be for the persistence of the MD resulting in usual female reproductive tract. However, the SRY leads to AMH expression that promotes regression of the MD and allows the WD to develop. The developing testis expresses androgens that act upon the androgen receptor (AR), which results in virilization of the genital tubercle into a penis enclosing the urethra, and the genital folds into the scrotum. In the absence of AMH, the MD develops into the Fallopian tubes, uterus and cervix, and upper two-thirds of the vagina. The MD meets the genital sinus at the site of the future hymen and allows the lower third of the vagina to become separate from the urethra with both opening onto the perineum.
If the gonads are dysgenetic, they cannot respond to the SRY gene and therefore will not express AMH. This allows the development of the MD, regression of the WD and results in the female phenotype.
The External Genital and Urinary Opening
The external genitalia develop from the cloacal membrane and form the genital tubercle, which develops into the clitoris and the cloacal fold forming the paired genital swellings that in turn form the labio-scrotal folds. The cloacal fold forms the genital and anal folds resulting in separation between the anus and the urogenital sinus, which further divides into the urethra and the vagina. This sequence of events results in the usual three separate openings onto the female genital area.
Male external genital development is mediated by androgens, with virilization to females occurring in the presence of higher than usual androgens expressed. Conversely under-virilization may occur if androgens are not expressed or recognized by the developing male fetus. Interestingly, there appears to be a continuum in anatomical development between androgens and clitoral-to-urethra distance, with those with the lowest recognition of androgens showing the longest distance between structures [5].
Clinical Presentation
DSDs may be recognized at birth when a baby is born with atypical external genitalia. In some cases, a baby with marked virilization may be assigned male, only to return extremely unwell within a few days with an unrecognized diagnosis of salt-wasting congenital adrenal hyperplasia (CAH). DSDs may also present in childhood with the development of an inguinal hernia where the gonad has traveled into the labio-scrotal fold. For many others, a DSD becomes apparent at puberty. This may be with the absence of periods, for those with an internal WD, or may be virilization to some degree for those with normal androgen receptor function [6].
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia is the most common DSD with an incidence of 1:14000 births. It is an autosomal recessive condition, with several different subtypes; 90 percent of which are due to a deficiency of the enzyme 21-hydroxylase. The role of this enzyme is to enable cortisol and aldosterone production, as part of the delta 4 pathway, and its deficiency results in two effects: first, the development of a salt-wasting condition (Classical CAH), which is life threatening and results in death if not promptly recognized and treated with steroid replacement. Second, the precursors from the cortisol pathway lead to an excess of androgens causing external virilization of the female fetus.
As a result of androgenization in utero, the clitoris develops larger than usual and appears more prominent. The vagina is tucked inside the pelvis, “taking off” from the back of the urethra, leaving a single urogenital sinus opening on the perineum. The labial majora appear more rugose, having an appearance more typical of scrotal tissue.
Surgical Management
The advent of steroid treatment for those with salt-wasting CAH changed an immediately life-threatening condition into one with long-term management issues. Surgery to alter the genital area to a more typical female appearance therefore became a standard part of treatment. In more recent years, patients, families, and support groups have challenged this approach.
Indications for surgery include to allow penetrative intercourse, provide a conduit for menstruation, avoidance of urinary tract infections, and to reduce or avoid surgery in adolescence. In addition, it is often argued that a more typical female appearance to the genital area will promote parental bonding and reduce psychological distress for the child.
Surgical Approach
The mainstay of the surgical approach is to reduce the size of the clitoris and bring the vagina to open separately on the perineum to create a more typical female appearance. The clitoris consists of paired corpora with erectile tissue, with the neurovascular bundle running along the dorsal aspect. Nerves fan out around the glans, innervating the covering clitoral hood skin. The tail of the clitoris runs along the inner aspect of the pelvis on each side; therefore, the perineal clitoral tissue can reasonably be considered as the tip of the iceberg. The clitoris is highly innervated and forms a major component of female sexual pleasure and sensation. It has no other known function.
Surgical techniques have varied over the years, but the principle is to reduce the size and/or appearance of the clitoral tissue without long-term damage to function. Originally this involved removing the clitoral glans and clitoral hood, with the vagina being brought down to form a second perineal opening. An increasing appreciation of the importance of the clitoris in sexual pleasure and the role of female sexual function led to this approach being refined. The clitoral recession technique was developed to avoid removing any tissue, with the corporal bodies folded and sutured in place. This had the effect of reducing the prominence of the clitoral glans without dividing tissue. However, pain was a common complaint, particularly at the time of arousal, due to erectile tissue becoming trapped.
Further techniques involved dividing the clitoral hood skin, removing the corporal bodies, and setting the clitoral glans back into position. This was often combined with a vaginal procedure to draw the vaginal opening down to the perineum, with the clitoral skin being utilized to form labia minora. This is known as the one-stage procedure. Variations of this approach remain the mainstay of current surgery for those born with atypical genitalia.
Timing of Surgery
Current practice is for surgery to be performed in infancy, with proponents arguing the surgery is likely to be technically more straightforward due to the shorter distance involved. There may also be the effect of maternal estrogen, which promotes healing, and lasts for a few months after birth.
Results of Surgery
A few long-term outcome studies follow those who underwent childhood surgery. Cosmesis is reported variably, with surgeons often claiming excellent results. However, studies including assessments by researchers not part of the operating team have shown disappointing results [7]. There is no evidence that early childhood surgery protects against urinary tract infections [8]. In addition, studies have shown there is risk to sexual function with clitoral surgery [9]. The majority of individuals will still require surgical intervention at adolescence, which may not have been expected by those who have undergone one-stage surgery. There is also no evidence that childhood surgery promotes parental bonding or improves psychological outcomes for the child. In contrast, some parents have written powerfully to suggest that of all the parenting concerns in having a child with congenital adrenal hyperplasia, the appearance of the genital area was not a major one [10].
Some form of surgery is likely to be needed to allow penetrative intercourse and facilitate tampon use. Obstruction to menstruation is unlikely in those who have not undergone surgery, and menstrual flow can occur through the common channel. Assessment may be made in early adolescence to ensure that no obstruction is present. Therefore, many clinicians would argue that surgery should be deferred until adolescence and would point to the importance of an individual being involved in the consent process [11]. A baby clearly cannot consent to cosmetic surgery, and the parents are being asked to make decisions on her behalf.
Surgery in adolescence will allow the endogenous effect of estrogen on the healing tissues, which is thought to be of importance in childhood surgery. There is no significant cohort of children who have not undergone childhood surgery, with the difficulty or otherwise of primary surgery in adolescence remaining largely unknown.
Controversies of Surgery
The surgical community appears to be in two camps; those who work within pediatric surgical surgery who think that early surgery in infancy is advisable, and those who work in adult surgical services who are often faced with the complications of childhood surgery. While the controversies of surgery for those with atypical genitalia are likely to continue to be hotly debated, some issues are incontrovertible.
Surgery to the clitoral area is a cosmetic procedure
Any surgery will interrupt nerve fibers
Surgery will cause a risk to sexual function
The child does not need a vagina
The vagina may need surgery to allow menstrual flow and penetrative intercourse
Complete Androgen Insensitivity Syndrome
Complete androgen insensitivity syndrome (CAIS) is the most common DSD for those with 46XY. It occurs in 1:40000 births and is an X-linked recessive condition. The androgen receptor (AR) gene is located at Xq11–12. AR mutations result in variable resistance to signal transduction through the receptor that cannot respond to testosterone and its derivatives, meaning the external genitalia are unable to virilize. This results in a typical female appearance to the external genitalia with normal labia, clitoris, and urethra and lower third of the vagina. However, the gonads are fully functional testes that therefore express anti-Mullerian hormone, leading to the development of the Woolfian duct and regression of the Mullerian duct, as described earlier. The absence of the uterus and upper vagina therefore means the vagina is shortened and blind ending.
Diagnosis of CAIS
Those with CAIS typically present with primary amenorrhea with otherwise apparently normal secondary sexual characteristics. CAIS may also present in childhood with an inguinal hernia, with further investigations revealing this to be a testis. Breast development is normal, and girls are often tall, achieving male-typical height derived from the Y chromosome. However, there is usually no pubic or axillary hair development as this is mediated by the androgen receptor. In contrast to previous decades, current adolescents often desire hair removal and are less likely to be distressed by this feature.
Due to the genetic nature of the condition, on further enquiry it is not unusual to identify family members who may also have CAIS. However, 30 percent of cases result from do novo mutations and will have no family history. Because of the historical secrecy and stigma attached to all DSDs, information may be elusive, but the knowledge of an aunt or sister who was unable to have children may be significant.
A karyotype will be 46XY, and further blood tests will show normal functioning of all parts of the testosterone biosynthetic pathway. Targeted genetic studies will confirm a suspected mutation on the androgen receptor. Approximately 95 percent of clinical CAIS will have an identifiable androgen receptor mutation.
Gonadectomy
Gonadal malignancy risk for women with CAIS has traditionally been estimated to be around 5 percent, and the gonads are usually retained until later adolescence to allow completion of normal pubertal development, including breast development. Current practice would be to perform a laparoscopic gonadectomy in the late teenage years. Once the gonads are removed, girls need to take hormone replacement therapy (HRT) until the age of the natural menopause at 50. Recent work has suggested that the cancer risk in adults may be underestimated but accurate data are simply not available [12]. Historical studies may contain diagnostic inaccuracies, and participation in research studies may be flawed following an era of nondisclosure. Increasingly, some women may prefer to retain their gonads in preference to taking HRT long term, or to avoid the risk and inconvenience of surgery. These concerns need to be balanced against the unknown risks of deferring surgery and the difficulties in safe ongoing gonadal surveillance. This needs a clear discussion in adolescence and requires knowledge and understanding of the condition.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
