Summary
Differences in Sex Development (DSD) is an umbrella term which covers conditions arising from a difference in observed and expected sex development. This could include karyotype, gonadal tissue, or genital appearance. Previously alternative terms were used, such as intersex, pseudo-hermaphrodite and testicular feminisation, but these were inaccurate and generally disliked by patients. A consensus was reached in 2006 to change the terminology to disorders of sex development, with individual conditions referred to by their genetic basis [1]. This has been largely accepted in the medical literature, with older more pejorative terms falling from use. Whilst more accurate, the term DSD has not been without its critics, and there is a move towards describing this group of conditions as differences in sex development, which would seem to fit more appropriately with the increased understanding in anatomical variance in those with no known medical condition.
11.1 The Evolution of Differences in Sex Development
Differences in Sex Development (DSD) is an umbrella term which covers conditions arising from a difference in observed and expected sex development. This could include karyotype, gonadal tissue or genital appearance. Previously alternative terms were used, such as intersex, pseudo-hermaphrodite and testicular feminisation, but these were inaccurate and generally disliked by patients. A consensus was reached in 2006 to change the terminology to disorders of sex development, with individual conditions referred to by their genetic basis [Reference Lee, Houk, Ahmed and Hughes1]. This has been largely accepted in the medical literature, with older more pejorative terms falling from use. Whilst more accurate, the term DSD has not been without its critics, and there is a move towards describing this group of conditions as differences in sex development, which would seem to fit more appropriately with the increased understanding in anatomical variance in those with no known medical condition. Similarly, where anatomical change exists, this is now referred to as showing typical or atypical anatomy. These terms will be used in this chapter. Individual conditions are referred to by their descriptions, such as 46XX or 46XY DSD, along with the underlying cause of the condition.
11.2 Prevalence
When the widest definition of DSD is applied the incidence is thought to be approximately 1 in 1000 live births, but this includes more frequently occurring conditions such as Turner syndrome, which is discussed in Chapter 10. For most individual DSD diagnoses, incidence is significantly rarer. Many conditions are autosomal recessive so a family history may be present, although many cases will arise due to new genetic mutations. Incidence is also therefore increased in communities where consanguinity is prevalent. DSD has a history long shrouded in secrecy and shame, so details may not be forthcoming, but enquiring gently about any older female relatives who were unable to have children may offer some suggestion of a DSD family history.
11.3 Presentation and Investigation
Many conditions, such as those which present with atypical genitalia will be apparent at birth. For those with 46XX DSD (congenital adrenal hyperplasia) babies may also present with a salt-wasting crisis in the first few days of life. This is most common in those who have been markedly virilised at birth and mistakenly assigned as a boy. Although the clitoris will be enlarged, labia majora fused and appear very scrotal in appearance, there will be no descended testes and should ring alarm bells for any examining paediatrician.
For those where a DSD is apparent at birth, care will be offered by a specialist DSD team, with local hospitals having a link to a tertiary centre. The core team will consist of a paediatric endocrinologist, psychologist, paediatric urologist and specialist paediatric nurses, with other members including a geneticist, biochemist, radiologist and gynaecologist as needed. International standards exist regarding investigations and expected standards of care [Reference Ahmed, Achermann, Arlt, Balen, Conway and Edwards2,Reference Cools, Nordenström, Robeva, Hall, Westerveld and Flück3].
However, many other conditions will not be diagnosed until adolescence and will either come to the attention of paediatric endocrinologists, with a failure to enter puberty, virilisation at puberty, or to gynaecologists, presenting with primary amenorrhoea. Again, care should be offered with a DSD team, with paediatric endocrinologists, psychologists, gynaecologists as the core members.
For adolescents initial assessment at presentation should include FSH, LH, E2, Prog, testosterone and karyotype. A pelvic ultrasound scan will identify the presence of a uterus or not and may be able to locate intra-abdominal gonads. However, it will not be able to confirm whether these are testes or ovaries, and girls and their parents should only be advised of this once all test results are back and a diagnosis is able to be confirmed. Where surgery for removal of gonads may be planned, an MRI would be the imaging modality of choice. This allows the gonads to be clearly identified, as they may be ectopically placed and lie anywhere in the line of descent.
Table 11.1 summarises the initial investigations and findings for those with the more common DSDs.
| Karyotype | Condition | External female genital appearance | Internal gonads and structures | Androgens (female levels) |
|---|---|---|---|---|
| 46 XX | CAH | Atypical | Ovaries, uterus, tubes and upper vagina | Raised |
| 46 XY | CAIS | Typical | Testes | Raised |
| 17βHSD/5αRD | Atypical | Testes | Raised | |
| Pure gonadal dysgenesis | Typical | Dysgenetic testes, uterus, tubes and upper vagina | Normal |
11.4 Diagnosis
Where a 46XY karyotype is present, it is likely either an interruption in the biosynthesis or action of testosterone has occurred, or the gonads are dysgenetic. In either scenario, virilisation may or may not have occurred. For those with a 46XX with an atypical appearance to the genital area congenital adrenal hyperplasia (CAH) is the most likely cause, which is due to a block in the enzymes catalysing steroid development. This leads to an excess of androgens, causing intrauterine virilisation of a female baby. Figure 11.1 shows the pathways of testosterone synthesis, along with the enzymes needed for each step. A deficiency in any enzyme will cause a block and affect the production of hormones further down the pathways.
Figure 11.1 Testosterone and steroid biosynthetic pathway with enzymes shown.
Previously diagnoses were often evasive, resulting in many 46XY conditions, with virilisation being grouped under ‘partial androgen insensitivity syndrome’. A contributory factor may have been girls having initial and limited investigations, with removal of gonads in hospitals which lacked extensive experience in DSD. The development of DSD services in tertiary care and the ability for rapid referral and review has minimised this, meaning all investigations and surgery will be under the care of a multidisciplinary team. Genetic studies have also developed rapidly over the last 20 years, allowing for the reliable diagnosis of many conditions, including those defects in the testosterone biosynthetic pathway. The net effect of these organisational and scientific advances is that girls and their families should have accurate diagnosis of their condition. The importance of this should not be underestimated. This allows understanding and explanations to be given, along with expectations for the future. It also allows access to peer support groups, and the option to take part in research studies. Finally, it also allows for genetic studies for unaffected family members, along with information on likely inheritability.
Once a clear diagnosis of a DSD has been made, it may be appropriate to offer screening to younger siblings in anticipation of other affected family members. Care should be taken with this, and involvement of an experienced DSD psychologist is mandatory.
11.5 Disclosure of Diagnosis
Historically the diagnosis of a DSD was rarely given or was clouded in inaccurate detail [4]. Women may have been advised that they had ‘diseased ovaries’ and needed an operation to remove them. Whilst this may have been with the best of protective intentions, this approach is inappropriate and deprives an individual of her medical information. It also does not allow for unaffected family members to have information on likely carrier status, and precludes any individual having the option to take part in research studies. More globally this leads to a lack of knowledge of long-term outcomes of treatments and health conditions, limiting information which can be offered to patients and parents of those who are newly diagnosed.
The overall effect of such an approach by clinicians was inadvertently to promote secrecy and shame and cast a stigma which is still felt by many patients. Medical details are of course always private, but are not shameful, and full disclosure of diagnosis must take place for any adolescent with a DSD.
This should be performed in a graded way, in conjunction with a psychologist. Timing will be individualised but generally would occur in mid-adolescence. Information regarding previous treatments, methods of diagnosis, karyotype, potential for sexual function and pleasure, and fertility status must be fully covered so she ultimately has a full understanding of her medical condition. This would also involve working with parents to help support the process of discussing the diagnosis and dealing with questions as they arise, promoting a stance of appropriate privacy and understanding as opposed to secrecy and shame.
11.6 46XX DSD
Congenital Adrenal Hyperplasia (CAH), also known as 46XX DSD, is an autosomal recessive condition affecting 1:14,000 births. The commonest type of CAH is due to a lack of 21 hydroxylase, the enzyme catalysing conversion of the steroid pathway (see Figure 11.1). This leads to an excess of androgens in utero, which has the effect of virilising the female fetus. The clitoris is larger than usual, with the urethra opening near to the glans. The labia majora have a rugose appearance and may be fused. There is one single opening onto the perineum, with the vagina arising somewhere from the back of the urethra, internally. The appearance of the genital area is classified according to Prader stages, and is graded from 1 to 5 (Figure 11.2).
