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Disorders of sex development (DSD)
Introduction
Disorders of sex development (DSD) are a group of conditions where the development of chromosomal, gonadal or anatomical sex is atypical. Individuals may present with a blend of male and female characteristics, for example a baby with ambiguous genitalia at birth or an adolescent girl with primary amenorrhoea who on investigation is found to have an XY karyotype. The term ‘DSD’ is a recently adopted classification, which replaces the older terms of ‘intersex, hermaphroditism, pseudohermaphroditism and sex reversal’. This older nomenclature is confusing to clinicians and can be felt as pejorative by patients.
Definitions
The prosaic definition of ‘sex’ is: ‘a species dimorphism, represented at different planes by chromosomes and the genes they carry, gonads, sex ducts, external genitalia, bodily habitus, secondary sex characters and behaviour or psychological attitudes’. ‘Phenotypic sex’ is the apparent sex, judged by external characteristics. Older terms no longer in regular use, include: ‘gonadal sex’, referring to whether there is a testes or ovary present and ‘karyotypic sex’, referring to the chromosome status. ‘Sexual orientation’ refers to the direction of erotic interest, and ‘gender identity’ refers to a person’s self-representation as male or female. Psychosexual development is highly complex and is influenced by many factors, including chromosomes, pre- and postnatal exposure to hormones and brain structure, as well as social influences and family dynamics.
Causes of gender identity disorder or gender dissatisfaction in the absence of atypical sex development are not discussed in this chapter.
Some fundamental principles
1. In the normal fetus, the chromosomal complement of the zygote determines whether the gonad becomes a testis or ovary. The first step in the pathway to a male or female phenotype is dependent on the SRY gene (sex-determining region of the Y chromosome). This gene, helped by other testes-determining genes, causes the gonad to begin development into a testis.
2. Ovarian development was in the past considered a ‘default’ development due solely to the absence of SRY; however, recently, ovarian-determining genes have also been found.
3. All fetuses have Müllerian and Wolffian ducts and the potential to develop male or female internal and external genitalia.
4. This process can go wrong at any stage, leading to the birth of a baby with a DSD.
5. DSD can be diagnosed at birth but can also present at adolescence.
6. All babies should be assigned to a sex of rearing. In the presence of a DSD, this is decided by the parent and a multidisciplinary specialized team. Birth registration can be delayed until agreement is reached.
7. Medical management includes genital surgery to reinforce the chosen sex of rearing, but this is a controversial and topical issue.
Normal sex differentiation
The chromosomes
Chromosomal complement is the only sex characteristic of the early conceptus. Central to the accumulation of knowledge of sex chromosome anomalies was the discovery of the nuclear chromatin body, a microscopic blob found under the nuclear membrane of all female cells. It is now clear that one X chromosome is necessary for cell viability, but once ovarian differentiation has been initiated, the second X has no function and condenses to form the Barr body (Fig. 6.1) (see History box). More than two X chromosomes will mean that there are additional bodies – the formula being ‘X chromosomes − 1 = number of Barr bodies’ (see Fig. 6.2).
Fig. 6.2Sex chromatin in relation to X chromosomes.
Barr bodies are peripheral blobs consisting of nuclear chromatin. There is always one less Barr body than the number of X chromosomes.
The Y chromosome
It has long been known that the short arm of the Y chromosome controls testicular development, but identification of the gene has proved a long task. Studies were based on cases in which the gonads and other sex features were contrary to the chromosomes, so-called ‘sex reversal’. It is now clear that a gene called SRY (sex-determining region of Y) is responsible. It encodes a DNA-binding protein, which probably influences other genes to produce differentiation of the primitive gonadal streak into testis. The detail of SRY’s mode of action is now the focus of attention. A very few XX males do not have SRY, so some other genetic material must, in certain circumstances, be able to induce testicular differentiation.
Mixed chromosomes
It is not uncommon for lymphocytes to have mixed sex chromosome complements. This can be due to mosaicism arising from post-fertilization mitotic errors or very rarely, to chimerism, when the cell-mix derives from two separate acts of syngamy (union of gametes). Syngamy may result from dispermic conceptions – one sperm fertilizing the ovum nucleus and another uniting with an unextruded second polar body (see Fig. 6.3) – or from dizygous twins with transfer of tissue soon after conception.
Very rarely, an unextruded second polar body may be fertilized in addition to the haploid ovum nucleus; if the sperms involved are of different sexes, an XX/XY chimera will result.
