Issues Magazine

Differences of Sex Development

By Rajini Sreenivasan,1 Peter Koopman,2 Andrew Sinclair3 & Vincent Harley4

Most people are born either male or female. For people born with a difference or disorder of sex development, this is not so simple.

The question of whether one’s baby is a boy or girl may turn out to be perplexing for some parents. Children born with a difference or disorder of sex development (DSD) may differ from typical males or females in terms of their chromosomes, hormones or reproductive organs.

How do DSDs arise? How are they clinically diagnosed and managed? What are the issues faced by individuals with DSDs and their families?

Typically, boys have an X and a Y sex chromosome, while girls have two X chromosomes. One form of DSD, known as sex chromosomal DSD, occurs when the chromosomal constitution of an individual is atypical.

For example, a male carrying an additional X chromosome (XXY) would develop Klinefelter syndrome. Such individuals may have reduced testis function and consequently low testosterone levels, leading to males with small penis size, undescended testes, breast development and infertility.

Likewise a woman with Turner syndrome, lacking an X chromosome (XO), has loss of ovarian function, fails to undergo puberty and is infertile.

DSD also occurs where a person has normal chromosomal constitution with variations in the formation of reproductive organs. Testes and ovaries usually develop from the same tissue within the embryo using instructions from a number of genes. Once formed, the gonads produce sex hormones (testosterone by males; oestrogen by females) and the internal and external genitals then develop. DSD in such individuals may be caused by mutations in any of the genes controlling the development of these reproductive organs, or controlling sex hormone production or action.

For example, some people with an X and a Y chromosome have female external genitals and internal testes. This may be caused by gene mutations that disrupt the development of the testes or that affect the ability to produce or respond to testosterone. Other individuals may have two X chromosomes but have male reproductive organs, due to gene mutations that disrupt ovarian development or that lead to increased testosterone production.

A spectrum of features, ranging from mild to severe, exists for people with DSDs. These include a misplaced urethra, fused labia that resemble a scrotum, a micropenis, enlarged clitoris and underdeveloped testes or ovaries. Some DSDs, such as those involving adrenal defects, may even be life-threatening and need immediate medical intervention.

When a baby is born with ambiguous external genitals, its DSD condition is apparent and may be diagnosed at birth. Other cases may go completely undiagnosed at birth, particularly where babies are born with typical female or male external genitals but have atypical internal reproductive features. Such people may seek medical assistance during adolescence for delayed or absent puberty, masculinisation in a girl or breast development in a boy, unaware of their condition until this point.

Diagnosis of DSDs is challenging, with only a small proportion of genetic causes known. For example, only about 30% of XY DSDs can be genetically diagnosed currently. Therefore, much remains to be discovered about the underlying causes of the undiagnosed cases.

The discovery of the currently known DSD genes was possible by identifying genetic variations in people with DSD and by characterising the functional consequences of these gene differences in model organisms such as mice, or in cultured cells.

DSDs can be inherited, or they may arise spontaneously. Current technologies make it possible to identify the causative factor of the DSD condition: DNA sequencing can identify variations in genes that are required for sex development. Large-scale diagnostic screens are now available whereby multiple known DSD genes can be sequenced in people with DSDs. Variations in the number of copies of DSD genes can also be determined, which can indicate how the condition may have developed.

When no known genetic cause has been identified, whole genome sequencing may reveal causative mutations in genes not previously known to be involved in sex development. The difficulty lies in sorting out which of the hundreds of gene differences between affected and non-affected individuals is causative.

Sequencing the DNA of family members and testing sequence variant gene activity are also performed in the research laboratory. The identification of novel genes is crucial to the progress of DSD research and improved diagnosis for individuals with DSD.

The psychological issues faced by people with DSDs and their families can be enormous. Individuals with DSDs undergo frequent physical examinations by their doctors, causing stress and embarrassment. DSDs often result in the stigmatisation of affected individuals and their families.

For instance, people with DSDs have reported being discriminated against and bullied in schools. In some countries it is common for people with DSDs to be ostracised by their community from an early age.

When a child is born with a DSD, gender assignment can be complicated and therefore delayed, leaving parents feeling anxious. Parents are often in a dilemma as to whether or not they should leave their child as they are, whether hormonal therapies would suffice, or if surgeries are necessary.

Atypical genital appearance or even genital ambiguity does not usually present a medical concern, and the main issue is societal acceptance of differences. In the past, medical professionals often advised parents to make a decision on their baby’s sex, and surgery would then be performed as early as possible to remove the undesired set of reproductive organs in what was then termed “corrective surgeries”. Unfortunately, these interventions have sometimes resulted in considerable trauma to affected individuals later in life.

In Australia today, a child born with a DSD will be examined by an experienced multidisciplinary team, ideally comprising paediatric endocrinologists, surgeons, urologists, psychologists or psychiatrists, gynaecologists, neonatologists, geneticists, social workers, nurses and medical ethics specialists. The team ensures that a comprehensive medical consultation is made, and that parents are fully informed and involved in decision-making with regard to gender assignment.

Normally the chromosomal constitution of the individual is determined first. This is followed by measurements of levels of hormones and other male or female markers, genetic diagnosis and pelvic ultrasound or magnetic resonance imaging. Issues taken into consideration when managing a child with DSD include genital appearance, genetic diagnosis, options for hormonal therapies or surgery, and future fertility.

Several treatment options are available for the management of DSDs. Hormone replacement therapy allows puberty to proceed as it would for a typical boy or girl. Genital surgery may be recommended for improved function of the genitals, while removal of the gonads may be necessary where the risk of cancer is high. However, any surgical intervention on infants or in early childhood is strongly challenged due to the lack of informed patient consent, the inability to predict the future gender identity of the child (i.e. whether the child self-identifies as a boy or a girl) and the irreversible changes induced by the surgery. As a result, some parents may opt to postpone any medical intervention until their child is old enough to decide their sex for themselves.

The decision-making around genital surgery on newborns is currently being debated. Senator Rachel Siewert (Chair of the Senate Community Affairs References Committee) has recently commissioned a Senate Committee report entitled “Involuntary or coerced sterilisation of intersex people in Australia” (the term “intersex” refers to DSDs). The committee has recommended that “all proposed intersex medical interventions for children and adults without the capacity to consent require authorisation from a civil and administrative tribunal or the Family Court”. An alternative viewpoint exists that the multidisciplinary team brings expertise to help parents make decisions regarding the welfare of their children, as with any other medical condition affecting infants.

It is both unfeasible and expensive to manage all DSD cases in the population through the court system. It would be fitting for the Family Court, however, to be involved in those circumstances where decisions cannot be agreed upon between the multidisciplinary team and families involved.

Many individuals with DSD do not identify both physically and psychologically with any one particular sex. The legal recognition of a non-specific sex category for use in Australian passports (2011) and the Register of Births, Deaths and Marriages (2014) is a major milestone in the acceptance of people with DSDs who choose not to conform to either male or female sexes. Similar laws are already in place in India, Nepal, Bangladesh, New Zealand and Germany.

While the recognition of a non-specific sex solves some issues with regard to satisfying the gender identity of people with DSDs and increasing their acceptance in community, other issues still need to be addressed. For example, questions remain on the legality of marriage between males or females and a person of indeterminate sex, since current laws define marriage as a union between a man and a woman.

In circumstances where gender is used as a basis for grouping people, such as in sports, the position of an individual with a non-specific sex still remains unclear. However, agencies such as the International Olympic Committee have agreed that individuals with DSDs have every right to participate provided their condition is managed by a medical team.

Ultimately, improvement of the lives of people with DSDs relies heavily on the availability of information on what exactly DSDs are, how they manifest, how they are diagnosed and clinically managed, the medical consequences and available therapies. Efforts to provide information and resources to people with DSDs and their families have been facilitated by the exchange of information between DSD clinicians and scientists investigating the genetic causes of DSDs (e.g., developed by our laboratories). Virtual research networks and web-based DSD registries storing patient data have been developed in Europe, the USA and Australia.

Further research into the genetic causes of DSDs will ensure that DSD diagnosis will be considerably improved. The more information disseminated to people with DSDs, their families and society, the more likely that affected individuals will better understand their condition, make more informed decisions with regard to its management, and gain a wider acceptance in the community.