A new genetic cause for intersex

A study led by the Hudson Institute of Medical Research has discovered a new genetic condition that contributes to our understanding of why some people are born intersex — ie, with reproductive organs, sexual anatomy or chromosome patterns that do not fit the typical definition of male (XY) or female (XX).

Hudson sex genetics experts Professor Vincent Harley and Dr Stefan Bagheri-Fam, along with an international research team, discovered a rare genetic intersex disorder called craniosynostosis with sex reversal (CSR). Their study, published in the journal Human Molecular Genetics, shows how a mutated form of the FGFR2 gene, already known to cause craniosynostosis (where the joints between the bones of a baby’s skull close before it is fully formed), can also cause XY sex reversal.

“The umbrella term ‘intersex’ has many genetic causes, the majority of which go undiagnosed,” Professor Harley noted. In fact, only 30% of people with intersex conditions are diagnosed with a specific genetic cause or disorder.

“Our team has identified how a mutation in the FGFR2 gene can concurrently cause craniosynostosis and XY sex reversal, and, as a result, we have identified a new syndrome called CSR.”

Researchers analysed the genetic data from a patient who, as a teenager, was diagnosed with the form of intersex called XY gonadal dysgenesis. While chromosomally XY, the patient presented as a woman with external female genitalia. Internally, the sexual organs (gonads) had failed to develop into either testes or ovaries.

Genetic sequencing by paediatrician Dr Makoto Ono revealed that the patient carried the mutated FGFR2 gene, already a known cause of craniosynostosis. Dr Bagheri-Fam and a team of Yale University researchers subsequently went on to study mice with a very similar mutation.

Of the 16 mice, one displayed complete sex reversal (where gonads shrink to resemble ovaries and the testes cords can’t be identified). The 15 remaining mice showed signs of mild sex reversal, suggesting people who carry the mutated FGFR2 gene could have testicular defects developed in utero that are mild and therefore go undiagnosed.

In addition to sex reversal, the presence of additional symptoms not typical of existing craniosynostosis syndromes (such as elbow and knee contractures and short stature) led the scientists to designate a new syndrome, CSR. Professor Harley hopes his team’s identification of a new, rare syndrome will lead to earlier diagnosis, better treatment and decreased stress for the 1–2% of the population who are intersex.

“By identifying the genetic causes, clinicians are better equipped to precisely treat and manage the health risks and conditions associated with specific genetic intersex conditions,” Professor Harley said. Such conditions include psychological trauma, infertility, lifelong endocrine care and multiple surgeries.

Furthermore, the team’s work opens up a whole new range of candidate intersex genes in the FGFR2 pathway that could be incorporated into future genetic analysis aimed at intersex diagnosis. According to Professor Harley, “The challenge now is to continue our specialised research to give hope to other sections of the intersex community.”