Studies identify two new genetic causes of rare childhood bone condition

Researchers in Oxford have discovered two new genetic causes of craniosynostosis – a rare bone condition that can inhibit brain growth in children.

The work will give affected families much greater understanding of the condition and inform individual treatment plans for patients.

Andrew Wilkie, Nuffield Professor of Pathology at Oxford University and honorary consultant at Oxford University Hospitals NHS Trust, led the two studies published online today in the journal 'Nature Genetics'.

The studies were based on genetic data from more than 400 families treated at the specialist Craniofacial Unit at Oxford's John Radcliffe Hospital over a 20-year period. Every gene in the family members' DNA was sequenced in full at Oxford University, allowing the two new genetic causes of craniosynostosis to be identified.

About 1 in 2,200 children is born with craniosynostosis, a condition where the sutures between the bony plates of the skull fuse together early, before the skull has finished growing, leading to an abnormally shaped head. In some cases, the fusing of the sutures does not leave enough space for the growing brain. This can increase pressure inside the skull, and can also cause hearing, vision and breathing difficulties.

About 21 per cent of craniosynostosis cases have a genetic diagnosis. The identification of two new genes that are linked to the disorder takes that to about 24 per cent. Mutations in the two new genes are believed to account for 1 to 2 per cent of craniosynostosis cases each.

Professor Wilkie said he believed that, in total, about 30 per cent of cases had a genetic cause, with the remaining 70 per cent partly attributable to physical events during pregnancy.

Instances of craniosynostosis with a genetic cause carry a risk of being inherited and, in most cases, are more severe forms of the disorder.

Identifying a genetic cause, and then grouping together patients with the same underlying condition, allows medical staff to identify specific characteristics in each case. It gives individual families a greater understanding of the condition and allows the treating consultants to be alert to potential future issues for a patient.

The new research identified a gene called ERF that was mutated in some cases of craniosynostosis and had not previously been linked to the disorder. The team found that in these cases, complications became apparent at around age four or five – this is much later in childhood than the majority of craniosynostosis conditions, which are apparent at, or shortly after, birth. Complications associated with mutations in the ERF gene then quickly become more serious if the condition is not recognised and treated.

Another gene, TCF12, was also found to be mutated in some cases of craniosynostosis. Patients with these mutations presented with complications almost immediately after birth and required surgery. However, these complications tailed off and most patients have a good long-term prognosis.

Professor Wilkie said: "If consultants know the underlying genetic cause then they know what to look out for and they have a case management plan that is alert to the possible complications.

"It is about being fully aware of the condition, the characteristics, the cause and risks including the risk of it being inherited."

Professor Wilkie, who in 1995 was the first to characterise Apert syndrome, one of the most severe craniosynostosis conditions, said the collaboration of Oxford University researchers and NHS medical professionals ensured Oxford remained a world-leading centre for research and treatment of the condition.

Professor Wilkie said: "There is a very close working relationship between surgeons, geneticists and the rest of the craniofacial team based at Oxford's John Radcliffe Hospital. This is only possible within the NHS.

"It is made possible by harnessing those strengths along with recent advances in genetics that allow us to sequence far more genes, more quickly.

"In the past couple of years, our team has discovered four new genetic types of craniosynostosis, and through ongoing research we are working on a further three.

"To put that in context, it is about equal to what the entire world effort has been able to describe in the past 20 years.”

The Craniofacial Unit at the John Radcliffe Hospital is one of four UK centres of excellence for the condition. The team worked in collaboration with colleagues at the other centres and the findings will be made available to all.

The study was supported by the Wellcome Trust, with additional funding from the National Institute for Health Research Oxford Biomedical Research Centre, a collaboration between the Oxford University Hospitals NHS Trust and Oxford University.