The findings will be published in the open access journal BMC Developmental Biology to coincide with Rare Diseases Day on the 28th February.
Skull formation is normally a complex interplay of different signals from various tissues. Babies are born with sutures – gaps in the skull, which close up later on in development, allowing the skull to adapt to the rate of growth. In babies with Apert syndrome, mutations in a gene cause the fusion of those sutures to happen early, resulting in problems with the overall shape of the skull.
Nearly all (99%) of all cases of Apert Syndrome are caused by two key mutations in the same gene. Although both mutations are associated with skull defects, more severe facial malformations are seen with people carrying one of the mutations, whilst the other is associated with more severe malformations in the limbs of patients. These were the two mutations that the scientists looked at in mice. They took images of the skulls of mice with these mutations at stages throughout their development, both prenatally and on the day of birth, and characterized the growth patterns (links to images available below).
Professor Joan Richtsmeier, from Pennsylvania State University, says: “It would be difficult, actually impossible, to observe and score the exact processes and timing of abnormal suture closure in humans as the disease is usually diagnosed after suture closure has occurred. With these mice, we can do this at the anatomical level by visualizing the sutures prenatally using micro-computed tomography (3D x-rays) or at the mechanistic level by using immunohistochemistry, or other approaches to see what the cells are doing as the sutures close.”
They show that the skulls of mice with Apert syndrome mutations show unusual growth patterns while still in the womb. The two mutations caused distinct growth patterns, which continued following birth, and were consistent across samples of mice carrying those genetic mutations. This means that in addition to the mutation changing the size and or shape of cranial bones, persistent effects of the mutation change the growth pattern, pushing cranial morphology further and further from typical shapes. They hope that this knowledge could inform research in humans with the disease, and lead to better, more tailored treatment, by diagnosing it at the early stages, and adapting treatment to a child’s particular genetic profile.
Professor Richtsmeier says: “Currently, the only option for people with Apert syndrome is rather significant reconstructive surgery, sometimes successive planned surgeries that occur throughout infancy and childhood, and into adulthood. These surgeries are necessary to restore function to some cranial structures and to provide a more typical morphology for some of the cranial features. But, if what we found in mice is analogous to the processes at work in humans with Apert syndrome, then we need to decide whether or not a surgical approach that we know is necessary, is also sufficient. If it is not in at least in some cases, then we need to be working towards therapies that can replace or further improve surgical outcomes.”
Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice, Susan M Motch Perrine, Theodore M Cole III, Neus Martínez-Abadías, Kristina Aldridge, Ethylin W Jabs and Joan T Richtsmeier, BMC Developmental Biology