What is Craniosynostosis?

Craniosynostosis is a birth defect in which two or more bones in an infant’s skull fuse together prematurely.

During the early years of a baby’s life, the brain continues to grow in size. To accommodate the developing brain, the surrounding skull bones need to grow as well. That’s why there are gaps between skull bones in small babies. These gaps are gradually filled with time as the skull grows and eventually disappear completely as all the skull bones fuse with each other towards the completion of brain/head growth. The joints between the skull bones are known as ‘sutures’. Craniosynostosis can be classified based on the sutures involved (see figure below).

If the skull bones fuse before they are supposed to, it results in Craniosynostosis. Craniosynostosis is not good for the baby as it may lead to developmental disabilities, vision problems and deformity of the skull.

Figure:

(a) Unaffected individual; (b) metopic craniosynostosis; (c) bicoronal craniosynostosis (top), right unicoronal craniosynostosis (center), and left unicoronal craniosynostosis (bottom); (d) sagittal craniosynostosis; (e) bilateral lambdoid craniosynostosis (top), right unilateral lambdoid craniosynostosis (center), and left unilateral lambdoid craniosynostosis (bottom). Courtesy: Flaherty et al (2016)

Craniosynostosis (CS) is a common malformation affecting in ~4 per 10,000 live births, causing long-term complications for normal brain and skull growth. Most often, craniosynostosis appears as an isolated anomaly or ‘nonsyndromic craniosynostosis’ (NSC). Unilateral or bilateral fusion of the coronal suture accounts for 20–30% of all NSC cases.

The cause of coronal nonsyndromic craniosynostosis is not well understood, although the published literature suggests that it is a multi-factorial condition. About 5–14% of coronal craniosynostosis patients have a positive family history, with a specific genetic etiology identified in >25% of cNSC cases – the largest proportion among any NSC cases. Yet, the other causes for NSC and its phenotypic heterogeneity remain largely unknown.

In the first and only genome-wide association study (GWAS) of nonsyndromic craniosynostosis our group identified two regions, downstream of BMP2 and within BBS9, associated with a 4-5 fold increased risk of sagittal NSC. While both BMP2 and BBS9 are genes with a role in skeletal development, only the BMP2 locus was borderline significant in coronal cases, suggesting that synostosis of each suture represents a different disease caused by different sets of genes. Nature Genetics (2012). https://www.nature.com/articles/ng.2463

Recently, our group identified 5 novel pathogenic mutations, including three de novo mutations (i.e. not observed in the parents of the affected patient), in patients with nonsyndromic craniosynostosis. The results were published in Pediatric Research (2019). https://www.nature.com/articles/s41390-019-0274-2

Additional Resources:

Facts about Craniosynostosis by Centers for Disease Control and prevention (CDC)
Craniosynostosis by National Institutes of Health (NIH) Genetics and Rare Diseases