Research

Identification of genes involved in the development of the brain and face.

Craniosynostosis is a rare congenital condition, arising in 1:2100-2500 births. It is characterized by the premature fusion of cranial sutures. This fusion restrics normal growth of the skull, brain, and face and therefore needs surgical correction within the first year of life.

 

This challenging and complex condition can occur as part of a syndrome or in isolation. Increased knowledge about the structure and function of the human genome has enabled the discovery of the molecular etiologies of most forms of syndromic craniosynostosis. This in turn has led to novel insights in normal and abnormal sutural biology from the atomic to the population-based level. In parallel with the increase in basic biological understanding, advances in clinical diagnosis and treatment have been achieved including improved prenatal imaging technology and craniofacial surgical techniques at the Erasmus MC-Sophia Children's Hospital.

Because of the fusion, bone growth can occur strictly parallel to the affected suture in stead of perpendicular to the suture. The resulting growth pattern provided the necessary space for the growing brain, but results in an abnormal head shape and sometimes abnormal facial features.


Depending on what sutures close premanturely a typical shape of the head is presented:


Scaphocephaly is an early fusion of the sagittal suture. This suture runs front to back, down the middle of the top of the head. This fusion causes a long, narrow skull. The skull is long from front to back and narrow from ear to ear.

 

Plagiocephaly occurs in approximately one out of every 2,500 births. It involves fusion of either the right or left side of the coronal suture that runs from ear to ear. This is called coronal synostosis and it causes the normal forehead and brow to stop growing. Therefore, it produces a flattening of the forehead and the brow on the affected side, with the forehead tending to be excessively prominent on the opposite side. The eye on the affected side may also have a different shape. There may also be flattening of the back area (occipital).  Unilateral lambdoidal suture synostosis may cause plagiocephaly. Positional plagiocephaly is the most common cause of plagiocephaly. This is not caused by unilateral synostosis, but rather by sleeping in one position. The part of the skull that is dependent (in one position) tends to flatten out. Usually no intervention is needed.   

 

Trigonocephaly is a fusion of the metopic (forehead) suture. This suture runs from the top of the head down the middle of the forehead, toward the nose. Early closure of this suture may result in a prominent ridge running down the forehead. Sometimes, the forehead looks quite pointed, like a triangle, with closely placed eyes (hypotelorism).  

 

Besides an abnormal appearance severe functional problems can occur. As a result of the impaired growth of the skull for example, the intracranial pressure can be elevated. This can lead to:

- Impaired vision

- Intelligence loss

- Headaches

- Epilepsy

In addition, behavioural disorders such as ADHD and autism are more frequently seen in patients with craniosynostosis.


Treatment

At the Sophia Children’s hospital craniosynostosis is treated by a multidisciplinary team. 

Surgical intervention is performed in a combined approach of plastic surgeon and neurosurgeon. This surgery corrects the abnormal skull shape and in most cases prevents elevation of intracranial pressure. It does not however decrease the incidence of behavioural disorders.

The consequences of craniosynostosis are however not purely medical. Craniosynostosis results in an abnormal shape of the skull and although surgically corrected the external appearance may remain slighty abnormal. This has an effect on the social interaction of patients diagnosed with craniosynostosis. The emotional consequences of craniosynostosis should not be taken lightly. Therefore close collaboration with psychologists and social workers exists.

Furthermore the maxillofacial surgeon and orthodontists are involved for jaw and dental problems. Since many (syndromal) craniosynostosis patients suffer from relapsing ear infections and hearing deficits, the ENT-surgeon is also involved. The ophthalmologists are involved for measuring vision and papilledema (which is seen in increased intracranial pressure).


Patients who are thought to be syndromal but don’t have an identified mutation are defined as complex craniosynostosis patients. Next generation sequencing technology can be applied to study the underlying molecular etiology in these patients. With this technique the complete DNA sequence (exons and introns) can be determined with only a small amount of DNA of the patient. This technique is expected to bring new insights in a variety of hereditary diseases, one of which is craniosynostosis.


Erasmus MC - Sophia Children’s Hospital is the major craniofacial centre in the Netherlands and therefore has a large database of craniosynostosis patients available. This database is considered to be one of the largest patient databases of craniosynostosis in Europe. 

According to the standard protocol, every craniosynostosis patient is tested by conventional DNA diagnostic tests by the Department of Clinial Genetics. In most cases this does not bring forward a genetic cause. This implies the role of a genetic cause which is not yet known.

These patients are found eligible for whole genome sequencing.

The department of Bioinformatics, under supervision of Prof. Dr. P. van der Spek, has a large database of healthy controls available. Comparison of these controls with the DNA of the craniosynostosis patients is expected to provide further insights in the genetic cause of craniosynostosis.


Future treatment options

When the causative genetic factor is not known counseling of patients with craniosynostosis or facial clefts and their parents is difficult. In these cases no statements can be placed about heredity and the probability of repetition in other pregnancies. A more detailed understanding of phenotype-genotype correlation can improve screening on associated defects and therefore offers better therapy and function. With an improved understanding of the genetic causes of craniosynostosis hopefully other treatment options become possible in the future. In vivo animal studies have already provided promising targets in designing genetic and pharmacological strategies for systemic or adjuvant nonsurgical treatment.

 

Dr. Molewaterplein 50, Suite Ee-1540, 3015 GE Rotterdam. The Netherlands, Europe. Phone: +31 (0)10 70 43 491. Fax: +31 (0)10 70 44 161. E-mail: bioinformatics@erasmusmc.nl