6.5 to 8% of patients with apert's syndrome, 25.6% in patients with crouzon's syndrome and 27.8% of those with pfeifer's syndrome. ventriculomegaly is a usual finding in children with the apert syndrome. neurobehavioural impairment neurobehavioural impairment includes problems with attention and planning, processing speed, visual spatial skills, language, reading and spelling. a decreased iq may also be part of the problems. it has been suggested that these problems are caused by a primary malformation of the brain, rather than being a consequence of the growth restriction of the skull and elevated intracranial pressure. some evidence for this statement has been provided by studies using computed tomographic (ct) scans and magnetic resonance imaging (mri) to identify differences between the structures of the brains of healthy children and those affected with craniosynostosis. it has been found that corrective surgery of the cranial vault alters the morphology of the brain compared with the situation before surgical intervention. however the structure was still abnormal in comparison to children without craniosynostosis. causes advances in the fields of molecular biology and genetics, as well as the use of animal models have been of great importance in expanding our knowledge of suture fusion. research in animal models has led to the idea that the dura mater plays an important role in determining closure or patency of the suture. in contrast to the dura mater it appears that the periosteum is not essential in causing closure or patency. gene expression pattern during cranial suture fusion instead of describing the abnormalities in structure and form, research focuses nowadays at decoding the molecular interactions that underlie them. based on data from quantitative real-time pcr on samples of suture junctions during development, cranial suture fusion in mammals is a tightly orchestrated expression of genes in specific temporal order, leading to endochondral ossification. despite the progress that has been made, many things are still not understood about the suture biology and the exact causative pathways remain yet to be completely understood. multiple potential causes of premature suture closure have been identified, such as the several genetic mutations that are associated with syndromic craniosynostosis. the cause of nonsyndromic craniosynostosis however, is still greatly unknown. most likely, a role is played by biomechanical factors, as well as environmental, hormonal and genetical factors. new insights have given fuel to a debate whether there might be an intrinsic factor causing the premature fusion of the sutures. brain structures of children with craniosynostosis were evaluated using magnetic resonance imaging. differences were seen compared with the brain structures of normal children. the question now is whether these differences are caused by the craniosynostosis, or are the cause of craniosynostosis. biomechanical factors biomechanical factors include fetal head constraint during pregnancy. it has been found by jacob et al. that constraint inside the womb is associated with decreased expression of indian hedgehog protein and noggin. these last two are both important factors influencing bone development. environmental factors environmental factors refer for example to maternal smoking and the maternal exposure to amine-containing drugs. several research groups have found evidence that these environmental factors are responsible for an increase in the risk of craniosynostosis, likely through effects on fibroblast growth factor receptor genes. on the other hand, a recent evaluation of valproic acid (an anti-epilepticum), which has been implicated as a causative agent, has shown no association with craniosynostosis. certain medication (like amine-containing drugs) can increase the risk of craniosynostosis when taken during pregnancy, these are so-called teratogenic factors. hormonal factors hyperthyroid induced craniosynostosis is a hormone mediated premature closure. it is thought that the bone matures faster due to high levels of thyroid hormone. genetic factors in 6 to 11% of the children born with coronal synostosis, more often involving the bilateral cases than unilateral, other members of the family have been reported that were also born with the same condition. this finding is highly suggestive of a genetic cause, which has possibly been found in the fibroblast growth factor receptor 3 (fgfr3) and twist genes. fibroblast growth factor and fibroblast growth factor receptors regulate fetal bone growth and are expressed in cranial sutures during pregnancy. the transcription factor gene twist is thought to decrease the function of fgfr, thus also indirectly regulating fetal bone growth. a relation between the mutations in these genes and craniosynostosis is therefore possible. moloney et al. observed a fgfr3 mutation in as many as 31% of the cases with nonsyndromic coronal synostosis, thus showing that fgfr abnormalities play an important role in nonsyndromic craniosynostosis. in terms of syndromic craniosynostosis not only do fgfr3 and twist genes feature, but also fgfr1 and in particular fgfr2, which has been reported in 90% of the syndromic craniosynostoses such as apert, crouzon, peiffer and jackson–weiss. the mutations can be divided into mutations that lead to gain of function (in fgfr genes) and mutations that lead to loss of function (in twist genes). craniosynostosis is therefore likely the result of a disturbance in the fine balance that regulates the multiplication and maturation of the precursor bone cells in the cranial sutures. the familial rate, which is different for nonsyndromic and syndromic cases, provides an important clue. in the nonsyndromic cases, a positive family history is found in 2% of the cases with sagittal suture closure and in 6% to 11% of the cases with coronal suture closure. cranial sutures fontanelles and sutures as seen from above and to the left of the cranium of a child. the mesenchyme above the meninges undergoes intramembranous ossification forming the neurocranium. the neurocranium consists of several bones, which are united and at the same time separated by fibrous sutures. this allows movement of the separate bones in relation to one another; the infant skull is still malleable. the fibrous sutures specifically allow the deformation of the skull during birth and absorb mechanical forces during childhood they also allow the necessary expansion during brain growth. in the very first years of life the sutures serve as the most important centers of growth in the skull. the growth of the brain and the patency of the sutures depend on each other. brain growth pushes the two sides of the patent sutures away from each other, thereby enabling growth of the neurocranium. this means that the neurocranium can only grow if the sutures remain open. the neurocranium will not grow when the forces induced by brain growth are not there. this will occur for example when the intracranial pressure drops; the sutures do not experience stretching anymore causing them to fuse. diagnosis the evaluation of a child suspected to have craniosynostosis is preferentially performed in a craniofacial center. the three main elements of analysis include medical history, physical examination and radiographic analysis. medical history should in any case include questions about risk factors during pregnancy, the familial rate and the presence of symptoms of elevated intracranial pressure (icp). elevated icp symptoms of increased intracranial pressure – such as headache and vomiting – should be questioned after. an elevation of icp can be present in 4 to 20% of the children where only a single suture is affected. the incidence of icp in children with more than one suture involved can be as high as 62%. however, even though the children are affected, symptoms are not always present. physical examination fundoscopy should always be performed in children with craniosynostosis. it is used to find papilledema which is sometimes the only symptom of elevated intracranial pressure shown in these children. other parts of the physical examination include the measurement of the head circumference, the assessment of the skull deformity and the search for deformities affecting other parts of the body. the head circumference and the growth curve of the head provide important clues into making a differentiation between craniosynostosis, primary microcephaly and hydrocephalus. this differentiation has an important influence on the further treatment of the child. in a recent article cunningham et al. described several steps in which a pediatrician should observe the patient to assess skull deformity: the first is looking with a bird's eye view at the patient while the patient preferably faces the parent while sitting on the parent's lap. the goal is to assess the shape of the forehead, the skull length, the width of the skull, position of the ears and the symmetry of the frontal bones and . the second is looking at the patient from behind while preferably the child is in the same position as described above. it is important to look at the skull base (to determine whether it is level or not), the position of the ears and to the mastoid (to spot the possible presence of a bulge). the third point of view is the frontal view. the points to look at are: eye position, eye symmetry and twisting of the nasal tip. the implications of the deformities that are seen are extensively discussed under 'phenotype'. syndromal craniosynostosis presents with a skull deformity as well as deformities affecting other parts of the body. clinical examination should in any case include evaluation of the neck, spine, digits and toes. medical imaging radiographic analysis by performing a computed axial tomographic scan is the gold standard for diagnosing craniosynostosis. plain radiography of the skull may be sufficient for diagnosing a single suture craniosynostosis and should therefore be performed, but the diagnostic value is outweighed by that of the ct-scan. not only can the sutures be identified more accurately, thus objectively demonstrating a fused suture, but also evaluation of the brain for structural abnormalities and excluding other causes of asymmetric growth are possible at the same time. in addition to this, ct-scanning can visualize the extent of skull deformity, thereby enabling the surgeon to start planning surgical reconstruction. classification there are several ways to classify craniosynostosis. for example, one can consider the number of closed sutures. if only one of the four sutures is prematurely closed (single suture craniosynostosis), the craniosynostosis is referred to as 'simple' (or 'isolated'). whereas when two or more sutures are no longer open, the craniosynostosis is 'complex'. a second classification scheme gives a clinical description of the resulting shape of the skull. this will be further discussed under phenotype. a third classification involves the presence or absence of an identified craniofacial syndrome. craniosynostosis where no extracranial deformations are present, is called non-syndromic or 'isolated' craniosynostosis. when there are extracranial deformations present, for instance involving the limbs, heart, central nervous system or the respiratory tract, you may speak of a syndromic form of craniosynostosis. more than 180 identified syndromes show deformations due to craniosynostosis. the following syndromes are associated with fibroblast growth factor receptors: name of syndrome other signs and symptoms (along with craniosynostosis; may not all be present) omim reference gene crouzon syndrome wide-set, bulging eyes • beaked nose • flat face 123500 fgfr2, fgfr3 apert syndrome fused fingers or toes • flat midface 101200 fgfr2 crouzonodermoskeletal syndrome wide-set, bulging eyes • beaked nose • flat face • dark, velvety skin folds • spine abnormalities • benign growths in the jaw 134934 fgfr3 jackson–weiss syndrome enlarged, bent big toes • flat midface 123150 fgfr1, fgfr2 muenke syndrome coronal synostosis • skeletal abnormalities of the hands or feet • hearing loss 602849 fgfr3 pfeiffer syndrome broad, short thumbs or big toes • webbed or fused fingers or toes 101600 fgfr1, fgfr2 in addition, the following syndromes have been identified: name of syndrome other signs and symptoms (along with craniosynostosis; may not all be present) omim reference gene loeys–dietz syndrome wide-set eyes • split uvula or cleft palate • arterial tortuosity • aortic root dilatation • aneurysms 609192 610168 613795 608967 610380 tgfbr1, tgfbr2, smad3 saethre–chotzen syndrome facial asymmetry • low frontal hairline • drooping eyelids • webbed fingers or toes • broad big toes 101400 twist1 shprintzen–goldberg syndrome bulging eyes • flat face • hernias • long, thin fingers • developmental delay • intellectual disability 182212 fbn1 deformational plagiocephaly the main difference between plagiocephaly based on craniosynostosis and deformational plagiocephaly is that there is no suture fusion in the latter one. the malleability of the neonatal skull allows the skull to change shape due to extrinsic forces. with the tests a pediatrician should perform, as explained above, the difference is quite easy to make. in deformational plagiocephaly the skull does not show a bulging of the