Craniosynostosis

Craniosynostosis
Classification and external resources
Child with premature closure (craniosynostosis) of the lambdoid suture. Notice the swelling on the right side of the head
ICD-10	Q75.0
ICD-9	756.0
OMIM	218500
DiseasesDB	3160
eMedicine	med/2897
MeSH	D003398

Craniosynostosis (from cranio, cranium; + syn, together; + ostosis relating to bone) is a condition in which one or more of the fibrous sutures in an infant skull prematurely fuses by ossification,^[1] thereby changing the growth pattern of the skull.^[2] Because the skull cannot expand perpendicular to the fused suture, it compensates by growing more in the direction parallel to the closed sutures.^[2] Sometimes the resulting growth pattern provides the necessary space for the growing brain, but results in an abnormal head shape and abnormal facial features.^[2] In cases in which the compensation does not effectively provide enough space for the growing brain, craniosynostosis results in increased intracranial pressure leading possibly to visual impairment, sleeping impairment, eating difficulties, or an impairment of mental development combined with a significant reduction in IQ.^[3]

Craniosynostosis occurs one in 2000 births. Craniosynostosis is part of a syndrome in 15 to 40% of the patients, but it usually occurs as an isolated condition.^[4][5] It is important that families seek out the opinion of a Pediatric Craniofacial Physician who has experience with craniosynostosis for proper diagnosis, surgical care, and followup.

An overview of the cranial sutures

The sutures

The mesenchyme above the meninges undergoes intramembranous ossification forming the neurocranium.^[2] The neurocranium consists of several bones, which are united and at the same time separated by fibrous sutures.^[2] This allows movement of the separate bones in relation to one another; the infant skull is still malleable.^[2] The fibrous sutures specifically allow the deformation of the skull during birth^[2] and absorb mechanical forces during childhood^[5] They also allow the necessary expansion during brain growth.^[2]

In the first years of life the sutures serve as the most important centers of growth in the skull.^[2] The growth of the brain and the patency of the sutures depend on each other.^[6] Brain growth pushes the two sides of the patent sutures away from each other, thereby enabling growth of the neurocranium.^[6] This means that the neurocranium can only grow if the sutures remain open.^[6] The neurocranium will not grow when the forces induced by brain growth are not there.^[7] This will occur for example when the intracranial pressure drops; the sutures do not experience stretch anymore causing them to fuse.^[8]

The infant's skull consists of the metopic suture, coronal sutures, sagittal suture, and lambdoid sutures.^[2] The metopic suture is supposed to close between three to nine months of age.^[7] The lambdoid, sagittal and coronal sutures are supposed to close between 22 to 39 years of age.^[7]

Epidemiology

It is estimated that craniosynostosis affects 1 in 2,000 to 2,500 live births worldwide.^[2] Sagittal synostosis is the most common phenotype, representing 40 to 55% of nonsyndromic cases.^[2] The second most common type is the coronal synostosis representing 20 to 25%.^[2] The metopic synostosis comes third with 5 to 15% and the lambdoid synostosis is only seen in 0 to 5% of nonsyndromic cases.^[2]

In about 5 to 15% more than one suture is affected, which referred to as complex craniosynostosis. This is generally part of a syndrome.^[2]

An overview of causes of premature fusion

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.^[2] 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.^[2] In contrast to the dura mater it appears that the periosteum is not essential in causing closure or patency.^[2]

Instead of describing the abnormalities in structure and form, research focuses nowadays at decoding the molecular interactions that underlie them.^[2] 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.^[2] The cause of nonsyndromic craniosynostosis however, is still greatly unknown.^[9] Most likely, a role is played by biomechanical factors, as well as environmental, hormonal and genetical factors.^[9]

Biomechanical factors

Biomechanical factors include fetal head constraint during pregnancy.^[10] 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.^[10]

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.^{[11][12][13][14][15]}

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.^[16]

Hormonal factors

Hyperthyroid induced craniosynostosis is a hormone mediated premature closure.^[17] It is thought that the bone matures faster due to high levels of thyroid hormone.^[17]

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.^[18] 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.^[18]

Fibroblast growth factor and fibroblast growth factor receptors regulate fetal bone growth and are expressed in cranial sutures during pregnancy.^[5] The transcription factor gene TWIST is thought to decrease the function of FGFR, thus also indirectly regulating fetal bone growth.^[5] 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.^[19]

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 ^[20][21][22] 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).^[21][22] 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.^[2]

Discussion

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.^[9] Differences were seen compared with the brain structures of normal children.^[9] The question now is whether these differences are caused by the craniosynostosis, or are the cause of craniosynostosis.

An overview of various classifications of craniosynostosis

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’.^[5]

• 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.^[5] When there are extracranial deformations present, for instance involving the limbs, heart, central nervous system or the respiratory tract,^[7] you may speak of a syndromic form of craniosynostosis. More than 180 identified syndromes show deformations due to craniosynostosis.^[5] 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 • mental retardation	182212	FBN1

Phenotype

Children born with craniosynostosis have a distinct appearance, otherwise known as the phenotype. The features of the phenotype are determined by which particular suture is closed.^[23] The fusion of this suture causes a certain change in the shape of the skull; a deformity of the skull.^[23]

Virchow’s law dictates that, when premature suture closure occurs, growth of the skull is typically restricted perpendicular to the fused suture and enhanced in a plane parallel to it, thus trying to provide space for the fast growing brain.^[24] Using this law, the pattern of skull deformity in craniosynostosis can often be predicted.^[24]

File:Scaphocephaly frontal and side view.png

Scaphocephaly frontal and side view ^{[25] [26]}

Scaphocephaly

An illustrative example of this phenomenon is scaphocephaly; the name providing a direct hint regarding the deformity of the skull. The literal meaning of the Greek derived word ‘scaphocephaly’ is boathead. Premature sagittal suture closure restricts growth in a perpendicular plane, thus the head will not grow sideways and remain narrow.^[9][27] This is best seen in a view standing above the child looking downwards at the top of the head.^[7] Compensatory growth occurs forwards at the coronal suture and backwards at the lambdoid suture giving respectively a prominent forehead, called frontal bossing, and a prominent back portion of the head, called coning.^[9][27] When viewed from sideways the resulting shape of the head will look a bit like a boat.

Trigonocephaly

Trigonocephaly is a result from the premature closure of the metopic suture.^[9][27] Using Virchow’s law again to predict the resulting deformity, this fusion will result in a narrow forehead, which is even further emphasized by ridging of the suture.^[9][27] Compensatory growth occurs at both the coronal sutures, thereby pushing the forehead forwards.^[9][27] The resulting shape can best be assessed from a top view again, which will reveal a somewhat triangular form of the head.^[7] Trigonocephaly is also a Greek derived word, which can be translated as triangular shaped head. A facial feature of metopic synostosis is hypotelorism; in the frontal view, it can be seen that the width between the eyes is smaller than usual.^[27]

Plagiocephaly

The Greek word plagios means skew. Plagiocephaly can be subclassified in Anterior Plagiocephaly and Posterior Plagiocephaly.

Anterior Plagiocephaly

Anterior plagiocephaly is a clinical description of unilateral coronal synostosis.^[9][27] Children born with unilateral coronal synostosis develop due to compensatory mechanisms a skew head; a plagiocephaly.^[9][27]

The sagittal suture ‘divides’ the coronal suture in two halves; unilateral meaning that either the right side or the left side to the sagittal suture is fused. This fact immediately raises an important point. Unlike closure of the sagittal or the metopic suture, right and left are not the same in unilateral coronal synostosis.^[9][27] This asymmetry shows in the skull deformity, as well as in the facial deformity and the complications.^[9][27]

This time, the skull deformity can only partly be predicted using Virchow’s law. Growth is arrested in the plane perpendicular to the fused suture and the forehead is flattened, but only at the ipsilateral side of the head.^[9][27] Ipsilateral indicates the same side of the head as where the suture is closed. Compensatory growth occurs in a parallel plane, as well as in a perpendicular plane.^[9][27] An increase in growth at the metopic and the sagittal suture accounts for the parallel plane and will result in bulging at the temporal fossa and an increase in width of the skull.^[9][27] Compensatory growth in the perpendicular plane occurs on the side of the head with the patent coronal suture, the contralateral side.^[9][27] Half of the forehead will bulge forwards as a result.

Assessment of the skull from a top view shows asymmetry of the frontal bones, an increased width of the skull and a forward displacement of the ear at the ipsilateral side of the head.^[7] Assessment of the skull from a frontal view will show asymmetrical features of the face, including a displacement of the chin point of the jaw and a deviation of the tip of the nose.^[9][27] The chin point is located more to the contralateral side of the head, due to the ipsilateral forward displacement of the temporomandibular joint together with the ear.^[9][27] The tip of the nose will also point towards the contralateral side.^[9][27] Complications based on the skull deformation include malocclusion of the jaw and in as many as 90% - a subtle form of - strabismus, the last being caused by the asymmetrical placement of the orbits.^[27]

Posterior Plagiocephaly

Unilateral lambdoid synostosis is also called posterior plagiocephaly, indicating that this gives, just like unilateral coronal synostosis, a ‘skew head’. The difference is that this time, the deformity mostly shows at the occiput.

Remembering Virchow’s law, restriction of growth will occur at the ipsilateral side of the head; compensatory growth will occur at the contralateral side of the head. This growth pattern exerts an effect at the base of the skull, which is not even when the child is assessed from a point of view standing behind the child, as well as on the cervical spine, which shows a curvature.^[28] In addition, an asymmetry of the ears can be seen, with the ear on the ipsilateral side placed further to the back. Also, again from a point of view standing behind the child, a bulging of the mastoid can be seen.^[28] Minimal forehead asymmetries are typically seen.^[27]

Brachycephaly

Brachycephaly, or a ‘short head’, is the result of a closure of both the coronal sutures.^[27] Following Virchow’s law, this will result in a child’s head with a restriction of growth in the forward direction and in the backward direction; recessed frontal bones and a flattened occiput.^[27] Compensatory growth will occur sideways, due to the sagittal suture, and upwards, due to the lambdoid sutures.^[27]

Pansynostosis

The word pansynostosis is also Greek derived and can be translated as ‘all one bone’, indicating that all of the sutures are closed.^[29] In general practice, the term is used to describe the children with three or more sutures closed.^[29]

Pansynostosis can present in several ways. The appearance can be the same as that seen with primary microcephaly: a markedly small head, but with normal proportions.^[8] However, pansynostosis can also appear as a Kleeblattschädel (cloverleaf skull), which presents with bulging of the different bones of the cranial vault.^[8]

Diagnosis and preoperative assessment

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

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).

Risk factors during pregnancy

• Certain medication (like amine-containing drugs) can increase the risk of craniosynostosis when taken during pregnancy, these are so called teratogenic factors.^[12][15]

The familial rate

• The familial rate, which is different for nonsyndromic and syndromic cases, provides an important clue.^[30][31] In the nonsyndromic cases, a positive family history is found in 2% of the cases with sagittal suture closure^[30][31] and in 6 to 11% of the cases with coronal suture closure.^[18] In the syndromic cases, approximately 50% of the children may present with a positive family history.^[27]

Symptoms of elevated ICP

• Symptoms of increased intracranial pressure – such as headache and vomiting – should be questioned after.^[32][33] An elevation of ICP can be present in 4 to 20% of the children where only a single suture is affected.^[32][33] The incidence of ICP in children with more than one suture involved can be as high as 62%.^[34] However, even though the children are affected, symptoms are not always present.

Physical examination

Fundoscopy should always be performed in children with craniosynostosis.^[35] It is used to find papilledema which is sometimes the only symptom of elevated intracranial pressure shown in these children.^[35]

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.^[8] The head circumference and the growth curve of the head provide important clues into making a differentiation between craniosynostosis, primary microcephaly and hydrocephalus.^[8] This differentiation has an important influence on the further treatment of the child.^[8]

In a recent article Cunningham et al.^[7] 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 parents 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 [occiput].
• 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.^[6] Clinical examination should in any case include evaluation of the neck, spine, digits and toes.^[6]

Radiographic analysis

Radiographic analysis by performing a computed axial tomographic scan is the gold standard for diagnosing craniosynostosis.^[36][37]

Plain radiography of the skull may be sufficient for diagnosing a single suture craniosynostosis and should therefore be performed,^[36][37] but the diagnostic value is outweighed by that of the CT-scan.^[38] 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.^[38] In addition to this, CT-scanning can visualize the extent of skull deformity, thereby enabling the surgeon to start planning surgical reconstruction.^[39]

Differential Diagnosis

Deformational Plagiocephaly

The main difference between plagiocephaly based on craniosynostosis and deformational plagiocephaly is that there is no suture fusion in the latter one.^[7] The malleability of the neonatal skull allows the skull to change shape due to extrinsic forces.^[7]

With the tests a pediatrician should perform, as explained above, the difference is quite easy to make.^[7] In deformational plagiocephaly the skull does not show a bulging of the mastoid and in these patients the skull base and position of the ears is level, all in contrary with plagiocephaly due to craniosynostosis.^[7] Displacement of one ear to the front is characteristic for deformational plagiocephaly.^[7]

Primary microcephaly

Primary microcephaly shows a clinical image of craniosynostosis, but due to a different cause. The primary failure is the absence of growth of the brain, rendering the sutures of the cranial vault useless.^[8] As a consequence, the sutures close, presenting a pansynostosis like image.^[8] A differentiation between these two conditions can be made with a computed tomography (CT) scan. The subarachnoid spaces are typically enlarged with primary microcephaly, whereas they are reduced or absent in true pansynostosis.^[8]

An overview of presenting symptoms

Not all cranial abnormalities seen in children with craniosynostosis are solely a consequence of the premature fusion of a cranial suture. This is especially true in the cases with syndromic craniosynostosis. Findings include elevation of the intracranial pressure; obstructive sleep apnoea(OSA); abnormalities in the skull base and neurobehavioral impairment.^[27]

Elevated intracranial pressure

When the ICP is elevated the following symptomes may occur: vomiting, visual disturbance, bulging of the anterior fontanel, altered mental status, papilledema and headache.^[40]

The main risks of prolonged elevated intracranial pressure may include cognitive impairment and impaired vision through prolonged papilledema.^[8] These are the main reasons why fundoscopy should be performed during the physical examination of children with craniosynostosis.^[8]

The causes of an elevation of the intracranial pressure are best understood using the Monro-Kellie doctrine.^[41] The Monro-Kellie doctrine reduces the cranial vault to a box with rigid walls.^[41] This box contains three elements: brain, intracranial blood and liquor.^[41] The sum of volumes of these three elements is constant.^[41] An increase in one should cause a decrease in one or both of the remaining two, thereby preventing an elevation of the intracranial pressure.^[41] A compensatory mechanism involves the movement of liquor from the cranial vault towards the spinal cord.^[41] The volume of blood in the cranial vault is auto-regulated by the brain, and will therefore not decrease that easily.^[41]

Intracranial pressure will rise as a result of continued brain growth within the rigid skull.^[8] It appears that in children with craniosynostosis, the expected decrease of intracranial liquor is probably not occurring as it should according to the Monro-Kellie hypothesis.^[32] This is shown when the brain expands in the fixed skull, which gives a faster rise in intracranial pressure than would be expected.^[32]

Obstructive sleep apnoea

The short stops in breathing during the sleep are the mainstay of OSA. Other symptoms can be difficulty in breathing, snoring, day-time sleepiness and perspiration.^[4] The main causative agent of OSA is the [midface hypoplasia], which also poses a risk to the eyes that can be seen bulging out of the eye sockets. Other factors, such as a micrognathism and adenoid hypertrophy, are likely to contribute in causing OSA.^[4] The most common syndromic forms of craniosynostosis; i.e. Apert, Crouzon and Pfeiffer, have an increased risk of developing OSA. The children have nearly 50% chance of developing this condition.^[4]

A theory regarding the involvement of OSA as a causative agent for elevated intracranial pressure suggests an association with the auto-regulation of blood flow in the brain.^[33] Certain cells in the brain respond specifically to an increase of CO2 in the blood.^[3][42] The response involves vasodilatation of the cranial vault blood vessels, increasing the volume of one of the elements in the Monro-Kellie doctrine.^[3][42] The increase of CO2 concentration in the blood is a consequence of impaired breathing, especially seen when the child suffering from OSA is sleeping.^[3][42] It is well documented that the highest spikes in intracranial pressure often occur during sleep.^[3][42]

Abnormalities in the skull base

Impaired venous outflow is often caused by a hypoplastic jugular foramen.^[33] This causes an increase in the intracranial blood volume, thereby causing an increase in intracranial pressure.^[33]

This can be further complicated with a possible Arnold-Chiari malformation, which can partially obstruct the flow of liquor from the neurocranium to the spinal cord.^[5] The Chiari malformation may be asymptomatic or present with ataxia, spasticity or abnormalities in breathing, swallowing or sleeping.^[5]

Due to the impaired venous outflow, which may be further complicated with a Arnold-Chiari malformation, there is often a clinical image of hydrocephalus present. Hydrocephalus is seen in 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.^[43] Ventriculomegaly is a usual finding in children with the Apert syndrome.^[44]

Neurobehavioural impairment

Neurobehavioural impairment includes problems with attention and planning, processing speed, visual spatial skills, language, reading and spelling.^[9] A decreased IQ may also be part of the problems.^[9]

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.^[9] It has been found that corrective surgery of the cranial vault alters the morphology of the brain compared with the situation before surgical intervention.^[9] However the structure was still abnormal in comparison to children without craniosynostosis.^[9]

An overview of the treatment

Goal of surgery

The primary goal in surgical intervention is to allow normal cranial vault development to occur.^[6] This can be achieved by excision of the prematurely fused suture and correction of the associated skull deformities.^[6] If the synostosis goes uncorrected, the deformity will progressively worsen not only threatening the aesthetic aspect, but also the functional aspect.^[6] This is especially the case in the asymmetric conditions, such as unilateral coronal synostosis, with compromised function of the eyes and the jaw.^[6] In addition signs of compromised neurodevelopment have been seen amongst all the synostoses, although this may also be caused by primary maldevelopment of the brain and can thus not be prevented by surgical intervention.^[45]

Timing of surgery

The prevention of the complications mentioned above plays an important role in the discussion about the timing of the surgery. The general consensus is now to perform surgery in early infancy, i.e. between six to twelve months.^[6] In this time frame the efficacy of surgery is enhanced due to several reasons:

• The bone is still more malleable and can be remodelled relatively ‘simple’ by greenstick fractures of the bone.^[6] At approximately one year of age the bone has become more mineralized and brittle and needs to be fastened to the surrounding bone with sutures or an absorbable plate.^[6]
• Reshaping of the cranial vault most commonly means excision of the bones and adjustment of the shape.^[6] Replacement of the bones can leave ‘gaps’ which are readily re-ossified before the age of one year, but need bony filling thereafter.^[6]

The reason why most surgeons will not intervene until after the age of six months is the greater risk that blood loss poses before this age.^[6] If possible it is preferred to wait until after three months of age when the anaesthetic risks are decreased.^[6]

Surgery is not performed in early childhood in every country. In some countries surgical intervention can take place in the late teens.

It is important that families seek out a Pediatric Craniofacial Physician who has experience with craniosynostosis for proper diagnosis, surgical care, and followup.

Basic elements of surgery

There are a few basic elements involved in the surgical intervention aimed at normalization of the cranial vault.

• One is minimization of blood loss, which is attempted by injection of vasoconstrictive agents (i.e. epinephrine) seven to ten minutes before scalp incision.^[6] In addition is the initiation of surgery delayed until blood products are physically present in the operating room.^[6]

• Another general agreement is the avoidance of the use of titanium plates in the fixation of the skull.^[46][47] The complication following this procedure is gradual movement of the titanium plates towards the brain, induced by resorption of the innermost bone layer of the skull and deposition of new bone on the outermost layer, thereby integrating the titanium plates.^[46][47] In some cases, the plates were even seen coming in direct contact with the brain.^[46][47] Absorbable plates are now used instead.^[46][47]

Surgical intervention per particular fused suture

Sagittal craniosynostosis/scaphocephaly

There are two surgical procedures which are commonly used to treat sagittal synostosis.^[6] Which of the two is the best is still heavily debated amongst the surgeons treating this condition.^[6] It is generally agreed upon that the cephalic index is used to asses the efficacy of the surgical intervention.^[6]

• Firstly, the extended strip craniectomy will be discussed, which is a further developed form of the traditional craniectomy.^[6] The traditional procedure involved only the excision of the closed suture, hoping that the compensatory skull deformations would automatically be corrected by the fast growth of the brain during the first year of life.^[6]
  This did not quite result in a true normalization of the cranial vault, causing the development of numerous modifications.^[48][49] One of those is the extended strip craniectomy. This procedure can be performed by using a endoscope and became more popular due to rapid recovery of the child and the reduced need for blood transfusion.^[48][49] The patient is afterwards placed in a custom made molding helmet to correct the resting deformities of the skull.^[48][49]

• With the total cranial vault remodelling, which is the other widely used surgical procedure, the compensatory deformities are corrected during the operation, in addition to excision of the fused suture.^[50] Most of the bones that together form the cranial vault – i.e. the frontal, the parietal and the occipital bones – are removed and reshaped to normalize the contours.^[50] The bones are then replaced and fixated to form a cranial vault with a normalized shape.^[50]

Retrospective analysis has given indication that the use of total cranial vault remodelling provides the children with a better cephalic index than does the extended strip craniectomy.^[51]

An approach that is currently evaluated is the use of springs. This intervention is likely most effective when used in the time frame between three to six months.

Metopic synostosis/trigonocephaly

The main elements of metopic suture closure are a low volume of the anterior cranial fossa, the metopic ridging and hypotelorism.^[52] These problems are all addressed during the surgical intervention.^[52]

The volume is increased by placing the frontal bones and the supraorbital rim further forwards.^[6] This is done by excision of the bones after which they are reshaped with greenstick fracturing.^[6] Replacement of the bones provides a possibility for the correction of the hypotelorism at the same time.^[6] A bone graft is placed in between the two halves of the supraorbital bars, thereby increasing the width between the orbits.^[6] The metopic ridge can be corrected with a (simple) burring.^[27]

Unilateral coronal synostosis/anterior plagiocephaly

The treatment of unilateral coronal synostosis typically exists out of two parts: the forward advancement of the supraorbital bar and the correction of the orbital asymmetry.^[6]

The supraorbital bar is the rim just above the eye socket. As discussed under phenotype, the supraorbital and the frontal bone are typically recessed at the ipsilateral side of the head.^[6] The goal is to position this bar together with the frontal bone in a plane three millimetres further forwards than the vertical plane of the cornea.^[6] A two-dimensional sagittal image is used to pre-operatively determine the extent of movement, which can vary between seven to fifteen millimetres, depending on the severity of the deformity.^[6]

The orbital asymmetry exists typically of a narrower and taller orbit at the ipsilateral side of the head.^[6] The contralateral orbit, however, is wider than usual.^[6] The symmetry is restored by extracting a small piece of bone from the supraorbital bar at the contralateral side, thereby reducing the width.^[6] This bone fragment is introduced into the supraorbital bar on the ipsilateral side, thereby increasing the width.^[6] The height of the orbit is just altered at the ipsilateral side, by extracting a piece of bone.^[6] The correction of the nasal tip, which points towards the contralateral side, is not performed during childhood.^[27]

Unilateral lambdoid synostosis/posterior plagiocephaly

An excision of the flattened occipital bone with release of the fused suture tends to correct the cranial vault deformity.^[27]

Bilateral coronal synostosis/brachycephaly

The treatment of bilateral coronal synostosis shows great overlap with the treatment of unilateral coronal synostosis; in both surgical interventions is the forward advancement of the supraorbital rim together with the frontal bones an important part of the procedure.^[6][27] Again is the plane three millimetres further forwards than the vertical plane of the [cornea] the appropriate position to place the bone.^[6][27] The increased height of the skull is addressed in the same procedure.^[27] Parts of the flattened occiput are extracted and given a rounder shape by greenstick fracturing them.^[27]

Pansynostosis/kleeblattschädel

The treatment of pansynostosis comprises the expansion of the anterior cranial vault, as well as the posterior cranial vault.^[8] This can be accomplished in one procedure, but is generally performed in two.^[8]

References

1. ^ Silva, Sandra; Philippe Jeanty (1999-06-07). "Cloverleaf skull or kleeblattschadel". TheFetus.net. MacroMedia. http://www.thefetus.net/page.php?id=340. Retrieved 2007-02-03. 
2. ^ ^{a b c d e f g h i j k l m n o p q r s t u} Cranial sutures: a brief review. Slater BJ. et al. Plast Reconstr Surg. 2008 Apr;121(4):170e-8e. Review
3. ^ ^{a b c d e} Intracranial pressure and intracranial volume in children with craniosynostosis. Gault DT. et al. Plast Reconstr Surg. 1992 Sep;90(3):377-81.
4. ^ ^{a b c d} Obstructive sleep apnea in children with syndromic craniosynostosis: long-term respiratory outcome of midface advancement. Bannink N. et al. Int J Oral Maxillofac Surg. 2010 Feb;39(2):115-21
5. ^ ^{a b c d e f g h i} Genetics of craniosynostosis. Kimonis V et al. Semin Pediatr Neurol. 2007 Sep;14(3):150-61
6. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al} Management of craniosynostosis. Panchal J. et al. Plast Reconstr Surg. 2003 May;111(6):2032-48
7. ^ ^{a b c d e f g h i j k l m} Evaluation of the infant with an abnormal skull shape Cunningham ML et al. Curr Opin Pediatr. 2007 Dec;19(6):645-51. Review
8. ^ ^{a b c d e f g h i j k l m n} Pansynostosis: a review Blount JP Childs Nerv Syst. 2007 Oct;23(10):1103-9. Review
9. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x y} Neurodevelopment of children with single suture craniosynostosis: a review Kapp/Simo KA et al. Childs Nerv Syst. 2007 Mar;23(3):269-81. Review
10. ^ ^{a b} Expression of Indian Hedgehog, BMP-4 and Noggin in craniosynostosis induced by fetal constraint. Jacob S. et al. Ann Plast Surg. 2007 Feb;58(2):215-21
11. ^ Craniosynostosis and maternal smoking. Carmicheal SL et al. Birth Defects Res A Clin Mol Teratol. 2008 Feb;82(2):78-85
12. ^ ^{a b} Maternal exposure to prescription and non-prescription pharmaceuticals or drugs of abuse and risk of craniosynostosis. Gardner JS. et al. Int J Epidemiol. 1998 Feb;27(1):64-7
13. ^ Further evidence for an association between maternal smoking and craniosynostosis. Honein MA et al. Teratology. 2000 Sep;62(3):145-6
14. ^ Maternal smoking and craniosynostosis. Källén K et al. Teratology. 1999 Sep;60(3):146-50
15. ^ ^{a b} Nitrosatable drug exposure during pregnancy and adverse pregnancy outcome. Olshan AF. et al. Int J Epidemiol. 1989 Dec;18(4):891-9
16. ^ Valproic acid monotherapy in pregnancy and major congenital malformations. Jentink J. et al. N Engl J Med. 2010 Jun 10;362(23):2185-93. Review
17. ^ ^{a b} Premature craniosynostosis: A common complication of juvenile thyrotoxicosis. Johnsonbaugh RE et al. J Pediatr. 1978 Aug;93(2):188-91
18. ^ ^{a b c} Molecular analysis of patients with synostotic frontal plagiocephaly (unilateral coronal synostosis). Mulliken JB. et al. Plast Reconstr Surg. 2004 Jun;113(7):1899-909
19. ^ Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis. Moloney DM. et al. Lancet. 1997 Apr 12;349(9058):1059-62
20. ^ Passos-Bueno MR; Serti Eacute, AE; Jehee, FS; Fanganiello, R; Yeh, E (2008). "Genetics of Craniosynostosis: genes, syndromes, mutations and genotype-phenotype correlations". Front Oral Biol 12 (1): 107–43. doi:10.1159/0000115035. PMID 18391498. 
21. ^ ^{a b} Cranial suture biology. Lenton KA et al. Curr Top Dev Biol. 2005;66:287-328. Review
22. ^ ^{a b} Craniosynostosis: genes and mechanisms. Wilkie AO et al. Hum Mol Genet. 1997;6(10):1647-56. Review
23. ^ ^{a b} Craniosynostosis. Kabbani H. et al. Am Fam Physician. 2004 Jun 15;69(12):2863-70
24. ^ ^{a b} Cranial vault growth in craniosynostosis. Delashaw JB. et al. J Neurosurg. 1989 Feb;70(2):159-65
25. ^ http://smilesforkids.missouri.edu
26. ^ http://smilesforkids.missouri.edu
27. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae} MOC-PS(SM) CME article: management considerations in the treatment of craniosynostosis. Persing et al.Plast Reconstr Surg. 2008 Apr;121(4 Suppl):1-11
28. ^ ^{a b} The Differential Diagnosis of Posterior Plagiocephaly: True Lambdoid Synostosis versus Positional Molding. Huang MHS. et al. Plastic & Reconstructive Surgery: October 1996 - Volume 98 - Issue 5 - pp 765-774
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30. ^ ^{a b} Craniosynostosis. I. Sagittal synostosis: its genetics and associated clinical findings in 214 patients who lacked involvement of the coronal suture(s). Hunter AG et al. Teratology. 1976 Oct;14(2):185-93
31. ^ ^{a b} Genetic study of scaphocephaly. Lajeunie E et al. Am J Med Genet. 1996 Mar 29;62(3):282-5
32. ^ ^{a b c d} Intracranial pressure monitoring in children with single suture and complex craniosynostosis: a review. Tamburrini G. Childs Nerv Syst. 2005 Oct
33. ^ ^{a b c d e} The effects of craniosynostosis on the brain with respect to intracranial pressure. Bristol RE. Semin Pediatr Neurol. 2004 Dec;11(4):262-7
34. ^ Management of craniosynostoses. Renier D et al. Childs Nerv Syst. 2000 Nov;16(10-11):645-58. Review
35. ^ ^{a b} Papilledema in patients with Apert, Crouzon, and Pfeiffer syndrome: prevalence, efficacy of treatment, and risk factors. Bannink N et al. J. Craniofac Surg. 2008 Jan;19(1):121-7
36. ^ ^{a b} Are routine preoperative CT scans necessary in the management of single suture craniosynostosis? Cerovac S. et al. Br J Neurosurg. 2002 Aug;16(4):348-54.
37. ^ ^{a b} Value of computed tomography in the evaluation of craniosynostosis. Goldstein SJ et el. Comput Radiol. 1982 Nov-Dec;6(6):331-6
38. ^ ^{a b} Craniosynostosis. Aviv RI. et al. Clin Radiol. 2002 Feb;57(2):93-102
39. ^ Management of nonsyndromic craniosynostosis. Ghali GE et al. Atlas Oral Maxillofac Surg Clin North Am. 2002 Mar;10(1):1-41
40. ^ Long-term functional outcome in 167 patients with syndromic craniosynostosis; defining a syndrome-specific risk profile. de Jong T. et al. Journal of Plastic, Reconstructive & Aesthetic Surgery (2010) 63, 1635 1641
41. ^ ^{a b c d e f g} The Monro-Kellie hypothesis: applications in CSF volume depletion. Mokri B et al. Neurology. 2001 Jun 26;56(12):1746-8
42. ^ ^{a b c d} Assessment of quality of continuous intracranial pressure recordings in children. Eide PK et al. Pediatr Neurosurg. 2006;42(1):28-34
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45. ^ Single-suture craniosynostosis: a review of neurobehavioral research and theory. Spetlz ML et al. J Pediatr Psychol. 2004 Dec;29(8):651-68. Review
46. ^ ^{a b c d} Observations on the use of rigid fixation for craniofacial deformities in infants and young children. Fearon JA et al. Plast Reconstr Surg. 1995 Apr;95(4):634-7; discussion 638
47. ^ ^{a b c d} Transcranial migration of microfixation plates and screws. Case report. Duke BJ et al. Pediatr Neurosurg. 1996 Jul;25(1):31-4; discussion 35
48. ^ ^{a b c} Endoscopic craniectomy for early surgical correction of sagittal craniosynostosis. Jimenez DF et al. J Neurosurg. Jan 1998;88(1):77-81
49. ^ ^{a b c} Endoscopic craniectomy for early correction of craniosynostosis. Barone CM et al. Plast Reconstr Surg. Dec 1999;104(7):1965-73; discussion 1974-5
50. ^ ^{a b c} Evolution of the treatment for sagittal synostosis: a personal record. Francel P. Craniofacial Anomalies: Growth and Development from a Surgical Perspective. New York, NY: Thieme; 1995
51. ^ Sagittal craniosynostosis outcome assessment for two methods and timings of intervention. Panchal J et al. Plast Reconstr Surg. May 1999;103(6):1574-84
52. ^ ^{a b} Metopic synostosis. Francel P et al. Neurosurgical Operative Atlas. Vol 9. Rolling Meadows; Ill: American Association of Neurological Surgeons; 1999:91-111

External links

• Overview of craniosynostosis from Children's Hospital Boston
• Craniosynostosis — comprehensive overview (American Family Physician)
• GeneReview/NIH/UW entry on FGFR-Related Craniosynostosis Syndromes