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Josephine Jung graduated from Medical School in Berlin in 2014. After completing Abstract Embryology her M.D. Thesis in Craniosynostosis is a group of conditions The human cranium is divided into the neuro- Berlin she moved characterised by the premature fusion of cranium housing the brain, and the viscero- to London and is one or more cranial vault sutures. This may cranium, comprising the face. The neurocra- working as a Clinical Research Fellow lead to abnormal cranial development with nium forms from embryonic in Neurosurgery at severe and craniofacial deformities of neural crest (frontal bone) and paraxial King’s College Hospital London. and if the condition is left untreated, other mesoderm (parietal bone) origin,13 which complications such as raised intracranial surrounds the brain and forms primary ossi- pressure and cranial growth restriction may fication centres termed bone spicules. Each Jordan Lam be implicated. island of mineralised tissue migrates and is an Academic Craniosynostosis can arise as part of a undergoes intramembranous ossification to Foundation Trainee in genetic , or nonsyndromically form the plates of the . These the East Midlands. He where the pathophysiology remains less clear. plates remain separated in early infanthood, is pursuing a career in neurosurgery. Occurring in 1 in 2,000 to 2,500 live births, allowing for passage during labour and diagnosis is carried out shortly after birth and continued growth of the brain after birth. treatment of craniosynostosis mostly involves The metopic suture fuses between 3 to 9 surgery varying from less invasive procedures months whilst the sagittal, coronal and lamb- in those patients diagnosed early to single or doid sutures do not stop growing until the Ruth-Mary repeated open calvarial reconstruction in the second decade and eventually fuse within more complex cases. the third decade.14-16 Each plate approaches deSouza This article reviews the different types of one another but remains separated by the obtained her medical craniosynostosis with their variable pres- formation of a suture: the two halves of the degree in 2008 from King’s College entations, underlying genetic mutations, frontal bone by the metopic suture; the frontal London and her associated complications and neuro-psych- and parietal bones by the ; the MRCS in 2010. ological outcomes before discussing its two halves of the parietal bone by the coronal management with distinct emphasis on suture; and the parietal and occipital bones surgical treatment options within a multi- by the . , namely Ian Anderson disciplinary team. membrane-covered “soft spots”, are located at is a Consultant the intersection of sutures: the larger anterior Neurosurgeon at Introduction at the intersection of the metopic, Leeds General Craniosynostosis is a group of conditions coronal and sagittal sutures and the smaller Infirmary. Having characterised by premature fusion of one or posterior fontanelle at the intersection of trained in Leeds, he has previously more of the cranial vault sutures. This can the sagittal and the lambdoid sutures. These undertaken a lead to abnormal cranial development and fontanelles usually fuse by the age of 18 Neurovascular give rise to severe skull and craniofacial months and 3 to 6 months respectively.14 Fellowship at King’s deformities. Craniosynostosis can arise as part College Hospital. of , with specific gene mutations Types resulting in other non-cranial manifestations Premature fusion of the sutures implicates in addition to , or nonsyndromically that the normal growth of the neurocranium where the pathophysiology remains less clear. is arrested at one or more sites. In order to Paul Chumas Both types of craniosynostosis can be familial accommodate the growing brain, compen- is a Consultant or sporadic. Occurring in 1 in 2,000 to 2,500 satory growth occurs at other sites leading to Paediatric live births,1-3 infants are diagnosed at birth or abnormal cranial development and deformity. Neurosurgeon in 4 Leeds General within a few months thereafter and should This was described in 1851 through Virchow’s Infirmary. preferably have treatment within their first law that states that if a suture prematurely year of life.5 If the condition is left untreated, fuses, growth is arrested perpendicular to the craniosynostosis can lead to further deformity suture and is increased parallel to it.17,18 Thus, and other complications such as raised intra- it explains the characteristic and predictable Correspondence to: 6-7 Josephine Jung, cranial pressure and cranial growth restric- patterns of cranial growth that occur as a result Department of Neurosurgery, tion. The treatment mostly involves surgery of the premature fusion of distinctive sutures King's College Hospital, London, UK. varying from less invasive procedures in (see Figure 1, adapted from Senarath-Yapa et Conflict of interest statement: those patients diagnosed early8-10 to single or al., 201219). None declared repeated open calvarial reconstruction in the Sagittal synostosis is the most common type, 11,12 Provenance and peer review: more complex cases. There are a number accounting for 40-55% of nonsyndromic cran- Submitted and externally reviewed of clinicians involved in the care of children iosynostosis.17,20 Caused by premature fusion with this condition, highlighting the import- of the sagittal suture, growth is arrested in Date first submitted: 14/12/17 Date resubmitted after peer review: 25/9/18 ance of a multidisciplinary team. This article the transverse direction and increased in Acceptance date: 3/10/18 will review the different types of craniosyno- the anteroposterior direction, resulting in an stoses with their variable presentations, the anteroposterior elongation with frontal bossing To cite: Jung J, Lam J, deSouza R-M, Anderson I, Chumas P. ACNR 2018;18(2):5-11. underlying genetic mutations, complications and occipital prominence. This characteristic and neuro-psychological outcomes before “long boat” shape skull is termed scapho- discussing its management with distinct cephaly (derived from skaphos: Greek term emphasis on surgical treatment options within for skiff). a multidisciplinary team. Coronal synostosis has been superseded

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A Normal skull D Unicoronal synostosis with nasal deviation (left) / Bicoronal synostosis with brachiocephaly (middle/right) Frontal Coronal bone suture Squamous Parietal suture bone

Lambdoid suture Sphenoid bone Coronal Occipital suture bone Temporal bone Coronal suture B Metopic synostosis with

Metopic suture anterior

Metopic suture E Unilateral lambdoid synostosis with posterior anterior contralateral Saggital synostosis with frontal C bossing Lambdoid suture Sagittal suture

Sagittal suture

Ipsilateral ear inferior anterior and posterior

normal anterior Figure 1. Cranial sutures and deformity of single suture craniosynostosis. With permission from Senarath-Yapa.

by metopic as the second most common This narrowing of the frontal bone produces "Mercedes Benz" sign due to the changes on nonsyndromic synostosis as several studies a pointed triangular forehead with orbital the X-rays.27 Bilateral lambdoid synostosis is have shown over the past decade.3,21,22 It occurs hypotelorism and a ridge along the fused associated with a Chiari I abnormality (with in 20-24% of nonsyndromic cases23,24 and can metopic suture and there may be compensa- protrusion of cerebellar tonsils through the be either unilateral or bilateral. tory posterior growth causing widening of the Foramen magnum) and can appear similar to Premature fusion of the coronal suture parietal regions. This is called trigonocephaly due to coronal synostosis. bilaterally produces the opposite pattern (trigonos: Greek term for triangle). However, A similar presentation, and by far the of abnormal growth to sagittal synostosis, it is important to note that ridging not infre- most common one, can occur in positional arresting growth in the anteroposterior direc- quently occurs with normal fusion during the plagiocephaly ("moulding"), a prevalent tion and increased growth in the transverse first few months of life and does not require acquired cranial asymmetry that emerges at 6 direction, producing a short wide called surgery.26 weeks of age and can largely be attributed to brachycephaly (from the Greek term brachkus Lambdoid synostosis is rare, occurring in the supine sleeping position recommended for for short). Unilateral coronal synostosis causes 0-5% of non-syndromic cases17,20 and is usually infant safety (in the UK generally referred to as flattening of the ipsilateral forehead and unilateral. Due to premature fusion of one of the "Back to Sleep" campaign for the preven- displacement of the ipsilateral lesser wing of the lambda sutures there is arrested growth tion of Sudden Infant Death Syndrome).28-30 the sphenoid bone superolaterally called the of the ipsilateral occipital region causing The two can be difficult to distinguish (see “harlequin eye deformity” since radiograph- ipsilateral occipital flattening, posteroinferior Figure 2), but the ipsilateral ear is anteriorly ically it has the appearance of a masquerade displacement of the ipsilateral ear and tilting displaced in positional plagiocephaly and skull mask. Other features include ipsilateral nasal of the skull base towards the affected suture. base tilt is absent. Positional plagiocephaly is deviation and contralateral displacement Compensatory growth occurs at the contralat- asserted to be benign and may resolve spon- of the anterior fontanelle. This skull pattern eral occipital and frontal regions resulting in taneously in some cases32,33 or with simple produced by unilateral coronal synostosis is contralateral forehead and occipital protuber- measures such as position changes, “tummy termed anterior plagiocephaly (plagos: Greek ances as well as inferior mastoid elonga- time” and physical therapy for any torticollis for slant). tion. This posterior slanting shape is called that may be present.30,31 Metopic synostosis is found in 20-29% of posterior plagiocephaly. Bilateral lambdoid Although orthotic ("moulding") helmets non-syndromic cases but studies have shown synostosis is very rare and causes symmetrical are frequently used (particularly in Europe increasing prevalence.24,25 Premature fusion of flattening of the occiput with compensatory and the USA),33,34 Wijk et al. demonstrated the metopic suture causes arrested growth of heightening the skull. This is called posterior in (HElmet therapy Assessment in the cranium in the transverse direction anter- brachycephaly and in combination with Deformed ), a single blinded, random- iorly and increased anteroposterior growth. posterior sagittal synostosis also known as the ised controlled trial, that there is no benefit

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Unilateral plagiocephaly Positional Plagiocephaly Lambdoid Synostosis • Unilateral occipital flattening Unilateral Contralateral frontal frontal • Anterior displacement of bossing bossing Contralateral the ipsilateral ear frontal • Ipsilateral frontal bossing flattening (bossing opposite Anterior ear occiput) displacement • Contralateral forehead flattening Posterior ear displacement • Parallelogram shape Lambdoidal synostosis Contralateral • Ipsilateral flattening parietal of the occipitoparietal Unilateral bossing occipitoparietal region flattening Ipsilateral Contralateral occipitoparietal • Posterior displacement of occipitoparietal flattening the ipsilateral ear bossing • Contralateral parietal/ frontal bossing Windswept • Tilted cranial base with deformity mastoid deformity • 'Windswept' deformity Bilateral plagiocephaly Unilateral • Bilateral occipital occipitoparietal flattening flattening • Central posterior flattening • Posterior skull widening

• Bitemporal bossing Mastoid deformity

Figure 2. Positional Plagiocephaly. Adapted from International Society of Paediatric Neurosurgery (ISPN) website.31

from the administration of a moulding helmet particular note is the association between tions have been identified in Pfeiffer and and discouraged its use due to the association maternal use of sodium and metopic Jackson Weiss syndromes; FGFR2 mutations with large costs and prevalent side effects.35 craniosynostosis.42 On the other hand, most in Crouzon, Jackson Weiss, Apert, Pfeiffer and The overall consensus in the UK is to not types of syndromic craniosynostoses are inher- Beare Stevenson syndrome; and FGFR3 muta- recommend it. ited in an autosomal dominant fashion43,44 and tions in with Acanthosis, Synostoses occur in multiple sutures in genetic analysis studies have provided strong and Thantophoric dysplasia 5-15% of non-syndromic cases,17,20 presenting links to a number of genes.43 (see Table 1 and Figure 3). The mechanism with more complex deformities. Synostosis of One such group of genes implicated is resulting in significantly differing phenotypes three or more sutures is referred to as pansyno- the fibroblast growth factor receptor family, arising from the same mutation is yet to be fully stosis36,37 and can present either with micro- of which mutations in genes encoding understood. cephaly or as a “Kleeblattschädel” (cloverleaf FGFR1, FGFR2 and FGFR3 have been found TWIST1 (twist-related protein 1) is another skull), named due to the bulging of the frontal in syndromic craniosynostoses. These gene linked to craniosynostosis syndromes and temporal bones giving rise to a tri-lobular are receptor tyrosine kinases that undergo and mutations have been found in the Saethre- shaped skull. auto-phosphorylation upon fibroblast growth Chotzen syndrome. TWIST1 is a basic loop- factor binding and are involved in a vast helix-loop transcription factor and thought range of cell functions and developmental to be involved in determining the lineage Nonsyndromic craniosynostosis accounts for processes.45,46 Indeed, targeted mutagenesis of of osteoblasts. Cells over-expressing TWIST1 approximately 85% of cases3 and although individual FGFR isotypes has been shown to showed decreased response to FGF and positive family histories have been reported,38,39 lead to both lethal or viable defects in embryo- remained undifferentiated while cells under- the aetiology remains unknown. However, one logical development such as gastrulation,45 expressing TWIST1 differentiated into a mature cohort study genetic analysis found single placenta and limb bud formation,47,48 organo- osteoblast-like state.53 gene mutations in FGFR2, FGFR3, TWIST1 genesis49 and bone ossification.50 Therefore, it has been hypothesised that and EFNB1 in 11 out of 204 (5.4%) of non-syn- FGFR mutation results in gain of function TWIST1 is involved with delaying suture dromic cases, 9/11 of which were unilateral or causing abundant activation of the FGF/FGFR fusion, upstream of FGF. Indeed, the majority bilateral coronal.40 signalling pathway, which is then leading to of TWIST1 mutations found in Saethre-Chotzen Other factors, including increased thyroid expression of runt-related transcription-factor syndrome confer a loss of function through hormone level during pregnancy, and environ- 2 (RUNX2). The result is early onset differ- haplo-insufficiency.54 Furthermore, FGFR2 and mental stimuli such as head compression entiation of mesenchyme cells into osteo- FGFR3 mutations have also been found in in utero, maternal smoking and teratogenic blasts that deposit bone and eventually lead Saethre-Chotzen syndrome55 further supporting medications have also been implicated.41 Of to premature suture closure.51,52 FGFR1 muta- a common molecular pathway.

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More recently, Zhao et al., 2015 discovered Table 1. Genetic mutations and their craniofacial phenotype. that Gli1+ cells in the suture mesenchyme form Adapted from Senarath-Yapa et al., 2012 and Flaherty et al., 2016. The phenotypic features described may not be present in all individuals diagnosed with the condition. According to Wilkie et al., 2010, the osteogenic front, periosteum, dura and all Muenke syndrome is clinically not diagnostic as phenotypic appearances vary from no characteristics to craniofacial bones, and are involved in injury overlapping with other craniosynostosis syndromes. repair.56 Ablation of Gli1+ cells in mice was Gene Syndrome ? found to cause pansynostosis, arresting of skull Chromosome Characteristic phenotype growth and reduced injury repair. Moreover, the Gli1+ population was reduced in Twist1+/– FGFR1 8p Premature suture closure, brachycephaly, Yes (>90%) mice, a widely used model of craniosynostosis cutaneous , , high forehead, midfacial mimicking the TWIST1 mutation in Saethre- retrusion, beaked nose, , dental problems, , digit webbing, syndactyly, cloverleaf skull Chotzen syndrome, and causing increased deformity, developmental delay, cognitive deficits mesenchyme apoptosis and reduced prolif- eration. Therefore, the authors showed that Jackson Weiss syndrome Gli1+ cells in the suture mesenchyme form the FGFR2 10q Crouzon syndrome Premature suture closure, brachycephaly, Yes (>90%) Chiari I osteogenic stem cells of the craniofacial sutures flat forehead, midfacial retrusion, eye proptosis, and that pathogenesis of craniosynostosis may hypertelorism, mandibular prognathism, beaked nose, mild be due to reduced numbers of Gli1+ cells. limb abnormalities, variable cognitive function Jackson Weiss syndrome Associated complications Each type of craniosynostosis can vary in its Premature suture closure, brachycephaly, Yes (~70%) eye proptosis, midfacial retrusion, exorbitism, hypertelorism, severity of phenotypic features. In particular, heterotropia, high arched palate, cleft palate, structural brain sagittal and metopic suture synostosis may anomalies, cognitive impairment, complex syndactyly show a very mild clinical presentation in which only one bone ridge at the afflicted suture is Pfeiffer syndrome Yes visible and/or palpable. Therefore, parents are Beare Stevenson syndrome often confronted with health care professionals FGFR3 4p Crouzon syndrome with Acanthosis Premature suture who do not recognise the craniosynostosis in closure, brachycephaly, midfacial retrusion, acanthosis a timely manner shortly after childbirth. This nigricans may not only cause distress for the parents but also lead to delayed diagnosis and treatment.64 Muenke syndrome Premature suture closure brachycephaly, Yes (Seldom) orbital hypertelorism, midfacial retrusion, high arched In syndromic and complex nonsyndromic palate, hearing loss, mild anomalies of the hands and feet, craniosynostoses the patients may suffer from developmental delay cognitive impairment and raised (ICP). Several syndromic craniosyno- Thantophoric Dysplasia stoses are associated with skeletal hypoplasia EFNB1 Xq Craniofrontonasal syndrome Seldom of the midface resulting in a narrowed airway. In approximately 50% of cases this leads to TWIST1 7p Saethre-Chotzen syndrome Premature suture fusion, Yes (30-50%) OSAS (obstructive sleep apnoea syndrome). brachycephaly, high forehead, low frontal hairline, , Other risks and complications include cornea hypertelorism, broad nasal bridge injury due to exorbitism, malocclusion and

Figure 3. Most common craniosynostosis syndromes.

Crouzon syndrome,57 first described by the same family can have quite marked is the classic, most common and least severe Octave Crouzon in 1935, is the most differences in phenotype. type associated with turribrachycephaly, common of the craniosynostosis syndromes, hypertelorism, , maxillary occurring in 1 in 25,000 live births. Like the Apert syndrome is the second most common, hypoplasia causing mandibular prognathism majority of the syndromes including Apert, found in 1 in 100,000 newborns, the majority and characteristic broad thumbs. Type II is Pfeiffer and Saethre-Chotzen, it follows an of which are sporadic mutations in FGFR2. more severe, with a cloverleaf skull, severe autosomal dominant inheritance pattern7 It also affects the coronal sutures bilaterally , hydrocephalus and poor causing a brachycephaly60 with hypertelorism, and mutations have been found in FGFR2 prognosis. Type III is very similar to type II shallow orbits, exophthalmos and high arched 62 and FGFR3. Most commonly affected but lacks the cloverleaf skull. palate. However, maxillary hypoplasia is more are the bilateral coronal sutures causing severe than observed in Crouzon syndrome Saethre-Chotzen is found in 1 in 25,000 to brachycephaly. Also seen is hypertelorism, and can lead to life-threatening airway 50,000 newborns and caused by mutations shallow orbits resulting in exophthalmos, compromise. Also seen is an anterior open in TWIST1. The phenotype is heterogenous maxillary hypoplasia causing mandibular bite, downslanting palpebral fissures, a “parrot and synostosis can be bicoronal, unicoronal, prognathism, high arched palate and 63 beak” nose and syndactyly of the second, sagittal, metopic or multisutural leading low set ears associated with hearing third and fourth digits. to a great variety of head shapes. Other impairment. Crouzon syndrome is also features include a low hairline, ptosis, facial thought to convey an increased risk of raised Pfeiffer syndrome also occurs in 1 in 100,000 asymmetry and ear deformities. Additionally, intracranial pressure58 and this has been live births, most commonly due to FGFR2 syndactyly of the second and third digits proposed to be due to the early closure mutations, but FGFR1 mutations have been may be present. Overall, Saethre-Chotzen of the sagittal and lambdoid sutures.59 As a found in 5% of cases, causing a less severe syndrome perhaps displays the widest result cognitive function in individuals with presentation.61 The coronal, lambdoid phenotype of the common syndromic Crouzon syndrome is variable. Additionally, and sagittal sutures are all affected, but conditions and family members may this syndrome may well be progressive in heterogeneity of the syndrome has led to a remain undiagnosed due to portraying mild the first 2-3 years of life and even within classification into three clinical types. Type I phenotypic features (e.g. subtle ptosis).

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aesthetic/psychosocial problems. Associated have been identified as potential risk factors protocols for workup, delivery of anaesthesia, intracranial abnormalities in syndromic cran- for the development of metopic craniosyno- streamlined surgical procedures and complex iosynostoses are increased ICP, Chiari I malfor- stosis.42,73 post-operative care and assessment.79 mation, ventriculomegaly and hydrocephalus. Hydrocephalus and tonsillar descent (Chiari The involved specialties usually include Hearing loss is described for all types of I malformation) merit a specific discussion. Plastic Surgery, Neurosurgery, Otolaryngology, syndromic craniosynostoses. Visual pathol- Chiari I (for the purpose of this article refers to Dentistry, Audiology, Ophthalmology, ogies such as astigmatism and strabismus tonsillar descent and crowding of the foramen Speech & Language therapy, Developmental are very frequent in syndromic craniosyno- magnum) has a clear association with the Paediatrics, Neuropsychology, Medical stoses. In nonsyndromic craniosynostosis, syndromic craniosynostoses shown in Figure Genetics, Social Work and Nursing Care. Other specifically unicoronal craniosynostosis, chil- 3. An association between non-syndromic specialists, such as cardiologists and gastro- dren are at risk of developing astigmatism lambdoid synostosis (and not other sutures) enterologists, may be consulted for manage- in the eye opposed to the coronal suture and Chiari I has also been noted.74 Chiari I and ment of associated defects and clearance synostosis.65 Limb deformities are largely craniosynostosis co-existing have a significant for surgery. Often parents can easily be over- restricted to syndromic craniosynostoses, and association with syringomyelia,74 which needs whelmed by all the information discussed notably associated to the Apert syndrome. to be taken into account when evaluating and when meeting all the different specialists. Both types of craniosynostosis, nonsyndromic imaging these children. One of the hypotheses Moreover, congenital defects involving a and syndromic, may co-occur with cogni- for the aetiology of is the child's face and skull seem to evoke particu- tive and behavioural impairments. These are “box being too small for the contents” due to larly strong emotional responses from the either intrinsic due to the congenital defect occipital hypoplasia. Craniosynostosis, whilst parents, who must contend with a host of or secondary to intracranial hypertension or obviously not due to occipital hypoplasia, potentially stressful events and circumstances, physical deformities. Interestingly, there is results in the net same outcome of the skull including the infant's unusual physical appear- continued debate on decreased intracranial being disproportionately too small for the ance, the perspective of potentially life-threat- volumes, hydrocephalus and raised ICP in brain. This provides a plausible mechanism ening surgeries ahead, and the possibility of patients with single-suture craniosynostosis.27 for the association between Chiari and cranio- future neuropsychological and educational So far, there is little to no difference in intra- synostosis as well as potentially giving greater problems.4 cranial volumes among various types of cran- insights into the pathogenesis of Chiari malfor- iosynostoses to be found.66,67 Similarly, there mation itself. Diagnosis was no correlation between hydrocephalus Hydrocephalus associated with craniosyno- In order to achieve optimal treatment and and nonsyndromic craniosynostosis estab- stosis is common. There is variation in the satisfactory surgical outcome,80 early diag- lished,68 unless there is bilateral involvement reported figures for hydrocephalus across the nosis is essential in children with craniosyno- of the lambdoid suture. literature, but overall syndromic craniosyno- stosis. However, patients are not infrequently However, several studies have shown that stosis is associated with hydrocephalus in up referred late or not referred at all due to late children with nonsyndromic craniosynostosis to 30-70% of cases,68,75 as opposed to nonsyn- recognition of the head shape deformity.64 are at high risk of developing intracranial dromic craniosynostoses where it occurs in less Usually the abnormal skull shape is hypertension.58 In fact, elevated intracranial than 2%. Furthermore, there is no evidence to recognised shortly after birth by either the pressure was found in 24-30% of nonsyndromic suggest any causality between the two in most parents themselves, the treating obstetrician craniosynostoses.6,69 Yet in 1982, Renier et al.6 cases of nonsyndromic synostosis.76 or paediatrician, midwife or general practi- reported abnormal ICP recordings (meaning The first and key point is to establish whether tioner. The main diagnostic screening tools ≥15mmHg during Slow-Wave sleep) in 14% of one is dealing with genuine hydrocephalus are physical examination of the skull shape80,81 cases where only one suture is involved and in or static ventriculomegaly with no increased in combination with taking the history.82,83 The 47% of cases with multiple sutures intricated. pressure. This is not always a straightforward anamnestic flowchart of Bredero may serve However, in most nonsyndromic cases indi- task as the synostosis itself may cause raised as a guideline to distinguish craniosynostosis cation for surgery remains cosmetic. Invasive ICP and the clinical picture is complex, head from positional skull deformities.84 When cran- ICP monitoring is reserved for children with circumference is not possible to use and radio- iosynostosis is suspected, the paediatrician visual and/or developmental deficits, in cases logical signs may be atypical. should refer the child to a craniofacial centre where surgery has been refused and the head The mechanism of hydrocephalus in cran- for further diagnostic investigations. X-rays of circumference is falling off or they have a iosynostosis is believed to be a mixture of the skull (A-P, lateral, Towne's view) are still "Copper beaten skull" on X-ray - although this obstructive and absorptive77 arising from often performed in cases of suspected cran- is a weak clinical sign. venous hypertension.78 Brain atrophy may iosynostosis. If the result remains uncertain, Apart from its association with intracranial contribute to static ventriculomegaly, produ- the X-ray may be repeated after 1 to 2 months. hypertension, premature fusion of cranial cing a “hydrocephalus ex vacuo” picture.76 Alternatively, an experienced investigator can sutures is also known to affect the under- Although not the focus of this article, the exist- perform ultrasound scanning of the cranial lying brain morphology. In a series of studies, ence of acquired craniosynostosis secondary sutures. conducted by Aldridge et al. from 2002 to to shunt over drainage in the presence of CT-scan with 3D-reconstruction is performed 2005, the authors demonstrated that both non-fused sutures should be mentioned as well. as an alternative in some centres.64 Whilst the cortical and subcortical structures of the imaging will also give some detail relating central nervous system are dysmorphic in to the brain (hydrocephalus, etc.) it is asso- craniosynostosis. Specifically, studies of brain • Cranial growth restriction/ physical ciated with significantly more radiation and morphology in cases of sagittal and unicoronal deformity not necessarily of added value in many/most 85 synostosis have demonstrated that changes in • Raised ICP cases of "simple" craniosynostosis. Image the brain's structure are found in adjacent as findings may include bony ridging along the • Cognitive impairment well as distant and in subcortical regions away suture, heaping up of bone at the suture, from the fused suture.70-72 sutural narrowing, and indistinctness of the The highest percentage of associated intra- Multidisciplinary team suture as primary signs of craniosynostosis.86 and extracranial midline problems can be With regard to the number of complications Secondary signs include an altered calvarial found in children with metopic synostosis. that can arise intra- and post-operatively from shape, the general changes in shape and These patients also most commonly present open cranial vault procedures the multidisci- timing of closure of fontanels, and other with an IQ deficit. Birth weight, parental age plinary team concept has developed and facial anomalies. The lack of growth across a and sodium valproate use during pregnancy is widely used. It is largely based around suture commonly results in effacement of the

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underlying subarachnoid spaces. Patients with craniosynostosis may also have an enlarged subarachnoid space beneath regions of compensatory skull growth.87 In summary, the diagnosis of craniosyno- stosis is based on the calvarial shape with relation to a calvarial suture. Nonsyndromic craniosynostosis is diagnosed mainly clinically with help of X-rays and CT scans performed in Endoscopic Assisted Fronto-orbital CVR some centres. In contrast to that, syndromic Suturectomy Advancement and craniosynostosis is often more complex and • Saggital Remodelling (FOAR) Fronto Facial often requires both CT and MRI imaging to • Frontal • Frontal Advancement look at the structures within the posterior fossa • Coronal • Coronal (Uni-/bilateral) and Re- and venous drainage. For both syndromic and • Lambdoid modelling non-syndromic craniosynostosis other investi- Occipital Cranioplasty (FFAR) gations should include: regular measurement Modified Strip • Lambdoid • Syndromic of the head circumference (and the Cranial Craniectomy (MSC) with Index - width/length), ophthalmology, ENT, • Saggital Total Cranial Vault midface neurocognitive, Speech & Language assess- Remodelling (CVR) hypoplasia ments, and where appropriate dental review, Spring distraction • Sagittal measurement of overnight Oxygen saturations FOAR (to exclude sleep apnoeas associated with airway problems) and Plastic Surgery opinion for hand and feet abnormalities. Genetic testing and counselling can assist in Figure 4. Overview on operative techniques for simple craniosynostosis. Early surgery making or confirming a specific diagnosis and allows for brain growth to passively reshape skull. Later surgery aims to actively this may have prognostic implications both remodel skull shape. The time bar reflects procedure type in broad terms. for the individual patient but also for future planned pregnancies.64 on medical records or reported by parents, important issue in all children heavily engaged and five studies showed greater speech and in the healthcare system and relates to iatro- language impairment by more formal testing. genic factors such as handling by multiple • Physical examination and history taking A few studies uncovered impairment in visual different clinicians, experiencing pain, separa- • Diagnostic imaging: X-skull/ ultrasound, spatial skills, memory and attention, and school tion from parents and undergoing procedures 3D-CT scan of the head performance. Knight at al., 2014 also investi- (e.g. phlebotomy, imaging) against the infant’s gated the literature on correlations between will, with severe developmental and psycho- • Genetic testing neurodevelopmental outcome and a variety social implications later in life. Indeed, 10% of of factors: no articles to date have significantly children admitted to an intensive care unit were Neuropsychological outcomes correlated neurodevelopmental outcomes and found to develop PTSD, with parental stress In syndromic cases surgery is often indicated brain imaging, severity of deformity, sutures reactions as the strongest correlated predictor,95 for morphological (aesthetic) and func- affected, genetics or gender. Interestingly, highlighting again the importance of addressing tional (cognitive, airway, ophthalmic, etc.) there is mixed evidence for the association psychosocial issues within the whole family. reasons. However, in non-syndromic cases, between early surgery and the reduction of Unsurprisingly, psychosocial outcomes relating the indication for surgery is still generally neurodevelopmental impairments, with some to self-image and resilience are also influenced considered to be cosmetic. Although, recent studies reporting better outcomes with surgery by parental response and resilience.94 evidence suggests that corrective surgery within one year of age and worse outcomes Evidence on behavioural problems has been may also positively impact developmental with delayed surgery after four years;90 other mixed: using the Child Behaviour Checklist, outcomes assessed during long term follow up studies have reported no such difference.91-93 Becker at al., 2005 reported significant differ- in non-syndromic synostoses.88 In addition to cognitive difficulties, psycho- ences between children with craniosynostosis Many of the older studies looking at cognitive social aspects of craniosynostosis have been and the general population;96 whereas Van outcomes poorly defined mental retardation, investigated. Clearly during early years of der Vlugt et al., 2009 found no difference lacked control subjects, adequate follow-up infanthood, the major psychosocial burden to the general population when accounting periods and valid, standardised psychometric lies with the parents and this is reflected in for IQ.97 At school age, Kelleher et al., 2006 tests. On the other hand, more recent, high the need for parental support. Particularly, found that in children with nonsyndromic quality studies applying the above mentioned parents of a child with syndromic cranio- trigonocephaly, 33% required assessment by a principles including formal assessments, such synostosis may have to cope with negative school psychologist; 47% required remedial or as the Bayley Scales of Infant Development and reactions from others, a possible discrepancy resource hours; 20% required a special needs Wechsler Intelligence Scales for Children, have between deviating physical appearance and classroom due to behaviour issues; and 37% raised the possibility of mild cognitive impair- cognition, and be confronted with problems were reported to have behavioural issues such ment even in non-syndromic cases. A system- of school choice.64 Once the child grows older as attention deficit disorder, autism and hyper- atic review by Knight et al., 201489 of 33 articles and attends school, they may be themselves activity by their parents.98 with particular emphasis on methodological presented with psychosocial challenges and In later school life and adolescence, issues quality found 10 studies showing develop- management of these should in turn focus pertain to stigma and bullying, with a third of mental delays in motor functioning and cogni- on the child. A variety of outcomes such as craniosynostosis patients experiencing this.64 tion, including language, both before and after post-traumatic stress, successful completion Most cope sufficiently but continued support surgery. Five studies of school-age children with of treatment and the child’s resilience and is important, with social skills interventions single suture craniosynostosis found Intellectual coping strategies have been linked to parental proving beneficial.99 Another issue arising in Quotient to be within the normal range, but factors such as support as well as the parents’ adolescent patients is autonomy to make deci- three studies found increased learning, behav- own coping ability.94 sions relating to treatment as they reach the ioural and language deficits documented Post-traumatic stress disorder (PTSD) is an age required for consent: it is of vital import-

10 > ACNR > VOLUME 18 NUMBER 2 > NOVEMBER-JANUARY 2019 r e v i e w a r t i c l e

Figure 5: Sagittal craniosynostosis Figure 6: Metopic craniosynostosis Figure 7: Unilateral unicoronal craniosynostosis A and B: pre-operative photograph of a child with A and B: pre-operative photograph of a child with metopic craniosyonostosis (A A and B: pre-operative photographs (A frontal sagittal craniosynostosis (A frontal view, B lateral frontal view, B top view) resulting in a triangular headshape; C: pre-operative CT view, B top view) of a child with right unicor- view) resulting in a “long-boat” shaped skull; C and D: 3D Reconstruction demonstrating premature fusion of the metopic suture; D and E: onal craniosynostosis resulting in flattening post-operative photographs (C frontal view, D lateral post-operative photograph after treatment (D frontal view, E top view); of the ipsilateral forehead and displacement view) after treatment with spring distractors. F: post-operative CT 3D Reconstruction. of the ipsilateral lesser wing of the sphenoid bone superolaterally; C and D: post-operative photographs after treatment (C frontal view, D top view).

ance for them to be involved in the deci- between "passive" techniques and "active" complex syndromic craniosynostosis more sion-making process in order to optimise their remodelling procedures (see Figure 4). Passive than one surgery may be required. cooperation and satisfaction.100 Furthermore, methods involve resection of bone, thereby it is critical that adolescents have realistic allowing the developing and expanding brain expectations of treatment. to modify the skull shape (with or without assist- a. Early intervention: Endoscopic or open Although there have been no studies ance of a moulding helmet). As can be seen strip craniectomy or spring distraction following up nonsyndromic craniosynostosis from a standard head circumference chart the +/- post-operative orthotic helmet patients for psychosocial problems in adult- first few months of life are associated with the vs. hood, some have identified psychosocial greatest rate of skull growth (due to rapid brain b. Later intervention: Open calvarial problems in adults with syndromic cranio- growth) – most skull growth occurring in the first reconstruction synostosis. Relative to controls, adults with 2 years of life. More recently, these passive tech- Apert and Crouzon syndromes had a lower niques have been further refined by minimally level of education, were less often married, invasive techniques which are associated with Conclusions experienced less sexual relationships and smaller skin incisions and the need for less The identification of the underlying genetic more commonly had periods of depressive blood transfusions.9 Such techniques include mutations and molecular mechanisms in mood, but were as likely to report a positive endoscopic strip craniectomy (+/- moulding craniosynostoses has led to a breakthrough attitude to life as controls.101,102 Some adults helmet) as pioneered by Jimenez106,107 or the use in our understanding of these pathologies. A with non-surgically treated craniosynostosis of spring distraction.108-115 variety of procedures may be used to correct reported such pronounced psychological The active remodelling techniques, on the the deformity but over recent decades there problems that they were willing to undergo other hand, do not rely on the self-correcting has been increasing interest in early minimally correction in adulthood, a fundamentally capability, but attempt to obtain the desired invasive interventions where possible. Therefore, more complicated operation than in infants.103 skull shape by direct reconstruction (often early diagnosis of craniosynostosis is imperative. utilising rigid fixation using absorbable plates A multidisciplinary team approach in Treatment and screw).64 This type of surgery can also children with craniosynostosis and offering The surgical treatment of patients with be broadly divided into that used to correct support to the entire family, including the syndromic craniosynostosis was developed in sagittal synostosis116 (Figure 5) and that used parents, remains a vital factor in management Paris in the early 1970s by Tessier104 and then to treat metopic (Figure 6) and coronal syno- of children with these pathologies. Long-term later by Marchac and Renier.105 Surgery had a stosis (Figure 7) – which usually involves a follow-up is particularly important as these 2-fold aim: to achieve an enlargement of the fronto-orbital advancement and remodelling children may encounter various problems cranial volume so as to prevent sequelae of (FOAR). This latter procedure requires the throughout different stages in their develop- ICP (e.g. developmental delay, visual impair- orbital bar to also be removed as well as the ment, including school age, adolescence ment, etc.), and the correction of morpho- abnormal area of the front of the skull. and even further into early adulthood. Also, logic abnormalities of the cranium, the orbits, It has to be considered that in contrast to arising cognitive difficulties in non-syndromic and the upper jaw. open craniosynostosis correction surgeries, craniosynostoses may be very subtle.119 Since the first surgical intervention for cran- which are generally performed between the Consequently, children will benefit from iosynostosis, a great many surgical techniques ages of 6 to 18 months, minimally invasive continuous assessments throughout child- for the various types of craniosynostosis have procedures are performed much earlier within hood and early adulthood and in this way been described and it must be emphasized the first 3-6 months of age requiring early diag- neuropsychological issues can be discussed that there is no consensus on the optimal nosis and referral.117,118 and addressed accordingly. surgical techniques for skull reconstruction in However, the best surgical treatment has any form of craniosynostosis.26 to be evaluated by the surgeon for each References: A full list of references can However, a broad distinction can be made individual. Furthermore, especially in more be found online at www.acnr.co.uk

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