Overview of Craniosynostosis, P

HR Overview of craniosynostosis, p. 52-64 J VOLUME 3 | ISSUE 2

Pictorial Essay Neuro/Head and Neck Radiology Overview of craniosynostosis

Irene Vraka¹, Panagiotis-Athanasios Georgis², Ioannis Nikas³

¹Department of Radiology, P & A Kyriakou Children's Hospital, Athens, Greece ²Department of Neurosurgery, Agia Sophia Children's Hospital, Athens, Greece ³Imaging Department, Agia Sophia Children's Hospital, Athens, Greece

Submission: 2/2/2018 | Acceptance: 18/4/2018

Abstract

Although craniosynostosis is a well-described entity, craniosynostosis with emphasis to those concerning advances in genetics and radiology equipment have or even affecting diagnostic imaging. It appears that brought to light new evidence, which can possibly cranial ultrasound and foetal MRI, along with specif- change the imaging approach. A number of genes and ic MRI techniques for the skull, will be the future in mutations related to the disorder have been indenti- the imaging of craniosynostosis. Literature data on fied, whereas foetal MRI appears to be quite reliable the normal sutures' anatomy, as well as on the dis- in the clarification of fetal ultrasound findings. This order's classification, aetiology and treatment, have article includes the latest medical literature data on also been included.

Key words craniosynostosis; diagnostic imaging; cranium; children; suture fusion

Introduction who also attempted to explain the cranial deformities Craniosynostosis is a pathological condition of infancy, [1]. "Virchow's law", which still remains valid, propos- characterised by partial or complete premature fusion es that cranial deformities arise when growth of the of one or multiple cranial sutures (vault and/or base), skull is interrupted perpendicular to the affected su- resulting in characteristic skull shape deformities and ture, resulting in a skull growth which is parallel to this facial asymmetry. The term was first used by Virchow, suture. Nevertheless, the severity of the resulting de-

Corresponding Irene Vraka Department of Radiology, P & A Kyriakou Children's Hospital, Author, Thivon and Levadias Str, 11527, Ampelokipoi, Athens, Greece Guarantor E-mail: [email protected]

52 Overview of craniosynostosis, p. 52-64 HR VOLUME 3 | ISSUE 2 J

formities does not reflect the severity or the extent of increasingly being indentified [24]. Spontaneous mu- synostosis [2, 3]. tation of a syndromic gene has also been reported [26]. The prevalence of this entity in the general popula- On the other hand, the secondary form of craniosyn- tion is estimated to be 3-6 infants per 10,000 live births ostosis can be attributed to various causes. First, to me- [4-7] and is reported as the most frequent craniofacial chanical causes, including intrauterine compression of anomaly [8]. The most commonly affected sutures are the foetal skull against the bones of the maternal pel- the sagittal (40-56%) [9, 10] and the coronal (20-25%), vis or conditions that diminish growth stretch at su- the latter being reported more frequently in females tures, such as microcephaly, encephalocoele and shunt- [11]. The main causes of morbidity in craniosynosto- ed hydrocephalus. Second, to metabolic causes, such sis are increased intracranial pressure, headaches, neu- as hypophosphataemic vitamin D-resistant rickets, hy- rodevelopmental delay [12-15], visual defects and cos- percalcaemia, hyperthyroidism, renal osteodystrophy, metic deformities [6, 16, 17]. Hurler's syndrome, mucopolysaccharidoses and mucol- Normal cranial sutures are distinguished into ma- ipidoses, haematological diseases like sickle cell disease jor and minor. Major sutures are the single sagittal, and thalassaemia, as well as bony dysplasia. Similarly, separating the two parietal bones, the single metopic, there are studies associating craniosynostosis with spe- formed between the frontal bones, a pair of coronal su- cific medications, such as clomiphene citrate used for tures, between the frontal and the parietal bones and a infertility [27], fluconazole [28], sodium valproate [29] pair of lambdoid sutures, between the parietal and the and citalopram [30], along with other iatrogenic fac- occipital bones. Minor sutures include the pair of the tors, such as early postnatal shunt in hydrocephalus squamosal sutures, formed between the parietals and and early craniofacial irradiation for tumour control the temporal bones, the pair of the lateral mendosal su- [24]. Finally, the secondary form of craniosynostosis tures, the single transverse occipital suture and others. can be attributed to positive family history, advanced Cranial sutures are fused from back to front and from parental age [11, 31], certain habits and the use of ter- lateral to medial, except for the metopic suture, which atogens [4, 18, 24, 27, 32, 33]. fuses from front to back [18]. Moreover, idiopathic craniosynostosis can be divid- The exact time of fusion is not the same for each su- ed into nonsyndromic or syndromic type. Nonsyndro- ture. Normally, the metopic suture is the first to be mic craniosynostosis refers to an isolated fusion of one fused, at the age of two years, a process beginning at the or two sutures and is the commonest type of the disor- age of nine months. However, there are studies report- der (80-90%) [34]. Specifically, isolated coronal synos- ing earlier closure; Vu et al. [19] set the process of me- tosis indicates a strong genetic background, compared topic suture fusion between three and nine months and to other craniosynostoses, as in 1/3 of infants carrying Weinzweig et al. [20] suggested the ages between four this phaenotype, a single gene mutation can be detect- and eight months. Regarding the sagittal suture, fusion ed [35, 36]. Therefore, Wilkie et al. [35] suggested that initiates after the age of 22 years, whereas the coronal genetic testing in nonsyndromic craniosynostosis may sutures follow, two years later. Finally, the lambdoid be targeted only to infants with coronal or multisutural sutures begin to fuse after the age of 26 years. All these synostoses. sutures do not normally close before the age of 40 years On the other hand, syndromic craniosynostosis is [21, 22]. Unfortunately, in cases of craniosynostosis, fu- rarer (10-20%) [34], involving several sutures, as it is sion initiates at the prenatal period, perinatally or even part of a systemic disorder. This type of craniosynos- during early infancy [17, 23]. tosis is associated with other extra cranial anomalies, Based on aetiology, craniosynostosis can be divid- such as syndactyly and midface hypoplasia, as well as ed into idiopathic or primary and secondary. Idiopath- malformations of the heart, the trachea and the nerv- ic craniosynostosis is attributed to a possible develop- ous system, which guide differential diagnosis towards mental error, taking place during embryogenesis, for a specific syndrome, even though this is not always instance defective dural-mesenchymal signaling is- achievable. Syndromic craniosynostosis is likely to be sues [24] or shortly after birth, resulting in an intrinsic genetically influenced, either by a single gene disor- structure defect [25], even though genetic causes are der or by chromosomal abnormalities [24]. A wide va-

53 HR Overview of craniosynostosis, p. 52-64 J VOLUME 3 | ISSUE 2

a b c a b

d e

c d

Fig. 1: Dolichocephaly. a. Axial CT scan. b-e. 3D CT volume rendered images of a ten months old girl. Partial fusion of the sagittal suture (posterior half) results in increasing anteri- or-posterior diameter, along with bitemporal narrowing, due to the restriction of biparietal growth. Fig. 2: Dolichocephaly. a. Axial CT scan. b-d. 3D CT volume rendered images of a six months old boy. Complete fusion of the sagittal su- riety of mutations in several genes has been implicat- ture, increasing the anterior-posterior diameter, while narrowing ed, including these in FGFR1, FGFR2, FGFR3, TWIST1, the bitemporal one. Frontal and occipital bulging is observed. EFNB1, MSX2 and RAB23 genes. All the same, mutations in FBN1, POR, TGFBR1 and TGFBR2 have been correlat- a b ed to craniosynostosis, despite having an apparently low penetrance and not forming the major clinical feature of the phaenotype. Among the genes described, the FRGR family is the one which plays a central role in the growth and differentiation of the mesenchymal and neuroectodermal cells, as these genes bind to fibroblast growth factor receptor (FRFR) and initiate signal trans- duction [37]. They also regulate cranial suture fusion on a macroscopic level [9]. The FGFR2 gene is the main gene of this family and its mutations are correlated to c d multiple syndromic craniosynostoses. The latter cause various and multiple sutures' involvement, as they have variable clinical expressivity [38]. Consequently, the resulting syndromes are exclusively characterised by their extra cranial coexisting abnormalities [9], such as the presence of distinct limb and dermatological features [37]. Fig. 3: Brachycephaly. a-b. 3D CT volume rendered images. c-d. Axi- Different forms of craniosynostosis al CT scan of a four month old girl. Complete bicoronal suture fusion, In cases where only one major suture is affected, the resulting to restriction of the anterior-posterior calvarial growth and terms follow the Greek terminology, describing the pronounced biparietal growth. Consequent prominent frontal bone morphology of the resulting head deformities. Thus, and an occiput flattening. Courtesy: Andrea Rossi, Genoa.

54 Overview of craniosynostosis, p. 52-64 HR VOLUME 3 | ISSUE 2 J a b c

Fig. 4: Anterior plagiocephaly. a-c. 3D CT volume rendered images of a 21 months old boy. Right coronal suture fusion, which results to the flattening of the frontal bone on the affected side, but prominent frontal bossing to the contralateral side. There is also evident orbit asymmetry.

the term dolichocephaly (dolikhos=long and cephal- a b c i=skull) describes the skull's shape after the early synostosis of the sagittal suture (Figs. 1 and 2). Scaphoce- phaly (scaphe=boat) is a subgroup of dolichocephaly, including evident ridging of the sagittal suture, alike to the boat's keel. Similarly, the terms brachycephaly (brachy=short) and turricephaly (turri=tower) cor- d e respond to the synostosis of the bicoronal (Fig. 3) and the bilambdoid suture, respectively. The term plagiocephaly (plagios=oblique) corresponds to the asymmetry of the neurocranium, due to synostosis of only one of the pair of the coronal (anterior plagiocephaly) (Fig. 4) or the lambdoid sutures (posterior plagiocheph- aly) (Fig. 5). Trigonocephaly (trigonos=triangle) corre- Fig. 5: Uncorrected posterior plagiocephaly. a-c. 3D CT vol- sponds to the resulting deformity from synostosis of ei- ume rendered images. d. axial CT scan. e. coronal CT scan of ther the metopic suture (anterior trigonocephaly) (Fig. a three year old boy. The left lambdoid suture is fused, with 6) or the posterior third of the sagittal suture and both consequent bulging of the ipsilateral temporal and the con- the lambdoid sutures (posterior trigonocephaly). Ox- tralateral parietal region. Additionally, the posterior skull ycephaly (oxys=sharp) results from bilateral synosto- base is tilted downward on the affected side. sis of the paired coronal and lambdoid sutures [25, 39]. Courtesy: Andrea Rossi, Genoa. Nevertheless, in cases of combined synostosis of all major sutures, the skull has a cloverleaf appearance, which is the most impressive cranio-facial syndromic deform- dromes. The most significant complication in these cas- ity, termed pansynostosis (pan=whole) [18]. Pansynos- es is the raised intracranial pressure and the coexisting tosis can be identified in nonsyndromic cases, but usu- brain malformations, along with marked face and ex- ally appears in syndromic conditions [3]. tremities' involvement. The most common and clinically significant syn- Apert syndrome is characterised by bicoronal synos- dromes are the Apert, Crouzon, Pfeiffer, Vogt, Sae- tosis and severe symmetrical syndactyly of fingers and thre-Chotzen, Carpenter, Muenke, Antrley-Bixler, toes, the latter being the critical feature for the dif- Jackson-Weiss, as well as the mixed Apert-Crouzon syn- ferentiation of this from other FRFG2 syndromes. Oth-

55 HR Overview of craniosynostosis, p. 52-64 J VOLUME 3 | ISSUE 2

er craniofacial malformations include more sutures fu- may result to cloverleaf deformity of the skull (Fig. 8) sion, up to the cloverleaf deformity, flat forehead and or acro-brachycephaly, depending on the extent and retracted midface, proptosis and hypertelorism, low set the order of suture fusion. Accompanying facial fea- ears, hypoplastic maxilla, small and malformed skull tures are tall and flat forehead, proptosis, parrot-beak base and craniovertebral junction, frequently leading nose, midface and maxillary hypoplasia with progna- to Chiari I malformation, as well as vertebral fusion thism and basilar kyphosis [9, 25, 39]. A nasopharynx anomalies at the level of the cervix (Fig. 7) [9, 25, 39]. deformity is also present in this syndrome, predispos- Midface retraction and narrow pharynx usually cause ing to life-threatening obstructive sleep apnoea [25, airway compromise [9]. At the same time, brain malfor- 43]. As regards brain malformations, they are common mations include complete or partial absence or the cor- and include mainly midline anomalies, such as corpus pus callosum and significant hydrocephalus, especially callosum hypoplasia or even aplasia, Chiari I malfor- after craniectomy [25]. Finally, variable mental defi- mation and syringomyelia, as well as hydrocephalus. ciency and learning disability are present, even though Finally, Pfeiffer syndrome is also similar to Apert syn- individuals with normal intelligence have been report- drome and the differential diagnosis is based on the co- ed [18, 25]. Apert syndrome is inherited in an autosomal existing anomalies to the extremities, including syn- dominant way and is attributed to a FGFR2 gene muta- dactyly, which is restricted to soft tissues, while toes tion, located in the linker between the IgII and IgIII do- and thumbs are short and broad. Craniosynostosis in- mains [40]. However, Goriely et al. [41] reported that, volves the coronal and sagittal sutures, the latter form- in the vast majority of infants with Apert syndrome, de ing an intracranial bony crest [25]. As Pfeiffer's syn- novo mutations are detected, mainly originating from drome clinical phaenotypes are of different severity, it paternal sperm. is categorised in three types. Type I has the best prog- Crouzon syndrome is also inherited in an autosomal nosis, with normal individuals' intelligence. It is char- dominant way and the mutations are equally located in acterised by brachycephaly, midface hypoplasia, hy- the FGFR2 gene. Thus it is allelic with Apert syndrome, pertelorism and hearing loss accompanied by auditory even if specific mutations in the FGFR3 gene have been stenosis or atresia, along with hypoplasia or enlarge- indentified in infants whose craniosynostosis is accom- ment of the middle ear cavity. In type II, the main fea- panied with acanthosis nigricans on the skin [37]. Sim- tures include cloverleaf skull deformity and severe ilarly to Apert syndrome, Crouzon syndrome is related proptosis. Finally, type III includes the features of both to advanced paternal age and de novo come up of the previously mentioned types, along with mental retar- entity to the offspring [42]. Cranial features in Crouzon dation and hydrocephalus [9, 39]. Congenital brain syndrome include multiple suture involvement, which anomalies are rarer than in the previously described

a b c d

Fig. 6: Trigonocephaly. a. Axial CT scan. b-d. 3D CT volume rendered images of a four months old boy, depicting the fusion of the metopic suture and the consequent triangular morphology of the forehead, as well as the flattening of the two initial frontal bones.

56 Overview of craniosynostosis, p. 52-64 HR VOLUME 3 | ISSUE 2 J

a b a b

c d e

c d

Fig. 7: Apert syndrome in a three years old girl. a-b. Axial CT scan. c-e. 3D CT volume rendered images, demonstrating fusion of all sutures, with a small and malformed skull base.

syndromes and the Chiari I anomaly is a result of the al- Fig. 8: Crouzon syndrome. a-c. 3D CT volume rendered images tered relationships between the posterior fossa, the fo- of a ten days old girl. d. Photograph of patient at six months of ramen magnum and their contents [25]. age. There is an evident cloverleaf deformity of the skull, with It is of utmost importance, thus a great diagnos- tall and flat forehead, midface hypoplasia and elliptical orbits, tic challenge, to differentiate posterior plagiocepha- due to undeveloped supraorbital ridges ("harlequin eyes"). ly from deformational or positional posterior plagiocephaly. Deformational posterior plagiocephaly is the asymmetric flattening of the infant's head as a re- physicians [47-50]. In deformational plagiocephaly the sult of repeated pressure, after constant external forc- lambdoid suture is patent and is combined with ipsi- es, even prenatally on the maternal pelvis bones and/ lateral frontal bossing, which is not found in posteri- or postnatally, for instance lying on one side of the or plagiocephaly (Fig. 9) [18]. head on a flat surface, still without malformative al- All the same, the metopic ridge is a normal variant terations [44, 45]. Deformational posterior plagioceph- of the metopic suture closure, which has to be differ- aly usually presents some time after birth, progresses entiated for the same reasons from metopic synosto- until six months of age and remains stable thereafter sis. It occurs in 4% of asymptomatic children, aged 1-18 [46]. The resulting deformity of the skull is only of cos- months, without any other characteristic feature of the metic significance, responding to conservative meas- corresponding synostosis, such as trigonocephaly, hy- ures, such as changing sleep position or corrective hel- potelorism or medially upward slanted orbital roof [18]. mets. In contrast, posterior plagiocephaly needs early Birgfeld et al. [51] reported that infants with metopic surgical correction, as it may lead to the complica- craniosynostosis are usually younger than those with tions referred for craniosynostosis, which makes the metopic ridge. early diagnosis very important, even though some- times it is proving challenging. Deformational poste- Diagnostic approach rior plagiocephaly has been exponentially increasing Although the diagnosis of craniosynostosis can be clin- since 1992, probably due to the recommendation of the ical, all imaging techniques contribute to the accurate International Paediatric Societies, indicating that in- diagnosis of the entity, by demonstrating the exact ex- fants should sleep in the supine position, in order to tent of the suture fusion, the resulting craniofacial de- prevent sudden infant death syndrome, along with in- formities, as well as the coexisting anomalies or com- creased awareness of posterior plagiocephaly among plications. Therefore, the main goals of imaging are to

57 HR Overview of craniosynostosis, p. 52-64 J VOLUME 3 | ISSUE 2

a b c

Fig. 9: Deformational posterior plagiocephaly. a. Axial CT scan. b-c. 3D CT volume rendered images of an eight months old boy, imaging the patent coronal, sagittal and lambdoid sutures, without tilting of any part of the skull, despite its parallelogram shape.

confirm the clinical diagnosis, as well as to guide surgi- tory diagnostic accuracy, when they are of good quality cal planning and post treatment evaluation. and when they are interpreted by experienced readers. Three-Dimensional Computed Tomography (3D CT) is Nevertheless, even the utility of plain radiographs is in considered the gold standard for the diagnosis of crani- question, because there are cases where the quality is osynostosis in the assessment of infants with abnormal poor and crucial information is not provided. skull shape, as it can provide highly detailed 3D images Therefore, the most recent trend includes clinical ex- of the skull, along with information about the possible amination as the first step in the assessment of infants coexisting anomalies of the brain. As a rule, 3D CT is the with abnormal skull shape, which is considered to be imaging modality of choice for syndromic cases, pro- enough to diagnose almost all monosutural forms of vided that the number and extent of suture fusion are craniosynostosis [18]. Secondly, cranial ultrasound can depicted in detail, as well as possible coexisting brain provide additional information in cases where the di- anomalies. On the other hand, for non syndromic dis- agnosis is in question. Cranial ultrasound is radiation ease, the suggested diagnostic algorithm includes plain free and is currently increasingly recommended as the radiographs for the initial assessment, followed by 3D modality of choice for the investigation of neonates and CT only in the case of positive or equivocal results [52]. infants younger than one year of age, as it seems to be However, concerns about the exposure of infants to a highly specific and sensitive technique [8, 57]. It can radiation and the risks of sedation have led to a con- differentiate fused from patent sutures and, thus, posi- sensus, in order to avoid or at least to postpone 3D CT tional skull deformities from real craniosynostosis [18, for the end of the first year of life or as late as possible 58], which is the most common and the most critical in infants with suspected or diagnosed craniosynosto- question in daily clinical practice. However, cranial ul- sis [18, 34, 53, 54]. Plain radiographs have been indicat- trasound has its own limitations, as it cannot depict cra- ed as an alternative choice to 3D CT, estimating their ef- nial base sutures and is highly operator depended [45]. fective dose between 0.01-0.04 mSv, when the reported Furthermore, large studies evaluating its accuracy are effective dose of 3D CT is estimated to be between 0.2- not yet available. 2 mSv [18, 23, 55, 56]. They give answers to the majori- On the other hand, 3D CT is unavoidable in syndro- ty of clinical questions related to surgical planning and mic or even multisutural cases, as well as in compli- postoperative follow up in cases of monosutural crani- cated types of the disease, in order to plan the surgi- osynostosis [18]. In addition, plain radiographs are a cal treatment [18]. Furthermore, Magge et al. [59] have widely available, low cost examination, with a satisfac- emphasised the ability of CT to demonstrate inciden-

58 Overview of craniosynostosis, p. 52-64 HR VOLUME 3 | ISSUE 2 J

tal findings in the brain, some of which required addi- should be made, such as (a) proper delivery planning tional follow-up or management, for instance promi- and elective Caesarean section (b) early postnatal in- nent extra-axial cerebrospinal fluid, ventriculomegaly vestigation and early surgery or even (c) foetal surgery and Chiari malformation. However, as these children [66]. Even though prenatal diagnosis of syndromic cas- may undergo 3D CT more than once, not only for diag- es of craniosynostosis is difficult to be made before the noses, but also for the different stages of surgical cor- third trimester, where possible, foetal MRI can play a rections, an effort to minimise the radiation dose has complementary role to the previously operated foetal been made. Certain low-dose dedicated cranial proto- ultrasound, giving important information about cran- cols have been proposed, reducing the effective dose to iofacial relationships and coexisting brain and body 0.08 mSv or even to 0.02 mSv, an amount compatible to anomalies [67, 68]. At any rate, it is clear that cranial su- that of plain radiographs, archiving at the same time tures cannot be depicted directly on foetal ultrasound images of good quality for the diagnosis of craniosyn- or foetal MRI, but skull deformities and other indirect ostosis [60-62]. Additionally, even in syndromic cases, signs can indicate the disorder. Until now, a small per- brain ultrasound can play an important role, as it can centage of cases of isolated craniosynostosis are prena- depict the brain, without any anaesthesia needed, pro- tally diagnosed [69]. However, Helfer et al. [70] suggest- vided that the fontanels are open. Moreover, Soboleski ed that a foetal 3D ultrasound technique may improve et al. [63] suggested that increased sutures' width on se- the efficiency of conventional foetal ultrasound in the rial cranial ultrasounds may indicate increase of intrac- diagnosis of craniosynostosis in the near future. ranial pressure, which is a complication of craniosynostosis, important to be diagnosed in time. Treatment Magnetic Resonance Imaging (MRI) plays a limited A conservative management of craniosynostosis may in- role in the investigation of the skull in craniosynos- clude molding helmets and is typically applied in cases tosis, as it cannot reliably identify the cranial sutures. of secondary craniosynostosis with normal intracranial On the contrary, it is a method of great interest and of pressure, as well as in deformational posterior plagioceph- good prospective, as it involves no radiation, a parame- aly [39]. The remaining types of this entity, accompanied ter of utmost importance for the ages studied for crani- by restriction of brain growth and raised intracranial osynostosis. Bearing this in mind, Eley et al. [64, 65] sug- pressure, always require early surgical management. gested a new promising 3D MRI technique, called "Black There are two main indications for surgical treatment Bone" MRI, aiming to ameliorate the method’s accura- of isolated craniosynostosis, the first being the correc- cy in the diagnosis of craniosynostosis, by stressing the tion of the calvarium shape for aesthetic and psychoso- bone-soft tissue boundary and minimising soft tissue cial reasons, improving the patient's quality of life dur- contrast. The effectiveness and the value of this tech- ing early childhood or puberty (Fig. 10). The second is nique remain to be proven. However, being the meth- to ensure that there is enough space for brain growth od of choice for brain imaging, MRI is for the moment after the reconstruction of the skull [71]. an ideal diagnostic tool, supplementary to brain ultra- In cases of non-syndromic craniosynostosis, no de- sound, in the investigation of intracranial anomalies finitive or strict guidelines exist about the optimal time or complications associated with craniosynostosis [18]. or the type of surgical intervention. Treatment of these Moreover, as foetal MRI is a well established method children may vary, based on the patient's age at pres- of prenatal diagnosis, it can be applied for the earlier entation, location and number of craniosynostoses, se- detection of craniosynostosis. Even though large pro- verity of deformity and the final decision is up to the spective studies have not been published as yet, certain neurosurgeon. Surgery is suggested as soon as the in- interesting retrospective studies support this potential fant is able to tolerate it. In our institution we tend to application of foetal MRI in combination with foetal ul- treat children at the age of 6-12 months, because of suf- trasound. The goals of antenatal diagnosis in craniosyn- ficient available circulating blood resources compared ostosis is to avoid untreated cases and to differentiate to younger infants and improved and more permanent syndromic from isolated non-syndromic craniosynos- aesthetic outcome. In addition, during this life period tosis, thus to indicate cases where early interventions of rapidly growing cranial vault, the bones are malle-

59 HR Overview of craniosynostosis, p. 52-64 J VOLUME 3 | ISSUE 2

a b

Fig. 10: a. Flattening of the occiput on the side of the fused lambdoid suture, with compensatory bulging on the contralateral perieto-occiput. b. Postoperative image, depicting the correction of the lambdoid synostosis and the skull asymmetry.

a b Fig. 11: a. Triangular shape of the head, just before surgery. b. Coro- nal incision and elevation of the skin flap. The surgical reconstruction is based on the remodeling of the fused suture in the midline of the forehead and fronto-orbital reconstruction.

a b

Fig. 12: a. Head deformity (dolichocephaly) before surgery. b. Strip craniectomy, with perpendicular osteotomies.

able and heal effectively. However, in infants bearing to turn it back to the preoperative state, thus multiple severe deformities, surgical treatment may take place consecutive operations may be needed [71, 72]. earlier than the age of six months or even after the first In non-syndromic craniosynostosis, the surgical tech- year of life. nique includes a bicoronal zigzag or straight skin inci- As regards syndromic craniosynostosis, general prac- sion behind the hair line, which usually allows for good tice in craniofacial repair indicates early cranial vault handling of the whole skull, from the supraorbital rim repair, between six and nine months of life, in order to to the occiput (Fig. 11). The incision is extended anteri- achieve normal brain growth. Repair of facial structures, orly or posteriorly, depending on the treated pathology. including the orbit, the maxilla and the mandible, may be Subsequently, the surgical procedure is tailored by the delayed, between five and eight years of life, so as to deal synostotic suture and the degree of secondary cranial with aesthetic problems, as well as the position of the or- vault defect (Fig. 12). In general, the affected suture has bits, dental occlusion and pharyngeal function [72]. How- to be removed, placing burr holes around it, while the ever, it should be clearly stated that the continuous im- bone flap containing the suture has to be reconstruct- pact of genetic mutations on the developing skull tends ed and reassigned in the same location, facing the same

60 Overview of craniosynostosis, p. 52-64 HR VOLUME 3 | ISSUE 2 J

or a different direction. In certain types of craniosynos- tect the orbits, free the upper airway and improve aes- tosis, the supraorbital margin needs to be reconstructed thetic results [73]. as well. Moreover, the skull around the craniotomy is reconstructed by creating “barrel-stave” osteotomies and Conclusion bending or fracturing the bony segments outwards, in an Even though craniosynostosis is a well-known entity, there effort to increase intracranial volume. The decision for are still several topics for investigation, as new informa- the bony fragments fixation with absorbable plating sys- tion is coming up with advancing imaging modalities. At the tem and the possible use of subgaleal drains depends on same time, craniosynostosis is quite a demanding disorder, the medical institution and the surgeon’s preference. Re- as it affects infancy, an age with a lot of particularities. The cently, an increasing preference for endoscopic surgical challenges for the diagnosis and treatment of this entity are treatment of non-syndromic craniosynostosis has been significant, and their consequences will follow the patient noted. The endoscopic technique is based on the old open throughout his or her entire life. Thus, every diagnostic or suturectomy, according to which only the fused suture treating intervention has to be cautious and evidence based, is released, without reconstruction of a greater portion in order to have optimal outcomes for the infant. On the do- of the skull [71, 72]. main of diagnosis, there are still questions to be answered, Moreover, in surgical operations for syndromic crani- specifically on the possibility to effectively replace diagnos- osynostosis, the skin incision follows the same princi- tic methods with ionising radiation (plain radiographs and ples. However, the procedure following bone revelation 3D CT), with other, more infant-friendly methods, such as is quite complex and involves many surgical specialties. cranial ultrasound and MRI. Large, prospective and multi- The most frequently used techniques are fronto-orbital centre studies may be needed, in order to reliably establish advancement, cranial vault expansion with or without such diagnostic protocols. R the use of springs or distraction technology, monobloc frontofacial advancement and facial bipartition. All these Conflict of interest different approaches increase intracranial volume, pro- The authors declared no conflicts of interest.

References

1. Virchow R. Ueber den cretinismus, namentlich in 7. Stenirri S, Restagno G, Ferrero GB, et al. Integrated franken und uber pathologische schladelformen. Ve- strategy for fast and automated molecular charac- randl D Physic Med Gesellschaft 1851; 2: 230-245. terization of genes involved in craniosynostosis. Clin 2. Bristol RE, Krieger MD, McComb JG. Normally shaped Chem 2007; 53(10): 1767-1774. heads with no sutures, normally shaped heads with 8. Rozovsky K, Udjus K, Wilson N, et al. Cranial ultra- abnormal sutures, and abnormally shaped heads with sound as a first-line imaging examination for crani- normal sutures. J Craniofac Surg 2011; 22(1): 173-177. osynostosis. Pediatrics 2016; 137(2): e20152230. 3. Blount JP, Louis RG Jr, Tubbs RS, et al. Pansynosto- 9. Ko JM. Genetic syndromes associated with crani- sis: a review. Childs Nerv Syst 2007; 23(10): 1103-1109. osynostosis. J Korean Neurosurg Soc 2016; 59(3): 4. Nagaraja S, Anslow P, Winter B. Craniosynostosis. Clin 187-191. Radiol 2013; 68(3): 284-292. 10. Governale LS. Craniosynostosis. Pediatr Neurol 2015; 5. Boulet SL, Rasmussen SA, Honein MA. A popula- 53(5): 394-401. tion-based study of craniosynostosis in metropoli- 11. Lajeunie E, Le Merrer M, Bonaïti-Pellie C, et al. Ge- tan Atlanta, 1989-2003. Am J Med Genet A 2008; 146A netic study of nonsyndromic coronal craniosynos- (8): 984-991. tosis. Am J Med Genet 1995; 55(4): 500-504. 6. Kotrikova B, Krempien R, Freier K, et al. Diagnostic 12. Nguyen C, Hernandez-Boussard T, Khosla RK, et al. A imaging in the management of craniosynostoses. Eur national study on craniosynostosis. Cleft Palate Cran- Radiol 2007; 17(8): 1968-1978. iofac J 2013; 50(5): 555-560.

61 HR Overview of craniosynostosis, p. 52-64 J VOLUME 3 | ISSUE 2

13. Starr JR, Kapp-Simon KA, Cloonan YK, et al. Presur- 26. Lajeunie E, Crimmins DW, Arnaud E, et al. Genetic gical and postsurgical assessment of the neurode- considerations in nonsyndromic midline craniosyn- velopment of infants with single-suture craniosynostoses: a study of twins and their families. J Neuro- ostosis: comparison with controls. J Neurosurg 2007; surg 2005; 103(4 Suppl): 353-356. 107(2 Suppl): 103-110. 27. Ardalan M, Rafati A, Nejat F, et al. Risk factors asso- 14. Tamburrini G, Caldarelli M, Massimi L, et al. Intrac- ciated with craniosynostosis: a case control study. ranial pressure monitoring in children with sin- Pediatr Neurosurg 2012; 48(3): 152-156. gle suture and complex craniosynostosis: a review. 28. Lopez-Rangel E, Van Allen MI. Prenatal exposure to Childs Nerv Syst 2005; 21(10): 913-921. fluconazole: an identifiable dysmorphic phenotype. 15. Speltz ML, Kapp-Simon KA, Cunningham M, et al. Birth Defects Res A Clin Mol Teratol 2005; 73(11): 919-923. Single-suture craniosynostosis: a review of neurobe- 29. Lajeunie E, Le Merrer M, Marchac D, et al. Syndromal havioral research and theory. J Pediatr Psychol 2004; and nonsyndromal primary trigonocephaly: analy- 29(8): 651-668. sis of a series of 237 patients. Am J Med Genet 1998; 16. Aviv RI, Rodger E, Hall CM. Craniosynostosis. Clin Ra- 75(2): 211-215. diol 2002; 57(2): 93-102. 30. Durham E, Jen S, Wang L, et al. Effects of citalopram 17. Kabbani H, Raghuveer TS. Craniosynostosis. Am Fam on sutural and calvarial cell processes. PLoS One Physician 2004; 69(12): 2863-2870. 2015; 10(10): e0139719. 18. Kim HJ, Roh HG, Lee IW. Craniosynostosis: updates 31. Nazzaro A, Della Monica M, Lonardo F, et al. Prenatal in radiologic diagnosis. J Korean Neurosurg Soc 2016; ultrasound diagnosis of a case of Pfeiffer syndrome 59(3): 219-226. without cloverleaf skull and review of the literature. 19. Vu HL, Panchal J, Parker EE, et al. The timing of Prenat Diagn 2004; 24(11): 918-922. physiologic closure of the metopic suture: a review 32. Helfer TM, Peixoto AB, Tonni G, et al. Craniosynos- of 159 patients using reconstructed 3D CT scans of tosis: prenatal diagnosis by 2D/3D ultrasound, mag- the craniofacial region. J Craniofac Surg 2001; 12(6): netic resonance imaging and computed tomogra- 527-532. phy. Med Ultrason 2016; 18(3): 378-385. 20. Weinzweig J, Kirschner RE, Farley A, et al. Metopic 33. Cunningham ML, Seto ML, Ratisoontorn C, et al. Syn- synostosis: Defining the temporal sequence of nor- dromic craniosynostosis: from history to hydrogen mal suture fusion and differentiating it from synos- bonds. Orthod Craniofac Res 2007; 10(2): 67-81. tosis on the basis of computed tomography images. 34. Badve CA, K MM, Iyer RS, et al. Craniosynostosis: im- Plast Reconstr Surg 2003; 112(5): 1211-1218. aging review and primer on computed tomography. 21. Kirmi O, Lo SJ, Johnson D, et al. Craniosynostosis: a Pediatr Radiol 2013; 43(6): 728-742; quiz 725-727. radiological and surgical perspective. Semin Ultra- 35. Wilkie AO, Byren JC, Hurst JA, et al. Prevalence and sound CT MR 2009; 30(6): 492-512. complications of single-gene and chromosomal dis- 22. Kokich VG. The biology of sutures. In: Cohen Jr MM orders in craniosynostosis. Pediatrics 2010; 126(2): (ed). Craniosynostosis. Diagnosis, evaluation and e391-400. management. Raven Press, New York 1986, pp 93-94. 36. Kimonis V, Gold JA, Hoffman TL, et al. Genetics of 23. Calandrelli R, D'Apolito G, Gaudino S, et al. Identifi- craniosynostosis. Semin Pediatr Neurol 2007; 14(3): cation of skull base sutures and craniofacial anom- 150-161. alies in children with craniosynostosis: utility of 37. Passos-Bueno MR, Serti Eacute AE, Jehee FS, et al. Ge- multidetector CT. Radiol Med 2014; 119(9): 694-704. netics of craniosynostosis: genes, syndromes, mu- 24. Blaser SI, Padfield N, Chitayat D, et al. Skull base de- tations and genotype-phenotype correlations. Front velopment and craniosynostosis. Pediatr Radiol 2015; Oral Biol 2008; 12: 107-143. 45 Suppl 3: S485-496. 38. Kan SH, Elanko N, Johnson D, et al. Genomic screen- 25. Colosimo C, Tartaro A, Cama A, et al. The Craniosyn- ing of fibroblast growth-factor receptor 2 reveals a ostoses. In: Tortori-Donati P (ed). Pediatric neurora- wide spectrum of mutations in patients with syn- diology, brain, head and neak, spine. Springer-Verlag dromic craniosynostosis. Am J Hum Genet 2002; 70(2): Berlin Heidelberg, New York 2005, pp 1289-1315. 472-486.

62 Overview of craniosynostosis, p. 52-64 HR VOLUME 3 | ISSUE 2 J

39. Khanna PC, Thapa MM, Iyer RS, et al. Pictorial essay: 52. Vinocur N, Medina L. Imaging the evaluation of chil- the many faces of craniosynostosis. Indian J Radiol Im- dren with suspected craniosynostosis. In: Medina L, aging 2011; 21(1): 49-56. Applegate KE, Blackmore C (eds). Evident-based im- 40. Slaney SF, Oldridge M, Hurst JA, et al. Differential ef- aging in Pediatrics. Improving the quality of imag- fects of FGFR2 mutations on syndactyly and cleft pal- ing in patient care. Springer Science and Business Me- ate in Apert syndrome. Am J Hum Genet 1996; 58(5): dia, New York 2010, pp 43-52. 923-932. 53. Schweitzer T, Kunz F, Meyer-Marcotty P, et al. Diag- 41. Goriely A, McVean GA, van Pelt AM, et al. Gain-of- nostic features of prematurely fused cranial sutures function amino acid substitutions drive positive se- on plain skull X-rays. Childs Nerv Syst 2015; 31(11): lection of FGFR2 mutations in human spermatogo- 2071-2080. nia. Proc Natl Acad Sci USA 2005; 102(17): 6051-6056. 54. Schweitzer T, Böhm H, Meyer-Marcotty P, et al. 42. Glaser RL, Jiang W, Boyadjiev SA, et al. Paternal or- Avoiding CT scans in children with single-su- igin of FGFR2 mutations in sporadic cases of Crou- ture craniosynostosis. Childs Nerv Syst 2012; 28(7): zon syndrome and Pfeiffer syndrome. Am J Hum Gen- 1077-1082. et 2000; 66(3): 768-777. 55. Didier RA, Kuang AA, Schwartz DL, et al. Decreas- 43. Mitsukawa N, Satoh K, Hayashi T, et al. A reflecta- ing the effective radiation dose in pediatric crani- ble case of obstructive sleep apnea in an infant with ofacial CT by changing head position. Pediatr Radiol Crouzon syndrome. J Craniofac Surg 2004; 15(5): 874- 2010; 40(12): 1910-1917. 878; discussion 878-879. 56. Vazquez JL, Pombar MA, Pumar JM, et al. Opti- 44. Knudsen B, Christensen K, Baagøe S, et al. [Position- mised low-dose multidetector CT protocol for chil- al plagiocephaly in infants can be prevented] [Arti- dren with cranial deformity. Eur Radiol 2013; 23(8): cle in Danish]. Ugeskr Laeger 2011; 173(9): 644-648. 2279-2287. 45. Pogliani L, Zuccotti GV, Furlanetto M, et al. Crani- 57. Pogliani L, Mameli C, Fabiano V, et al. Positional pla- al ultrasound is a reliable first step imaging in chil- giocephaly: what the pediatrician needs to know. A dren with suspected craniosynostosis. Childs Nerv review. Childs Nerv Syst 2011; 27(11): 1867-1876. Syst 2017; 33(9): 1545-1552. 58. Proisy M, Riffaud L, Chouklati K, et al. Ultrasonogra- 46. Jones BM, Hayward R, Evans R, et al. Occipital pla- phy for the diagnosis of craniosynostosis. Eur J Radi- giocephaly: an epidemic of craniosynostosis? BMJ ol 2017; 90: 250-255. 1997; 315(7110): 693-694. 59. Magge KT, Magge SN, Keating RF, et al. Incidental 47. Argenta LC, David LR, Wilson JA, et al. An increase in findings on preoperative computed tomography for infant cranial deformity with supine sleeping posi- nonsyndromic single suture craniosynostosis. J Cran- tion. J Craniofac Surg 1996; 7: 5-11. iofac Surg 2014; 25(4): 1327-1330. 48. Kane AA, Mitchell LE, Craven KP, et al. Observations 60. Montoya JC, Eckel LJ, DeLone DR, et al. Low-Dose CT on a recent increase in plagiocephaly without syn- for Craniosynostosis: preserving diagnostic benefit ostosis. Pediatrics 1996; 97(6 Pt 1): 877-885. with substantial radiation dose reduction. AJNR Am 49. Turk AE, McCarthy JG, Thorne CH, et al. The "back J Neuroradiol 2017; 38(4): 672-677. to sleep campaign" and deformational plagioceph- 61. Ernst CW, Hulstaert TL, Belsack D, et al. Dedicated aly: is there cause for concern? J Craniofac Surg 1996; sub 0.1 mSv 3DCT using MBIR in children with sus- 7(1): 12-18. pected craniosynostosis: quality assessment. Eur Ra- 50. Willinger M, Hoffman HJ, Hartford RB. Infant sleep diol 2016; 26(3): 892-899. position and risk for sudden infant death syndrome: 62. Kaasalainen T, Palmu K, Lampinen A, et al. Limiting report of meeting held January 13 and 14, 1994, Na- CT radiation dose in children with craniosynosto- tional Institutes of Health, Bethesda, MD. Pediatrics sis: phantom study using model-based iterative re- 1994; 93: 814-819. construction. Pediatr Radiol 2015; 45(10): 1544-1553. 51. Birgfeld CB, Saltzman BS, Hing AV, et al. Making the 63. Soboleski D, Mussari B, McCloskey D, et al. High-res- diagnosis: metopic ridge versus metopic craniosyn- olution sonography of the abnormal cranial suture. ostosis. J Craniofac Surg 2013; 24(1): 178-185. Pediatr Radiol 1998; 28(2): 79-82.

63 HR Overview of craniosynostosis, p. 52-64 J VOLUME 3 | ISSUE 2

64. Eley KA, Watt-Smith SR, Golding SJ. "Black Bone" nofetal Trauma in Craniosynostosis. Plast Reconstr MRI: a potential non-ionizing method for three-di- Surg 2015; 136(2): 214e-222e. mensional cephalometric analysis--a preliminary 70. Helfer TM, Peixoto AB, Tonni G, et al. Craniosynos- feasibility study. Dentomaxillofac Radiol 2013; 42(10): tosis: prenatal diagnosis by 2D/3D ultrasound, mag- 20130236. netic resonance imaging and computed tomogra- 65. Eley KA, Watt-Smith SR, Golding SJ. "Black Bone" phy. Med Ultrason 2016; 18(3): 378-385. MRI: a novel imaging technique for 3D printing. Den- 71. Baird L, Mark M. Craniosynostosis. In: Albright AL, tomaxillofac Radiol 2017; 46(3): 20160407. Pollack IF and Adelson PD (ed.) Principles and prac- 66. Miller C, Losken HW, Towbin R, et al. Ultrasound di- tice of pediatric neurosurgery 3rd Edition, Thieme agnosis of craniosynostosis. Cleft Palate Craniofac J Medical Publishers, Inc., New York 2015, pp 237-248. 2002; 39(1): 73-80. 72. McKinnon M, Frim DM. Craniofacial Surgery. In: 67. Rubio EI, Blask A, Bulas DI. Ultrasound and MR im- Frim DM, Gupta N (ed). Pediatric Neurosurgery, Vade- aging findings in prenatal diagnosis of craniosynos- mecum Landes Bioscience, Georgetown, Texas, 2006, pp tosis syndromes. Pediatr Radiol 2016; 46(5): 709-718. 161-174. 68. Fjørtoft MI, Sevely A, Boetto S, et al. Prenatal diag- 73. Hayward R. Craniofacial Syndromes. In: Albright AL, nosis of craniosynostosis: value of MR imaging. Neu- Pollack IF, Adelson PD (ed.) Principles and practice roradiology 2007; 49(6): 515-521. of pediatric neurosurgery 3rd Edition, Thieme Medi- 69. Swanson J, Oppenheimer A, Al-Mufarrej F. Mater- cal Publishers, Inc., New York 2015, pp 249-266.

Ready - Made Vraka I, Georgis PA, Nikas I. Overview of craniosynostosis. Hell J Radiol 2018; Citation 3(2): 52-64.