10.2478/bjdm-2018-0001

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L BALKAN JOURNAL OF DENTAL MEDICINE A ISSN 2335-0245 IC G LO TO STOMA

Crouzon Syndrome: a Comprehensive Review

SUMMARY Chrystalla Kyprianou1, Athina Chatzigianni2 is a rare genetic disorder with autosomal dominant 1 Dental practice, Thessaloniki, Greece inheritance. The underlying pathological process is premature 2 School of Dentistry, Aristotle University of of the cranial sutures with subsequent phenotypic alterations of the Thessaloniki, Thessaloniki, Greece affected person. A review of the literature has been conducted in order to resume the overall characteristics of Crouzon syndrome such as cranio- maxillofacial malformations, clinical features, dentoalveolar characteristics, aesthetic impairments, and psychological background, as well as, the different therapeutic procedures, which combine surgical and orthodontic interventions. Facial and functional malformations in individuals with Crouzon syndrome could be significantly improved after a series of surgical and orthodontic procedures in almost all cases. A multidisciplinary treatment approach would provide the best outcomes in affected patients. Key words: Crouzon, Crouzon Syndrome, Diagnosis, Multidisciplinary Approach, REVIEW PAPER (RP) Orthodontic Management, Surgical Management Balk J Dent Med, 2018;1-6

Introduction Clinical features

The term “Crouzon syndrome” describes an Craniofacial and dentoalveolar characteristics autosomal disease, which results from hereditary mutations identified in specific genes in the human The syndromic patients are characterized by specific DNA chain.The molecular deformities most customarily craniofacial characteristics. The main feature of Crouzon occur in FGFR2 gene and, in rare instances, in the syndrome is the premature synostosis of craniofacial FGFR3 gene1-6. Moreover, recent studies have identified sutures, which leads to cranium deformity manifested mutations in FGFR1, MSX2, TWIST1, EFnB1, NELL1, as , or with dolichofacial growth pattern13. Moreover, concave facial GLI3 and TCF12 genes7-9. These mutations result in profile appears due to midfacial hypoplasia with implied premature synostosis of several sutures of the craniofacial retropositioned zygomaticomaxillary complex, while complex. Specifically, the fusion of the sagittal and the exopthalmus and ocular proptosis are connected to coronal sutures begins, in the most of the cases, during shallow orbits14,15. Part of the midfacial discrepancy the first year of life leading to the growth inhibition at includes the deviated nasal septum, which results in the affected sutures and compensative growth at other beaked nose1,16. 10 sutures . It is one of the most frequent The premature synostosis of several sutures of the syndromes, with estimated incidence of 1:60000 live middle third of the facial skeleton results in differentiation 11,12 births . of the intraoral anatomy in Crouzon patients. The The aim of this study was to investigate the available hypoplastic, narrow and high arched palate results in information on the general characteristics, the therapeutic decreased upper dental arch dimensions1,17. Also, severe needs and the existing management protocols of patients crowding of the primary and secondary dentitions, with Crouzon syndrome. anterior and posterior crossbite are usually diagnosed, 2 Chrystalla Kyprianou, Athina Chatzigianni Balk J Dent Med, Vol 22, 2018 as well as malformed teeth, delayed dental eruption accurate evaluation of fetal head, and sutures, as and impactions18-20. High risk of maxillary canine and well as detailed visualization of the whole fetal anatomy premolar impactions is evident in patients who present which contributes to the differential diagnosis between severe lack of space in the upper arch. In some cases, craniosynostosis syndromes34,35. In addition, MRI can about 40% of the patients with Crouzon syndrome, be considered complementary to the above mentioned ectopic dental eruption of the upper first permanent methods and seems to have negative predictive value36. molars is observed and also dental agenesis, especially of The syndromic nature of craniosynostosis is, finally, the lower second premolars and upper lateral incisors21-23. confirmed by molecular diagnosis. Specifically, mutations Class III malocclusion and Class III skeletal discrepancy in FGFR1, FGFR2 or FGFR3 genes are investigated is observed in all patients18-20. by amniocenteses, chorionic villus sampling or pre- implantation diagnosis37. Functional impairment It is worth to mention that due to the less severe The above mentioned characteristics result in some phenotype of Crouzon syndrome in relation to other functional complications. Eye exposure, as a result of craniosynostosis syndromes the prenatal diagnosis is shallow orbits, can result in corneal abrasions, scarring, confoundedly difficult38. The postnatal diagnosis of exposure keratitis or luxation of the eyeballs in acute the Crouzon syndrome requires extensive clinical and cases24. Additionally, increased intracranial pressure radiological examination. Cephalometric analysis of the may lead to bilateral optic atrophy, which bring about anteroposterior and lateral radiographies and CT scans nystagmus, strabismus or even blindness if the condition confirm clinical findings and shows the premature suture is not treated25,26. Bilateral atresia of auditory meatus closure39,40. Patients are usually examined by geneticists often causes the deafness1. Factors contributing to the in order to detect the associate mutations. respiratory distress or obstructive sleep apnea syndrome would have included the retrusive location of the maxilla or a very long and fleshy soft palate, which is often observed in Crouzon syndrome28. These situations are usually linked to hypertension and cardiac arrhythmia Treatment management or cardiac arrest27. As a consequence of the class III Patients with Crouzon syndrome present complex malocclusion, patients feel discomfort over the masseter abnormalities, which require early clinical management region during eating. of multidisciplinary teams. These teams should consist General findings of craniofacial surgeons, oral and maxillofacial surgeons, Beside the functional problems, patients with neurosurgeons, plastic surgeons, ENT (ear, nose and throat) Crouzon syndrome show some general clinical features surgeons,, orthodontists, dentists, dental technicians, speech such as cervical spine anomalies, acanthosis nigricans, pathologists, psychologists, ophthalmologists, nurses, increased intracranial pressure, hydrocephalus and speech-language pathologists, anesthesiologists, geneticists, occasionally mild mental retardation29-31. Developmental pediatricians and radiologists41,42. delays can also occur. Surgical intervention in the craniofacial region The surgical treatment of the syndromic patients consists of two phases. The first phase takes place in the Diagnostic procedure first year of life and is limited to the correction of the cranium deformity and prevention of the cranial pressure 43-45 Craniosynostosis can be suspected prenatally increase and optic nerve damage . The midfacial based on indirect signs visualized using two or three advancement, the second phase, takes place in older dimensional ultrasound, magnetic resonance imaging age. To achieve the desired result a combination of Le (MRI) or computed tomography (CT) scan32. Prenatal fort III osteotomy, or frontofacial Monobloc osteotomy 2D ultrasound diagnosis aims to visualize the cranium with distraction osteogenesis is required46,47. The use of shape, allowing the calculation of the cephalic index33 [CI: distraction osteogenesis overcomes the complications Cephalic Index expresses the relationship between the of the osteotomies, such as increased operative time, biparietal and occipto-frontal diameters]. Abnormal values relapse of midface protrusion, need for bone grafting of the CI correspond to patients with brachycephaly, and severe blood loss48,49. In cases of severe sleep scaphocephaly or . Regarding to the apnea, tracheostomy may be required as additional differentiated face morphology, common characteristics intervention50. Interventions on the lid occlusal suture or of Crouzon syndrome, such as , ocular tarsorrhaphy are part of the ophthalmologic management, proptosis and beaked nose can be identified by ultrasound while plastic is usually performed in adulthood to scan. Nowadays, 3D ultrasound scan provides more restore patients appearance51. Balk J Dent Med, Vol 22, 2018 Crouzon Syndrome 3

Several protocols have established through the (bimaxillary surgery). Rhinoplasty was performed in some years. McCarthy et al.51 published the parameters of care cases to refine the result. of craniosynostosis established in a multidisciplinary Won Lee et al.52 treated midfacial hypoplasia using meeting titled ‘‘Craniosynostosis: Developing Parameters dual midfacial distraction osteogenesis in 6 patients with for Diagnosis, Treatment, and Management’’ in 2010. mean age 7.2 years. Le Fort III or frontofacial monobloc Generally, according to this protocol the surgical was permormed in these patients and a rigid distraction interventions are divided in six treatment periods. device was placed. The first period includes early operative treatment for In contrast with the above mentioned protocols, synostosis and for selected suture fusion, aiming to Mtihlbauer et al.53 suggested the correction of the midfacial cranial vault decompression and suture release. Common hypoplasia alongside with the fixing of the cranium surgical procedures for this stage are the craniectomy deformity in the first months of life in order to improve or craniectomy and fragmentation of the cranium, the severe exorbitism, obstruction of nasal airways and anterior or posterior expansion, the endoscopic implied functional problems. Additional advantages of this strip-craniectomy with external molding, spring, or technique are the reduction of the psychological effect on distraction and the open cranial vault procedure which the patient and the technical advantages of the surgery due take place between birth and the first year of life. At the to the elasticity of bones and tissues and the anatomical same time, airway and ophthalmologic management characteristics in infancy. Nowadays, it is generally are strongly suggested. The second period (between 6 accepted that early distraction of the hypoplastic midface months to 4 years) aims to the fronto-orbital advancement usually requires secondary procedures in older age54, 55. and reshaping inclusive of cranial vault remodeling, strip craniectomy and midface or monobloc distraction Orthodontic and Orthognathic procedures osteogenesis. The correction of midface deformities, as Orthodontist specialists can evaluate and manage well as secondary cranial vault procedures and adjunct the patient’s growth pattern through various diagnostic procedures are made during the third or the fourth phase and therapeutic procedures. In that way, they play an (between 4 to 12 years). Conventional monobloc or Le Fort important role in the timing of craniofacial surgery. III combined with distraction osteogenesis are suggested Thus, it is generally recommended for each patient to be for the midfacial advancement. Hypertelorism correction monitored by an orthodontist from infancy to adulthood. is necessary in this period. Phase five (between 13 and Orthodontic treatment can be, also, divided into two 17 years) consists of adjunct procedures such as lateral periods, the preoperative and postoperative period. In the canthopexy, rhinoplasty and cranioplasty and secondary – preoperative period, early evaluation allows guidance of teeth complementary procedures when needed. The last period eruption, expansion of the maxilla with suitable appliances, begins after 17 years of living and includes orthognathic alignment of dentitions and preparation for orthognathic surgery for craniofacial dysmorphology or malocclusion surgery52. The creation of interdental spaces for osteotomies for skeletally mature patients. It is noticeable that several of is a common procedure56. Moreover, surgical prediction the aforementioned surgical procedures can be performed in tracings and splints are created57,58. After the orthodontic different periods depending on the functional, aesthetic, and preparation, the midfacial advancement is performed in psychological needs of each patient. adolescence. The postoperative orthodontic procedure 44 Pagnoni et al. suggested correction of cranio­ involves occlusion settlement and functional guidance, which synostosis between the ages of three and six months are essential after the surgery. These are arranged using and midfacial advancement with distraction procedures intermaxillary elastics or orthodontic appliances such as between the age of 4 to 5 years depending on the extremity reverse activators59. of malocclusion, psychological factors and the existence In cases where an additional orthognathic surgery is of obstructive sleep apnea. According to this protocol, needed in adulthood, the orthodontist in cooperation with hypertelorism is corrected in conjunction with the midfacial the maxillofacial surgeon will choose the appropriate time advancement or separately between the ages of 4 and 6 for the secondary surgery10. years. Le Fort I or II combined with mandibular osteotomy Vargervik et al.10 published the dental and is performed after full maturity to normalize appearance. orthodontic perspectives of craniosynostosis resulted 43 Kahnberg et al. suggested the use of distraction from the multidisciplinary meeting mentioned above. The osteogenesis by the age of 7 to 8 years in patients with orthodontist, as stated by the participants of the meeting, is severe form of deformity or psychological burden. In obligated to obtain and maintain photographic, radiographic the rest of the cases the midfacial advancement took and other imaging records from infancy to early adulthood. place between the ages of 16 and 18 years. The surgical Additionally, growth monitoring and dental extractions procedure consisted of Le Fort I or II osteotomy for the coordination with pediatric dentists are necessary until correction of the midface retrusion (single jaw maxillary the age of 7 years, as well as orthognathic procedures in surgery) and the additional set-back of the mandible coordination with surgeons. Between the ages of 7 and 12 or segmental osteotomy of the mandible when needed years, the first phase of the orthodontic treatment is carried 4 Chrystalla Kyprianou, Athina Chatzigianni Balk J Dent Med, Vol 22, 2018 out. Specifically, alignment of dentitions, active guidance of before the operation to facilitate transverse maxillary permanent teeth eruption, insertion of intraoral appliances expansion. A wafer was constructed for the final planning and midface advancement planning, with cephalometric of the surgery. Postoperatively, minor corrections were analysis prediction tracings, images and splints are necessary. made using intermaxillary elastics. The retention period The second phase of orthodontic treatment takes place duration varied between 6 and 24 months and removable between the ages of 12 and 21 years and includes orthodontic orthodontic appliances with a grid to avoid tongue thrust preparation for craniofacial and orthognathic surgery were used during this period. (midfacial advancement or distraction osteogenesis or Le Fort I osteotomy or facial bipartition procedure or 2- jaw Dental management surgical correction) using the same procedures mentioned Supervision by a pediatric dentist in early childhood in phase 1. In addition, management of dental impactions is critical in order to ensure satisfactory oral hygiene with surgical exposure and orthodontic assisted eruption, of patients with syndromic craniosynostosis. Because cooperation with other dental specialties for general dental of the anatomical discrepancies, these patients present treatment objectives (prosthodontics, periodontal care, decreased upper arch dimensions which lead to crowding, extractions and preventive dental care) and intraoral soft delayed and ectopic eruptions with implied propensity for tissue procedures are made at this stage. After surgery, the periodontal disease60. orthodontic treatment is completed, retention is placed and Furthermore, the morphological abnormalities st final records are obtained. Since the 21 year of life onwards of teeth, lower levels of calcium, phosphorus and a follow up assessment is obligatory at appropriate intervals. 56 magnesium in dentine in combination with the difficulties Nurko et al. splitted orthodontic therapy in two in maintaining the adequate oral hygiene, usually, lead to periods: (1) orthodontic treatment during childhood dental caries61,62. Fluoride supplementation, pit or fissure and (2) orthodontic treatment during adolescence. sealants, restorative treatment and oral hygiene guidance During childhood, the orthodontic therapy aims to are recommended after caries risk assessment51. The deal with ectopic eruptions, delayed tooth emerge, crowding and posterior crossbite in patients with mixed early localization of missing teeth is an important part dentition (5 to 12 years old). Recommended methods of general treatment planning. Therefore, the dentist is are the extractions, the use of a lingual arch and/ or obligated to keep baseline diagnostic records such as full fixed appliances and the palatal expansion. In patients head CT scans, cephalograms, intraoral and facial/head with suture closure in the palate, segmental surgery photographs. The oral examination needs to be repeated in Le Fort I level is proposed as alternative to palatal every 6 months or as indicated by the risk status of each expansion with orthodontic appliances. The preparation syndromic patient51. for midfacial advancement, which usually takes place Post-surgery patients with Crouzon syndrome refer between 6-10 years, requires extractions of the primary to a prosthodontist in order to replace missing teeth and teeth, fixed orthodontic appliances for acrylic surgical restore full anatomical dimension of peg or abnormally splint holding and full dimension rectangular arch wires, shaped teeth10. A life-long follow up evaluation is while a removable retainer is suggested after surgery to mandatory for all these patients. Critical knowledge and prevent dental relapse. understanding of the craniofacial growth are required for Later, during adolescence, the patient is prepared the dental specialist in order to treat syndromic patients for orthognathic surgery which requires full permanent effectively. dentitions and skeletal maturity (13-15 years for girls and 15-17 years for boys). The orthodontist aligns the teeth of each jaw without worrying about reverse overjet or dental occlusion using fixed appliances and arch compatibility Conclusions is checked on dental casts. Full dimension rectangular arch wires are placed and final records should be taken Patients with Crouzon syndrome need long term (panoramic and lateral cephalogram radiographs, dental management by scientists of various specialties. Facial casts, facial and intraoral photos and posteroanterior cephalometric radiograph for asymmetry evaluation). Root and functional malformations in individuals with Crouzon separation (4 to 5mm) is required to facilitate osteotomies. syndrome could be significantly improved after a series Final, predictions and surgical splints are created. Post- of surgical and orthodontic procedures in almost all the surgical orthodontic therapy starts approximately 4 to 6 cases. According to the above mentioned protocols, the weeks after the surgery. Vertical elastics are used to settle surgical treatment of craniofacial hypoplasia is obligatory. occlusion and prevent relapse or shifts different from However, the role of orthodontist is crucial both before centric relation. This procedure lasts about 6 months and and after surgery to reach the desired treatment plan goals. then a retainer is used full time for 12 months. Kahlberg et al.43 used fixed orthodontic appliances in order to align dentitions preoperatively. 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