Objective: Craniosynostosis is an abnormal and premature fusion of any cranial suture. This aims at presenting the case report Crouzon syndrome confirmed by clinical data and a genetic survey at the request of our Temporomandibular Disorders service.
Material and method: The Crouzon syndrome case presented in this article was diagnosed at the request of a Dentistry Service, at an adult age, without neurological involvement, with characteristic phenotype, and accompanied by a disorder in the bilateral temporomandibular joint complex. In this case report a woman aged 37 attended our service due to pain in both TMJs. Apart from being diagnosed with bilateral discocondylar dislocation and being prescribed a treatment she was requested a genetic survey, since she was very likely suffering from a syndrome given her phenotypic characteristics. Crouzon syndrome was then confirmed, and the patient was referred for a neurological study and for orthodontic-surgically treating her malocclusion.
It is very important to carry out not only an exhaustive oral study, but also a complete systemic assessment noting, in addition, the patient’s personal and family history when we come across above all a characteristic phenotypic aspect.
Conclusion: The early diagnosis is of vital importance in order to avoid or control the consequences of the syndrome, so in this case dentists play an important role to provide a multidisciplinary approach to treatment.
Crouzon syndrome (CS) is a rare genetic disorder caused by malformations in the mesenchyme and the ectoderm and is characterised by premature closure of one or more cranial sutures [1].
It presents autosomal dominant variants like Apert, Pfeiffer, Saethre-Chotzen, Carpenter and Jackson Weiss syndromes with the typical craniofacial features and another series of more specific abnormalities in each case [2-5].
These are some examples of over 100 syndromes like CS associated with craniosynostosis [6].
CS represents one of the most frequent congenital malformations in the skull development, with an estimated prevalence of 1:60,000 in the US (4) and an incidence of 1:25,000 worldwide births, as well as a frequency that ranges from 4.5 to 4.8% of all craniosynostosis [7-10]. Furthermore 20% of craniosynostosis include some specific syndrome with Mendelian transmission, whereas the remaining 80% are non-syndromic, being between 10 and 14% of them genetically transmitted [11]. Over 50 different mutations can be described in relation to this syndrome [9]. There is family history for this condition in 44-67% of cases [9].
CS has no racial or gender predilection [4,10,12]. Some authors highlight that when craniosynostosis affects the sagittal or metopic sutures the predominance increases in boys, whereas coronal craniosynostosis is more common among girls [13].
The underlying pathological process is premature synostosis of coronal, sagittal and occasionally lambdoidal sutures-as well as upper and posterior sutures of the maxilla along the wall of the orbit — which begins in the first year of life and is completed at 2-3 years of life [1,4]. In non-syndromic craniosynostosis sagittal suture is more frequently affected, specifically in 40-60% of cases, followed by coronal suture, which is affected in 20-30% of cases, and metopic suture in less than 10% of patients [3].
Once sutures are prematurely closed their growth potential is restricted, so the developmental arrest mainly affects the sagittal facial dimensions, the maxilla, the orbit and the calvaria, what could lead to hydrocephalus and/or mental retardation [13]. CS has been generally associated to bicoronal synostosis causing clinically a characteristic high, flat forehead [8]. In addition, it may cause hypoplasia in the facial middle third along with maxillary hypoplasia, superficial orbit or proptosis, pointed nose and occasional obstruction of upper airways, being bulging or exophthalmic eyes the most noticeable feature [8]. Ocular proptosis is not clearly present from the moment of birth, but gradually develops during the first years of life [14].
Of all the aforementioned clinical features cranial deformation undoubtedly is the most noteworthy feature in CS and can manifest as brachycephaly, oxycephaly or trigonocephaly, varying its severity from mild to serious [1].
It has been described in the literature that CS is not usually associated to craniosynostosis of the isolated bilateral squamous suture, although Tandon, et al. [8] published a case report with craniosynostosis of the squamous suture.
To allow brain development compensatory growth occurs towards other non-ossified sutures, what results in craniofacial deformities. In fact, if synostosis is located between the orbital area and the maxillary bones it leads to a development of the maxilla downwards and forward, with consequent underdevelopment of the facial middle third.
Sometimes congenital deformities in the temporomandibular joint (TMJ) complex are presented as a heterogeneous continuum of growth disturbances of the mandibular condyle, articular eminence, and temporal bone [15].
Exhaustive clinical and radiological examinations are required for correctly diagnosing craniosynostosis [1,16]. Nevertheless, although magnetic resonance imaging does not have such a significant role in the diagnosis of craniosynostosis or facial abnormalities related to CS it can be truly useful at brain level if the patient develops neurological symptoms [8].
The treatment for patients with Crouzon syndrome is interdisciplinary and will depend on the specific malformations, the craniofacial growth pattern and the psychosocial needs of each affected individual.
This paper aims at presenting the case report of a woman with Crouzon syndrome confirmed by clinical data and a genetic survey at the request of our Temporomandibular Disorders service, and with bilateral dislocation of temporomandibular joint complex.
A woman aged 37 attends the consultation in the Temporomandibular Disorders service of Clínica Odontológica Universitaria de Murcia (Spain), at Hospital Morales Meseguer, afflicted with pain in both TMJs.
In the case history the patient reports suffering from sleep apnoea and thyroid failure, with no other systemic condition and with noise in the left TMJ and pain in the masticatory muscles of both sides. The patient had oral parafunctional habits (bruxism).
In the clinical examination facial asymmetry is frontally seen, as well as hypertelorism, strabismus, exophthalmos, and from a profile view a hypoplastic jaw prone to mild mandibular protrusion. Despite having a phenotypic pattern related to some syndrome, the patient indicates that she has never been assessed in this regard and is therefore not diagnosed in this sense (Figure 1-3).
Figure 1-2. Patient’s profile and front views during the treatment with maxillary hypoplasia
Figure 3. Hypertelorism, exophthalmos, and strabismus
During muscle palpation we find in both sides pain in the masseter, temporal, internal and external pterygoid muscles, as well as the involvement of the occipital, trapezius and sternocleidomastoid muscles. The temporomandibular joint complex bilaterally presents both tenderness when opening and closing and reciprocal joint noise. During mandibular movements jaw deviation to the right is observed when opening it and to the left during protrusion (Figure 4).
Figure 4. Maximum intercuspidation, anterior crossbite and the deviation of the midline 3 mm to the right
In the dental examination a Class III, dental, molar and canine, bilateral malocclusion with grade 2 attrition is described in accordance with Smith and Knight’s classification, as well as anterior and posterior crossbite with no periodontal pathology and no absence of teeth [17] (Figure 5).
Figure 5. Maximum intercuspidation, with pre-surgical orthodontic treatment. Show bite embroider to edge (borde a borde) and the deviation of the midline 2 mm to the right
In the orthopantomograph no significant findings were seen, so a genetic survey and a magnetic resonance scan were requested as complementary examinations in order to show the temporomandibular joint complex. After the interpretation of the scan a temporomandibular pathology is confirmed-more specifically a disk, condylar dislocation with reduction on the right side and no reduction on the left side (Figure 6).
Figure 6. Above: Right and left TMJs with the mouth open. Below: Right and left TMJs with the mouth closed. Bilateral dislocation with reduction on the right side, and without reduction on the left side
A genetic survey of the FGFR2 gene (NM_000141.4) from the DNA of patient’s lymphocytes was performed with amplification of exons 7 and 8 of this gene by means of PCR, analysing in this way the mutations by applying the HRM (high resolution melting analysis) technique followed by direct sequencing of PCR fragments of interest.
As a result the mutation ofc.1Q12G>C (p.Gly338Arg) in heterozygosity, in exon 8 of the FGFR2 gene (NM_000141.4), was obtained, compatible with Crouzon syndrome (Figure 7). After this the patient was referred for the first time to the Neurology Unit and no significant finding was seen at the neurological level. From a medical point of view this case stands out because of the patient’s age of diagnosis, since she had never been assessed and therefore CS was never diagnosed. Thanks to this finding a genetic survey of the entire family was performed, in which a first cousin in adulthood suffered from Apert syndrome. She had not been diagnosed either.
Figure 7. Patient’s karyotype. The mutation of c.1Q12G > C (p.Gly338Arg) found in exon 8 of the FGFR2 gene in heterozygosity (NM_000141.4) has been detected
The clinical, ophthalmological, radiographic and genetic findings undoubtedly lead us to the systemic diagnosis of CS and to the dental clinical diagnosis of mixed temporomandibular disorder (muscular and articular).
The treatment plan consisted of several phases. The first phase focused on eliminating pain, so the patient was prescribed heat therapy, anti-inflammatory topical gel three times daily (diclofenac), physiotherapy and behavioural therapy to avoid bruxism.
Two-three months later the patient got better and was prescribed a Michigan-type splint for night use.
After being asymptomatic for one year she was referred to the Orthodontics and Maxillofacial Surgery Unit to correct maxillary hypoplasia and class III malocclusion.
As seen in figure 5, the patient is currently under pre-surgical orthodontic treatment waiting to undergo bimaxillary surgery (Le Fort I maxillary advancement and orthognathic surgery).
In the subsequent checks carried out at the Temporomandibular Disorders Unit the patient is totally asymptomatic. Once the post-surgical orthodontic treatment comes to an end she will be again referred to our service to assess the stability of the temporomandibular joint complex.
In 1912, the French brain surgeon Octave Crouzon (1874-1938) described a craniofacial dysostosis in a woman and her son, showing a triad composed by cranial deformation, facial abnormalities and exophthalmos, i.e., a hereditary syndrome currently known as Crouzon syndrome (CS) [2,8,18].
There are 5 primary ossification centres that along with 6 main sutures form a normally shaped adult head [8]. The physical abnormalities occurring in a baby with CS can vary in terms of severity from mild with a malformation in the middle third of the face, to severe forms with multiple cranial sutures fused and noticeable problems both in the middle third of the face and in the eyes and the rest of craniofacial structures [4]. Although such abnormalities are often present from the moment of birth they can progress over time. Despite the predilection of this condition for the Caucasian race, a case of a 7-year-old South African black boy with CS was reported [4].
CS is an autosomal dominant disorder with complete penetrance and variable expressivity, although it may appear as a mutation in the fibroblast growth factor receptor 2 gene (FGFR2) which is mapped in the chromosomal locus 10q25-10q26 and has variable expressivity [4,9,19]. Occasional mutations in FGFR3 are related to patients with CS and acanthosis nigricans, which is the main dermatological manifestation affecting 5% of patients and is characterised by velvety marks ranging from light brown to black (Figure 1). These marks are generally located on the neck, arms or the groin [2].
Keupp, et al. [20] described a case of blood relationship in a family with a Crouzon-like phenotype and multiple-suture synostosis, exophthalmos, hypoplasia in the facial middle third and mandibular protrusion, and without malformations in the limbs. The clinical findings are indistinguishable from autosomal dominant CS, although there are intra- and interfamilial variations. The homozygosity mapping and direct sequencing identified nonsensical mutations in the IL11RA gene of the chromosome 9p21.1-p13.d. Furthermore, these authors demonstrated that mutations in IL11RA are also found in the cases of initial suture closure in pansynostosis and evinced the participation of interleukin-11 in the development of the cranial suture and therefore the condition [20]. Among all the facial features, the ocular feature is one of the most noticeable and appears as strabismus (esotropia and exotropia), hypertelorism, and even as a spontaneous luxation of the eyeballs, thus affecting the vision. There might be more serious vision-threatening complications like exposure keratopathy and optic atrophy due to compression of the optic foramen [1]. These orbital defects additionally include bilateral proptosis. In our case report the patient had exophthalmos and strabismus, and no auditory involvement. In some studies case reports about patients with CS associated to epilepsy were even described [21]-also associated to lissencephaly (smooth brain) caused by a malformation in the cerebral cortex that may involve additionally cerebellar hypoplasia or dysgenesis of the corpus callosum [22].
Regarding the most common oral features, there are maxillary hypoplasia with consequent Class III skeletal malocclusion and crowding of the upper incisors with a Vshaped upper dentoalveolar arch, as well as mandibular protrusion. Our patient’s features matched this description.
Thus, García-Fajardo, et al. [23] affirm that patients with Class III malocclusion may lack anterior guidance and anterior disclusion during protrusive movements. This abnormality in the eccentric movements, along with bruxism, could trigger a temporomandibular disorder that sometimes can begin to develop in the uterus,
particularly during the first gestational trimester [6].
Nevertheless, several syndromes with congenital condylar deformity like mandibular dysostosis (Treacher Collins syndrome), hemifacial microsomia, Nager syndrome, Goldenhar syndrome or Hallermann-Streiff syndrome have a malformation in the TMJ, more severe than in CS, that may lead to surgical mandibular reconstruction [15].
The mental capacity of patients with CS generally is at a normal level. Mental disability occurs in approximately 12% of patients. Headaches and seizures are attributable to high intracranial pressure [14]. Upper airway obstruction develops secondary to septal deviation and nasopharyngeal narrowing [14]. None of these findings was found in our case – either the ophthalmic deficit, or the hearing deficit.
In our case it is important to highlight that the patient, despite having been diagnosed at an adult age, had no condition of neurological origin.
The association of congenital heart malformations to CS occurs very occasionally, so we did not find much information about this in the reviewed literature [24]. Dharamshi, et al. [25] describe the case repot of a patient diagnosed with CS and whose cardiovascular examination revealed a systolic murmur. The patient’s chest examination revealed crepitations and HVB. The rest of systems seemed to be normal. Management options from the perspective of the otorhinolaryngologist are diverse and revolve around craniosynostectomy, offsetting maxillary hypoplasia, addressing psychosocial and esthetic interventions, and ultimately requiring a multidisciplinary team approach
[3].
These patients have typical oral features. The upper jaw tends to be hypoplastic, with gothic palate, and the malar bones are depressed or driven inwards, giving a flat face appearance. In the jaw there is slight protrusion and the ramus of mandible tends to be bigger, just like in other syndromes like Apert syndrome. Regarding dental abnormalities, they usually have a very big or very small size, or a lack of some tooth buds (oligodontia).
An early diagnosis may guide the craniofacial growth and development with the purpose of minimising the consequences of this pathology, as well as improving the treatment success.
Very little documentation exists on the quality of life such patients can lead before and/ or after the treatment [26].
The early and precise diagnosis of CS in a patient is essential, playing an important role the confirmation by means of a genetic survey.
There is no conflict of interest directly or indirectly for either author.
The patient gave signed informed consent to publication of the case report and photographs.
- Kaur H, Singh Waraich H, Sharma CM (2006) Crouzon syndrome: A case report and review of literature. Indian J Otolaryngol Head Neck Surg 58: 381-382. [Crossref]
- Tay YC, Tan KH, Yeow VK (2013) High Le Fort I and bilateral split sagittal osteotomy in Crouzon syndrome. J Craniofac Surg 24: e253-255. [Crossref]
- Helman SN, Badhey A, Kadakia S, Myers E (2014) Revisiting Crouzon syndrome: reviewing the background and management of a multifaceted disease. Oral Maxillofac Surg 18: 373-379. [Crossref]
- Hlongwa P (2009) Early orthodontic management of Crouzon Syndrome: a case report. J Maxillofac Oral Surg 8: 74-76.
- Raviprakash Sasankoti M, Naveen Shanker V, Sankalp V, Neha Agarwal (2012) Crouzon Syndrome: Clinico-Radiological Illustration of a Case. J Clin Imaging Sci 2: 70.
- Kalanjiam V, Manoharan GVMG (2017) Crouzon syndrome - A rare case report. Int J Health Sci (Qassim) 11: 74-75. [Crossref]
- Sharma VP, Wall SA, Lord H, Lester T, Wilkie AO (2012) Atypical Crouzon syndrome with a novel Cys62Arg mutation in FGFR2 presenting with sagittal synostosis. Cleft Palate Craniofac J 49: 373-377.
- Tandon YK, Rubin M, Kahlifa M, Doumit G, Naffaa L (2004) Bilateral squamosal suture synostosis: A rare form of isolated craniosynostosis in Crouzon syndrome. World J Radiol 6: 507-510.
- Ahmed I, Afzal A (2009) Diagnosis and evaluation of Crouzon syndrome. J Coll Physicians Surg Pak 19: 318-320. [Crossref]
- Maspero C, Giannini L, Galbiati G, Kairyte L, Farronato G (2014) Non surgical treatment of Crouzon Syndrome. Stomatologija 16: 72-80.
- Vidal Sanahuja R, Gean Molins E, Sánchez Garre C, Quilis Esquerra J, García Fructuoso G, et al. (2012) Síndrome de Crouzon: a propósito de 2 casos. Entidades craneoestenóticas alélicas de los genes FGFR. Pediatr (Barc) 77: 272-8.
- Padmanabhan V, Hegde AM, Rai K (2011) Crouzon's syndrome: A review of literature and case report. Contemp Clin Dent 2: 211-214. [Crossref]
- Noetzel MJ, Marsh JL, Palkes H, Gado M (1985) Hydrocephalus and mental retardation in craniosynostosis. J Pediatr 107: 885-892. [Crossref]
- Pal US, Gupta C, Chellappa AAL (2012) Crouzon syndrome with primary optic nerve atrophy and normal brain functions: A case report. J Oral Biol Craniofac Res 2: 116-118.
- Galea CJ, Dashow JE, Woerner JE (2018) Congenital Abnormalities of the Temporomandibular Joint. Oral Maxillofac Surg Clin North Am 30: 71-82. [Crossref]
- Khominsky A, Yong R, Ranjitkar S, Townsend G, Anderson PJ (2018) Extensive phenotyping of the orofacial and dental complex in Crouzon syndrome. Arch Oral Biol 86: 123-130. [Crossref]
- Smith BG, Knight JK (1984) An index for measuring the wear of teeth. Br Dent J 156: 435-438. [Crossref]
- Maloth S, Padamashree S, Rema J, Yalsangi S, Ramadoss T, et al. (2010) Diagnosis of Crouzon´s syndrome. Hong Kong Dent J 7: 95-100.
- Murano I (2006) [Crouzon syndrome]. Nihon Rinsho Suppl 3: 416-417. [Crossref]
- Keupp K, Li Y, Vergel I, Hoischen A, Richardson R, et al. (2013) Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis. Mol Genet Genomic Med 1: 223-237.
- Gadze ZP, Vuksic M, Kovac AB, Nankovic S, Sulentic V (2017) Sleep-related hypermotor epilepsy in a patient with mild Crouzon syndrome. Act Neurol Belg 2017.
- Tan AP1, Mankad K2 (2018) A unique case of lissencephaly with Crouzon syndrome heterozygous for FGFR2 mutation. Childs Nerv Syst 34: 23-25. [Crossref]
- García- Fajardo Palacios C, Cacho Casado A (2007) La oclusión como factor etiológico en los trastornos temporomandibulares. RCOE 12: 37-47.
- Rokicki W, Rokicka A (2003) Coexistence of Crouzon syndrome with ventricular septal defect. Wilad Lek 56: 298-289.
- Dharamshi HA, Raza T, Mohsin Ali AA, Lilani Z, Ahsan SZ, et al. (2015) Premature craniosynostosis in a rare genetic disease- a case report. Iran J Public Health 44: 404-406.
- Stein JM (1975) The effect of adrenaline and of alpha- and beta-adrenergic blocking agents on ATP concentration and on incorporation of 32Pi into ATP in rat fat cells. Biochem Pharmacol 24: 1659-1662. [Crossref]
