Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250

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Case report

Dental and maxillofacial features of Noonan Syndrome: Case series of

ten patients
Jean-Christophe Lutz a, b, c, *, Romain Nicot d, e, f, Matthias Schlund d, e, Elise Schaefer b, h,
€l Ferri d, e, f
Fabien Bornert c, g, i, Florence Fioretti c, g, i, Joe
a
Oral and Maxillofacial Surgery Department, Strasbourg University Hospital, 1 avenue Moli ere, 67098, Strasbourg cedex, France
b
University of Strasbourg, Faculty of Medicine, 8 rue Kirschleger, 67000, Strasbourg, France
c
INSERM (French National Institute of Health and Medical Research), “Regenerative Nanomedicine” Laboratory, UMR 1260, Facult e de M edecine, FMTS,
67085, Strasbourg cedex, France
d
Oral and Maxillofacial Surgery Department, Roger Salengro Hospital, Avenue du Professeur Emile Laine, 59037, Lille, France
e
Universite Lille 2 Droit et Sant
e, 1 Pl. de Verdun, 59000, Lille, France
f
INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, Facult e de Pharmacie, 3, rue du Professeur Laguesse, BP83, 59006, Lille Cedex, France
g
Department of Dentistry / Oral Medicine and Oral Surgery, Strasbourg University Hospital, 1 Place de l’Ho ^pital, 67091, Strasbourg cedex, France
h
Medical Genetics Department, Strasbourg University Hospital, 1 avenue Moli ere, 67098, Strasbourg cedex, France
i
University of Strasbourg, Faculty of Dentistry, 8 rue Sainte Elisabeth, 67000, Strasbourg, France

a r t i c l e i n f o a b s t r a c t

Article history: Noonan syndrome (NS) is a relatively common congenital multiple-anomaly syndrome, resembling
Paper received 18 September 2019 Turner syndrome, but without chromosomal anomaly. Besides the unusual facies, the maxillofacial and
Accepted 26 January 2020 dental features of patients with NS are not well-summarized in the literature. The aim of this study was
Available online 6 February 2020
to describe these features and propose specific treatment guidelines for practitioners involved in oral and
maxillofacial care.
Keywords:
A retrospective multicentric study was conducted of 14 patients who were referred for NS screening.
Dentofacial deformities
In total, 10 patients were found to carry a mutation involved in NS or NS-related disorders. Fifty percent
Giant cells
Maxillofacial abnormalities
of the mutations affected PTPN11. All patients presented with the typical extraoral features, such as
Noonan syndrome macrocephaly, hypertelorism, ptosis, triangular face shape and ear dystrophy. Intraoral manifestations,
Orthognathic surgery including malocclusion (maxillary transversal deficiency, crossbite, anterior open-bite and class II
Orthodontics malocclusion), dental anomalies (delayed eruption, agenesis and dystrophy, odontoma) and radiologic
jaw lesions were identified in five out of 10 patients. These findings were searched in a review of the
literature to obtain a comprehensive description of oral and maxillofacial features in patients with NS.
The proposed treatment guidelines emphasize frequent coagulation anomalies that need to be consid-
ered prior to surgery. Early dental assessment and yearly follow-up with oral prophylaxis are recom-
mended. Orthodontics and orthognathic surgery are also of primary importance in the management of
NS patients.
© 2020 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights
reserved.

1. Introduction (Noonan and Ehkme, 1963; Noonan, 1994). Its frequency has been
estimated as 1 in 1,000 to 1 in 2,500 (Levine et al., 1991).
Noonan syndrome (NS) is a relatively common congenital Early descriptions of this syndrome by Jacqueline Noonan
multiple-anomaly syndrome that is well characterized in children included unusual facies (Figs 1Ae4B), congenital heart defects and
other symptoms (Noonan and Ehkme, 1963). Since these symptoms
resemble those of Turner syndrome (Scully et al., 2010), NS was
initially described as “male Turner syndrome” (Levine et al., 1991).
However, NS can affect both sexes and features grossly normal
* Corresponding author. Oral and Maxillofacial Surgery Department, Strasbourg chromosomes.
re, 67098, Strasbourg Cedex, France.
University Hospital, 1 avenue Molie
E-mail address: jean-christophe.lutz@chru-strasbourg.fr (J.-C. Lutz).

https://doi.org/10.1016/j.jcms.2020.01.011
1010-5182/© 2020 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
 J.-C. Lutz et al. / Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250 243

Fig. 1. Frontal facial photograph of patient 1 at ages 6 and 11 years. Note typical features of Noonan syndrome: broad and high forehead; hypertelorism; antimongoloid slant of the
palpebral fissures; bilateral ptosis; and low-set fleshy ears, with a posterior inclination. A: At age 6 years, note strabismus and mandibular laterognathia towards the left side. B. At
age 11 years, note the webbed neck (pterygium coli). (Courtesy of Dr. C. SCHWARTZ and Dr. E. SCHAEFER).

NS is the second most frequent cause of congenital syndromic fusion and basilar impression may be frequently found in NS
heart disease, namely valvular pulmonary stenosis and hypertro- (Miyamoto et al., 2014). Radio-ulnar synostosis and joint contrac-
phic cardiomyopathy (Marino et al., 1999). A large number of sys- tures have also been described (Noonan, 1994).
temic features, such as genital, kidney and lymphatic An increased risk of developing solid tumours, particularly
malformations, have been thoroughly described (Noonan and multiple giant-cell lesions and blood cancers, is also inherent to NS
Ehkme, 1963; Papadaki et al., 2012; Roberts et al., 2013; patients (Roberts et al., 2013). Moreover, various hematologic
Bhambhani and Muenke, 2014). Vision and hearing defects, anomalies affecting primary and secondary haemostasis are
abnormal skin pigmentation, digestive disorders, delayed puberty, frequent in NS (60%) and need to be carefully considered prior to
failure to thrive and low-normal intelligence have also been re- surgery, particularly because they might not be detected through
ported (Roberts et al., 2013; Bhambhani and Muenke, 2014). routine screening (Morice et al., 2017).
Orthopaedic deformities are often present in patients with NS. In contrast to the comprehensive description of systemic fea-
Chest deformity (pectus carinatum or pectus excavatum) is common tures in NS, only its general facial appearance has been well
(90%), in addition to hyperextensible joints and muscle hypotonia established. The present article aims to provide a detailed
(Noonan, 1994). Scoliosis and talipes equinovarus are reported description of dentomaxillofacial features of NS based on a series of
(10e15%) (Noonan, 1994). An increased carrying angle at the elbow 10 patients. Based thereon, we also propose specific dentomax-
is frequent and the fifth finger is sometimes curved. Cervical spine illofacial treatment guidelines.

Fig. 2. Lateral facial photograph of patient 1 at ages 6 and 11 years. Note the typical features of Noonan syndrome: broad and high forehead; and low-set fleshy ears, with a posterior
inclination. A: At age 6 years, note the skeletal class III tendency. B. At age 11 years, note low-set fleshy ears, with a posterior inclination. (Courtesy of Dr. C. SCHWARTZ and Dr. E.
SCHAEFER).
244 J.-C. Lutz et al. / Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250

Fig. 3. Frontal intraoral photograph of patient 1 at ages 6 and 11 years. A: At age 6 years, note the maxillary transversal deficiency, posterior crossbite, and anterior open-bite. B. At
age 11 years, note correction of the posterior crossbite after orthopaedic treatment. (Courtesy of Dr. C. SCHWARTZ and Dr. E. SCHAEFER).

Fig. 4. Lateral intraoral photograph of patient 1 at ages 6 and 11 years. A: At age 6 years, note the maxillary transversal deficiency, posterior crossbite, and anterior open-bite. B. At
age 11 years, note correction of posterior crossbite after orthopaedic treatment. (Courtesy of Dr. C. SCHWARTZ and Dr. E. SCHAEFER).

Table 1
Sample of patients affected with Noonan syndrome: Clinical and genetic features.

Patient # Age Gender Clinical Features Mutation (heterozygote)

1 11.7 M typical facies, webbed neck (pterygium coli), relative macrocephaly, broad and high forehead, K-Ras
hypertelorism, bilateral ptosis, triangular face shape, antimongoloid slant of the palpebral fissures,
low-set fleshy ears with posterior inclination, crossbite, anterior open bite, delayed dental eruption,
failure to thrive
2 20.2 F webbed neck (pterygium coli), bilateral ptosis and small, upturned (saddle) nose, micrognathia and PTPN11
cafe au lait spots, Class II malocclusion, dystrophy of tooth #10 and agenesis of tooth #16
3 17.8 M typical facies, hypertelorism, bilateral ptosis, triangular face shape, antimongoloid slant of the SOS1
palpebral fissures, low-set fleshy ears with posterior inclination, Class II malocclusion, 2 mandibular
odontomas, valvular pulmonary stenosis, atrial septal defect, ectopic testes, failure to thrive
4 14.8 F facial anomaly, amblyopia, teeth dystrophy with short apices of teeth #3, 7, 8, 24, 25, valvular PTPN11
pulmonary stenosis, mental retardation, unilateral megalencephaly, severe epilepsy
5 17.4 M typical facies, gastroesophageal reflux disease, tracheal stenosis, bronchopulmonary dysplasia, PTPN11
valvular pulmonary stenosis, ectopic testes, mental retardation, post-hemorrhagic hydrocephalus,
thrombocytopenia, failure to thrive
6 32.1 M typical facies, hypertelorism, triangular face shape, antimongoloid slant of the palpebral fissures, SOS1
low-set ear with helix distortion, mandibular radiolucent lesion around tooth #19.
7 14.9 F typical facies, macrocephaly, low-set fleshy ears with posterior inclination, achalasia, epilepsy PTPN11
8 11.6 M typical facies, keratosis pilaris of the forehead, hyperplastic sebaceous glands PTPN11
9 10.8 M typical facies, low-set fleshy ears with posterior inclination, laryngomalacia MEK1
10 5.7 M typical facies, triangular face shape, unilateral ptosis, low-set fleshy ears with posterior inclination NF1 intragenic deletion
Mean 15.7
SD 7.1
Sex Ratio 2.3

MEK1 as well as MEK2, BRAF, and KRAS are genes coding for transducers of the RASeMAPK signalling pathway. A mutation in their sequence results in the CFC syndrome and
Costello syndrome Noonan-related disorders. Mutations of the neurofibromin (NF1) gene, also in the RASeMAPK pathway, result in the Noonan-neurofibromatosis
phenotype.

2. Case report Hospital of Lille and Strasbourg, France. Overall, 12 patients un-
derwent genetic screening, of whom 10 were found to carry a
Between 2000 and 2018, 14 patients were referred for screening mutation known to be involved in NS or NS-related disorders.
of oral and maxillofacial malformations as part of NS to the Among these patients, 50% carried a mutation in PTPN11. The male
Department of Oral and Maxillofacial Surgery at the University to female sex ratio was 2.3 and the mean (standard deviation) age
 J.-C. Lutz et al. / Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250 245

Fig. 5. Orthopantomogram of patient 2, showing dystrophy of tooth #10 (yellow cir-

cle) and agenesis of tooth #16 (Courtesy of Pr. J. FERRI).

Fig. 8. MRI of patient 6 depicting a central giant-cell granuloma. The granuloma ap-
pears as an expanding formation developed in the posterior part of the left mandibular
corpus, located distally and vestibularly with respect to tooth #19, and displacing the
adjacent vestibular and lingual cortices. It measured 3
1.5 cm. Intermediate tissue
signal was found both in T1-and T2-weighted images (yellow arrows) (Courtesy of Dr.
Fig. 6. Orthopantomogram of patient 6 depicting a central giant-cell granuloma F. BORNERT).
appearing as a radiolucent lesion of the left mandibular corpus around tooth #19
(yellow arrows) (Courtesy of Dr. F. BORNERT).
Intraoral manifestations, including malocclusion, dental anom-
alies and radiologic jaw lesions were identified in five out of 10
was 15.7 (7.1) years. The clinical and genetic features of these pa- patients. Malocclusion was present in three out of 10 patients. This
tients are summarized in Table 1. consisted of maxillary transversal deficiency, crossbite, anterior
General NS manifestations, such as short stature, albeit within open-bite, as in patient 1 (Figs. 3A and 4A) and class II malocclusion,
the normal range, were always encountered. All patients of the as in patients 2 and 3. Dental anomalies were observed in five out of
present series presented with the typical extraoral features, such as 10 patients. This included delayed dental eruption of teeth #7 and
macrocephaly, hypertelorism, ptosis, triangular face shape, anti- 10 (eruption at age 11) in patient 1, the dystrophy of tooth #10 and
mongoloid slant of the palpebral fissures and low-set fleshy ears agenesis of tooth #16 in patient 2 (Fig. 5). There were two
with a posterior inclination (Figs. 1e3). Two patients had a webbed mandibular odontomas in patient 3. Patient 4 had tooth dystrophy
neck (pterygium coli) (Fig. 1B). with short apices of teeth #3, 7, 8, 24 and 25. Patient 6 presented
with a mandibular radiolucent lesion around tooth #19 (Figs. 6e8).
Treatment consisted of oral prophylaxis and dental follow-up in
all patients, surgical curettage of a giant cell lesion in patient 6 and
three orthodontic treatments (e.g., patient 1, Fig. 3A and B and 4A,
B). There was no case of orthognathic surgery.
This study was approved by the Strasbourg Hospital IRB and all
participants signed an informed consent agreement.

3. Discussion

3.1. Genetics

NS (Online Mendelian Inheritance in Man [OMIM] reference

163950) (Cao et al., 2017) is a genetically heterogeneous disorder
belonging to RASopathies, with an overall incidence of 1 in 1000
live births (Bezniakow et al., 2014). Autosomal dominant inheri-
tance can often be documented in NS, however, most cases are
sporadic due to de novo mutations (Levine et al., 1991; Bhambhani
and Muenke, 2014).
More than 10 genes in the RASeMAPK signalling pathway have
been associated with NS (Cao et al., 2017) and its ectodermal
Fig. 7. Cone beam computed tomography of patient 6 depicting a central giant-cell
manifestations (Bezniakow et al., 2014). Molecular testing is avail-
granuloma appearing as a radiolucent lesion in the left mandibular corpus around able for the three genes primarily affected in NS: PTPN11, mutated
tooth #19 (yellow arrows) (Courtesy of Dr. F. BORNERT). in about 50% of cases; SOS1, involved in about 10% of cases; and
246 J.-C. Lutz et al. / Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250

Table 2
Literature review of case reports and case series regarding the dental and maxillofacial features of Noonan syndrome.

Year Study Type of article Dental and Maxillofacial Findings Associated with Noonan Syndrome
of Clinical Radiological
Publication

1991 Levine et al. (1991) Case report (n ¼ 1) Abnormal auricles with a posterior inclination, slight webbing of the neck, and Bilateral maxillary and
micrognathia; Class II malocclusion with the dentition in good repair, normal mandibular multilocular
appearing mucosa, and bilateral expansions of the posterior maxilla and radiolucencies. All lesions
mandible which were asymptomatic. No extraoral obvious facial deformity included multiple, unerupted
except a “full cheeks” appearance. teeth.
1994 Sugar et al. (1994) Case report (n ¼ 1) Long and triangular face; hypertelorism with downward slanting of the
palpebral fissures; relatively large turricephalic skull with a broad neck,
prominent eyes with thick hooded eyelids, and a wide nasal base with bulbous
tip; very scarce eyebrows and coarse, thick skin sprinkled with large, plugged
comedo-like structures causing a bumpy surface. Moderate anteroposterior
maxillary deficiency marked mandibular prognathism with anterior open bite,
and excessive chin height but anteroposterior chin deficiency. Class III
malocclusion.
1996 Addante and Breen Case report (n ¼ 1) Investigated with regard to a maxillary mesiodens. Bilateral eyelid ptosis. Multilocular radiolucent lesions
(1996) “Fullness in his cheeks". involving the angle of the
mandible, with displacement of
the first and second molar tooth
buds.
2006 Wolvius et al. (2006) Case report (n ¼ 1) Noonan-like syndrome. Anterior open bite. Ocular hypertelorism, ptosis, broad Large, multilocular lesions
nasal bridge, posteriorly angulated ears, and a short neck with mild webbing. bilaterally in the posterior
Intraoral examination: absence of the mandibular permanent second molars. mandible. On the right side, the
second molar was situated at
the lower border of the jaw,
while on the left side, retention
of the second molar was seen.
The mandibular canal could not
be identified on either side.
2007 Shaw et Al. (2007) Case series (n ¼ 112) Orthodontic work had been performed in 37 of 72 (51%) patients to correct One patient had a mandibular
dental overcrowding, compared with 14% in the general UK population (Office tumor that was surgically
of National Statistics). Dental caries was a common cause of dental morbidity, resected and histologically
with 11 of 72 (15%) patients requiring extractions due to caries. confirmed to be a giant-cell
tumor.
2012 Karbach et al. (2012) Case report (n ¼ 1) Hypertelorism, downslanting palpebral fissures, low-set and posteriorly rotated Bilateral cystic lesions in the
ears, webbed neck, low posterior hairline. Delayed second dentition, maxilla and in the mandible,
misalignment of the teeth, and suspected keratocystic odontogenic tumor where they were
(KCOT). Oral examination: multiple malpositioned and impacted teeth. predominantly located in its
ascending part on both sides.
2013 Roberts et al. (2013) Review Tall forehead, low posterior hairline (newborn); Large head, tall and prominent
forehead (Infancy, 2e12 months); Features might appear coarse, elongated face
(Childhood 1e12 years); Myopathic facies (Adolescence, 12e18 years);
Distinguishing facial features are subtle, skin appears thin and transparent
(Adulthood > 18 years); Hypertelorism, downslanting palpebral fissures,
epicanthal folds (newborn); Hypertelorism, ptosis, or thick-hooded eyelids
(Infancy, 2e12 months); Blue green irises, arched and diamond-shaped
eyebrows (all ages); Low set, posteriorly rotated ears with thick helices (all
ages); Short and broad nose, depressed root, upturned tip (from newborn to 12
years), Bridge is high and thin (Adolescence, 12e18 years); Prominent
nasolabial fold Adulthood > 18 years; Deeply grooved philtrum, high wide peaks
of the vermilion, micrognathia; Excessive nuchal skin (newborn); Webbing
obvious (from adolescence).
2017 Morice et al. (2017) Case series (n ¼ 5) NS patient who underwent OMS procedures. Maxillary retrusion, Osteolytic lesions of the lower
hypertelorism, supernumerary teeth, low ears, lingual frenulum dystrophy, jaw (diagnosed as bilateral
impacted third molar teeth, progressive deformation of the lower jaw giant cell lesions of the
associated with tooth displacements. Multiple decidual decayed teeth. mandible through biopsy).
Giant cell lesions, affecting the
right maxilla and mandible
bilaterally.

“n” is the number of patients studied in the considered article.

RAF1, in 5%e10% (Bezniakow et al., 2014; Turner, 2014; Cao et al., protein), involved in signalling of neural crest cells (NCCs), which
2017). In the present series of 10 patients, a mutation of PTPN11 are known to participate in both skull and heart formation
was encountered in five cases (Table 1), which is consistent with (Nakamura et al., 2009). In particular, cranial NCCs are significantly
the ratio observed in the literature. However, a mutation of SOS1 involved in the formation of mesenchymal structures in the head
was observed only in two patients in our series. and neck (Chai and Maxson, 2006). Mutations within SHP2/PTPN11
Some genotypeephenotype correlations have already been appear to be responsible for NS cases presenting with both
recognized. The characteristic facial dysmorphia seems to be pre- craniofacial anomalies and cardiac disease (Nakamura et al., 2009).
sent in 91% of PTPN11 mutations (Bezniakow et al., 2014; Turner, The experimental ablation of PTPN11 specifically in pre-migratory
2014). PTPN11 encodes the tyrosine phosphatase protein (SHP2 NCCs, resulted in severe anomalies affecting large portions of the
 J.-C. Lutz et al. / Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250 247

3.3. Extraoral dysmorphia

As encountered in the present series, the common craniofacial

skeletal features include relative macrocephaly, a triangular face
shape with a broad and high forehead, hypertelorism with mild
antimongoloid slant (Figs. 1 and 2), pointed chin, micrognathia and
a high arched palate (Noonan, 1994; Scully et al., 2010; Roberts
et al., 2013; Cao et al., 2017).
The soft tissues display a short and/or webbed neck (pterygium
coli) (Fig. 1B), with low hairline and excess skin on the back of the
neck; ptosis (unilateral or bilateral) (Fig. 1); epicanthic folds,
exophthalmos and strabismus (squint) (Fig. 1A); a small, upturned
(saddle) nose; deeply grooved philtrum; and low-set, fleshy ears,
with helix distortion (Figs. 1 and 2) (Addante and Breen, 1996;
Scully et al., 2010; Cao et al., 2017). At all ages, blue-green irises
(Figs. 1 and 2) and arched and diamond-shaped posteriorly placed
eyebrows are encountered (Roberts et al., 2013) (Table 2).

3.4. Intraoral manifestations

Not all intraoral manifestations of NS are obvious in all cases and

may or may not be combined with general symptoms (Scully et al.,
2010; Mallineni et al., 2014; Cao et al., 2017). In our series, we
encountered supernumerary teeth and abnormal lateral incisors
(Fig. 5). Further, giant-cell lesions in the maxilla and mandible were
also observed (Figs. 6e8) (Table 2). These findings are consistent
with previous reports (Mallineni et al., 2014; Cao et al., 2017;
Morice et al., 2017).
Literature also mentions dental malocclusion, impacted teeth
(Mallineni et al., 2014), multiple unerupted permanent teeth and
multiple submerged and retained deciduous teeth (Uloopi et al.,
2015). Previous reports also describe hypodontia (Macmurdo
et al., 2016), taurodontism, macrodontia, enamel hypoplasia, as
well as double teeth, along with malocclusion, high arch palate and
Fig. 9. Guidelines for dental and orthodontics management in Noonan syndrome.
micrognathia (Mallineni et al., 2014) which was also observed in
our series. Furthermore, retroclined mandibular incisors, peri-
face and skull, including the mandible, the frontal and nasal bones. odontal problems, and multiple odontogenic keratocysts, as well as
The craniofacial anomalies were even more pronounced than heart progressive deformation of the lower jaw associated with tooth
defects (Nakamura et al., 2009). displacements have been reported (Morice et al., 2017; Cao et al.,
Mutation of SOS1, encountered in 10e13% of NS patients, ac- 2017), but were not present in our findings.
counts for 56% of macrocephaly (Tartaglia et al., 2007; Pierpont NS patients seem to have a higher incidence of open bite (29%)
et al., 2009; Roberts et al., 2013). Mutations in RAF1, involved in and posterior crossbite (30%) than the general population (Cao
3e17% of NS, result in lentigines and/or caf e au lait spots and et al., 2017). Such a malocclusion was observed in patient 1 of the
multiple naevi (Allanson and Roberts, 2001). present series (Fig. 3A). The distribution of class I occlusion and
Molecular genetic testing therefore seems crucial in NS. In class II malocclusion appears as normal in NS (Cao et al., 2017). The
children, it is a helpful adjunct to clinical examination, particularly present series is consistent with these data. Bifid uvula and occa-
in mildly affected patients, because it can confirm diagnosis in 70% sional cleft palate as well as poor tongue control have also been
of cases (Bhambhani and Muenke, 2014). It is also useful to provide described (Scully et al., 2010; Cao et al., 2017), however, these
specific management, namely, to consider the opportunity of features were not found among the patients in the present series.
growth hormone treatment (Roberts et al., 2013). In adult NS pa- All these intraoral manifestations can result in feeding difficulties
tients, molecular genetic testing can allow prenatal counselling if and facial growth disturbance, which may require multidisciplinary
ethically accepted (Roberts et al., 2013). management (Cao et al., 2017).
Giant-cell lesions histologically identical to central giant-cell
granuloma (CGCG) or multiple giant-cell lesions (MGCL) are likely
3.2. Dental and maxillofacial features of NS to occur in individuals with NS, as encountered in patient 6 in our
series. An orthopantomogram revealed a radiolucent lesion of the
Few publications have focused on the oral and maxillofacial mandible around tooth #19 (Fig. 6), which was further explored
manifestations of NS. We performed a literature review in PubMed through cone-beam computed tomography (Fig. 7) and MRI (Fig. 8),
using “Noonan syndrome” and “maxillofacial” as keywords and and was diagnosed as a CGCG through biopsy. This benign lesion of
retrieved 20 articles. Adding the keyword “dental” yielded seven the jaws can behave aggressively or non-aggressively, as may be
results. These findings are presented in Table 2. differentiated using clinical and radiological criteria. MGCL have
Based on this literature, the characteristic facies are very helpful rarely been reported in the hard and soft tissues of NS patients, but
in diagnosis, but usually become milder over the years (Noonan, none were found in our cases. These benign lesions are usually first
1994), making age-based specific growth charts useful (Roberts detected between ages 2 and 19 years (Romano et al., 2010; Karbach
et al., 2013; Bhambhani and Muenke, 2014). et al., 2012; Cao et al., 2017). They affect the mandible and, to a lesser
248 J.-C. Lutz et al. / Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250

Fig. 10. Guidelines for the management of giant-cell lesions in Noonan syndrome.

extent, the maxilla (Karbach et al., 2012), and sometimes result in Thereafter, patients can be referred to an orthodontist at the
jaw enlargement (Cao et al., 2017) (Table 2). Because NS can feature appropriate time, usually in early mixed dentition, to treat maloc-
bilateral, and sometimes symmetrical lesions of both jaws, it can be clusion (Shaw et al., 2007; Cao et al., 2017). The rehabilitation of the
easily misdiagnosed with cherubism (Dunlap et al.,1989; Edwards et musculature of the lower third of the face, which is often impaired in
al., 2005; de Lange et al., 2007; Papadaki et al., 2012). NS with NS patients, is also crucial (Mallineni et al., 2014). Fig. 9 summarizes
multiple giant-cell lesions seems to be a variant within the NS these treatment guidelines (Cao et al., 2017).
spectrum (Wolvius et al., 2006; de Lange et al., 2007) and has been NS patients may have a combination of platelet anomalies and
termed “Noonan/multiple giant-cell lesion syndrome” (Papadaki defects in coagulation factors (V, VII, VIII, IX, X and XI) (Morice et al.,
et al., 2012). Among RASopathies, cardiofaciocutaneous syndrome 2017), which can lead to severe consequences in orthognathic
and Costello syndrome are the ones overlapping the most with NS surgery (Sugar et al., 1994). However, no strong correlation could be
(Cao et al., 2017). Differential diagnosis of NS based on clinical ex- established between coagulation anomalies and the risk for
amination can also be quite challenging with regard to Turner syn- excessive perioperative bleeding in NS patients (Morice et al.,
drome in females (Noonan, 1994; Roberts et al., 2013), and Aarskog 2017). Referral to a haematologist is therefore recommended for
syndrome (Depeyre et al., 2018), especially in the first year of life all NS patients considered for oral and maxillofacial surgery, to
(Roberts et al., 2013; Cao et al., 2017). obtain complete blood screening. Even in the case of normal results,
Dental caries and gingival problems are often encountered in NS the haematologist must establish specific perioperative manage-
individuals (Shaw et al., 2007; Mallineni et al., 2014). Therefore, a ment guidelines (Morice et al., 2017).
first dental assessment between ages 1 and 2 years is recommended, Differentiation between cherubism and Noonan/multiple giant-
followed by a yearly dental assessment (Mallineni et al., 2014; Cao cell lesion (N/MGCL) syndrome is important, because giant-cell le-
et al., 2017), to facilitate oral prophylaxis (fissure sealants, preven- sions may behave aggressively, requiring appropriate treatment to
tive resin restorations (Uloopi et al., 2015)), early treatment of dental prevent morbidity (Papadaki et al., 2012). Surgical curettage was
anomalies (extraction of decayed, supernumerary and submerged used in patient 6 in our series, together with the extraction of tooth
teeth) and monitoring for dental crowding and malocclusion. #19. Surgical curettage is the most common treatment for
 J.-C. Lutz et al. / Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250 249

nonaggressive lesions (Wolvius et al., 2006; de Lange et al., 2007), References

but has recurrence rates of 11e49% (de Lange et al., 2007). Surgical
treatment may therefore range from a wait-and-see policy, until Addante RR, Breen GH: Cherubism in a patient with Noonan's syndrome. Journal of
Oral and Maxillofacial Surgery 54(2): 210e213, 1996
physical maturity in children and adolescents (de Lange et al., 2007; Allanson JE, Roberts AE: Noonan syndrome. In: GeneReviews®, Adam MP,
Karbach et al., 2012), to a more extensive procedure (0.5-cm addi- Ardinger HH, Pagon RA, et al. (eds). Seattle (WA): University of Washington,
tional safety margin) in aggressive lesions, or when young males are Seattle, Internet, 2001
Bezniakow N, Gos M, Obersztyn E: The RASopathies as an example of RAS/
affected, as they have a 72% recurrence rate (de Lange et al., 2007). MAPK pathway disturbances - clinical presentation and molecular patho-
The wait-and-see policy involves close monitoring of the patient genesis of selected syndromes. Development Period Medication 18(3):
with clinical and radiologic examination and multidisciplinary 285e296, 2014
Bhambhani V, Muenke M: Noonan syndrome. American Family Physician 89(1):
follow-up by maxillofacial surgeons and geneticists (Karbach et al., 37e43, 2014
2012). If no further growth of the lesion is demonstrated, surgical Cao H, Alrejaye N, Klein OD, Goodwin AF, Oberoi S: A review of craniofacial and
curettage and corrective orthodontic treatment can be conducted in dental findings of the RASopathies. Orthodontics and Craniofacial Research
20(Suppl. 1): 32e38, 2017 June
early adulthood (Karbach et al., 2012).
Chai Y, Maxson RE: Recent advances in craniofacial morphogenesis. Developmental
In cases of aggressive lesions and in adults, alternative therapies Dynamics 235(9): 2353e2375, 2006
have been reported that target either the recruitment or function of de Lange J, van den Akker HP, van den Berg H: Central giant cell granuloma of the jaw: a
review of the literature with emphasis on therapy options. Oral Surgery, Oral
osteoclast-like giant cells (de Lange et al., 2007): corticosteroids
Medicine, Oral Pathology, Oral Radiology & Endodontics 104(5): 603e615, 2007
(Morice et al., 2017), calcitonin (Wolvius et al., 2006; Papadaki et al., Depeyre A, Schlund M, Gryseleyn R, Ferri J: Dental and maxillofacial signs in Aar-
2012; van den Berg et al., 2016), imatinib, osteoprotegerin (de Lange skog syndrome: a review of 3 siblings and the literature. Journal of Oral and
et al., 2007). Other therapies possibly impact endothelial cells Maxillofacial Surgery 76(10): 2202e2208, 2018
Dunlap C, Neville B, Vickers RA, O'Neil D, Barker B: The Noonan syndrome/cher-
(interferon 2a) or osteoblast differentiation (interferon 2a) (Wolvius ubism association. Oral Surgery, Oral Medicine, Oral Pathology 67(6): 698e705,
et al., 2006). The use of a human monoclonal antibody to RANKL 1989
(denosumab) has also been described (de Lange et al., 2007; Naidu Edwards PC, Fox J, Fantasia JE, Goldberg J, Kelsch RD: Bilateral central giant cell
granulomas of the mandible in an 8-year-old girl with Noonan syndrome
et al., 2014; van den Berg et al., 2016). These non-surgical thera- (Noonan-like/Multiple giant cell lesion syndrome). Oral Surgery, Oral Medicine,
pies are usually combined with contour resection or surgical Oral Pathology 99(3): 334e340, 2005
curettage (Kaban et al., 1999; Papadaki et al., 2012; Morice et al., Kaban LB, Mulliken JB, Ezekowitz RA, Ebb D, Smith PS, Folkman J: Antiangiogenic
therapy of a recurrent giant cell tumor of the mandible with interferon alfa-2a.
2017) (Fig. 10), but none appear to be capable of eliminating CGCG Pediatrics 103(6 Pt 1): 1145e1149, 1999
in every patient when used as a monotherapy (de Lange et al., 2007). Karbach J, Coerdt W, Wagner W, Bartsch O: Case report: Noonan syndrome with
The facial features affecting NS patients, namely maxillary and multiple giant cell lesions and review of the literature. American Journal of
Medical Genetics 158A(9): 2283e2289, 2012
mandibular sagittal and transversal deficiency, high-arched palate
Levine B, Skope L, Parker R: Cherubism in a patient with Noonan syndrome:
with open bite, and increased facial height (Macmurdo et al., 2016), report of a case. Journal of Oral and Maxillofacial Surgery 49(9):
become more obvious with growth. Several cases of orthognathic 1014e1018, 1991
Macmurdo CF, Wooderchak-Donahue W, Bayrak-Toydemir P, Le J, Wallenstein MB,
surgical procedures performed in diagnosed NS patients with
Milla C, et al: RASA1 somatic mutation and variable expressivity in capillary
various perioperative courses (Sugar et al., 1994; Morice et al., 2017) malformation/arteriovenous malformation (CM/AVM) syndrome. American
have been reported. Surgeons need to consider the risks of abun- Journal of Medical Genetics 170(6): 1450e1454, 2016
dant and life-threatening bleeding inherent to the various coagu- Mallineni SK, Yung Yiu CK, King NM: Oral manifestations of Noonan syndrome:
review of the literature and a report of four cases. Romanian Journal of
lation anomalies encountered in NS, but orthognathic surgery Morphology and Embryology 55(4): 1503e1509, 2014
appears to be an acceptable treatment option after considering the Marino B, Digilio MC, Toscano A, Giannotti A, Dallapiccola B: Congenital heart
potential benefits and risks for the individual case. Accordingly, we diseases in children with Noonan syndrome: an expanded cardiac spectrum
with high prevalence of atrioventricular canal. Journal of Pediatric 135(6):
propose treatment guidelines in Fig. 9. 703e706, 1999
Miyamoto JJ, Yabunaka T, Moriyama K: Cervical characteristics of Noonan syn-
drome. The European Journal of Orthodontics 36(2): 226e232, 2014
4. Conclusion Morice A, Harroche A, Cairet P, Khonsari RH: Preoperative detailed coagulation tests
are required in patients with Noonan syndrome. Journal of Oral and Maxillo-
It is necessary that practitioners involved in oral and maxillo- facial Surgery 76(7): 1553e1558, 2017
Naidu A, Malmquist MP, Denham CA, Schow SR: Management of central giant cell
facial care are aware of the specific characteristics of NS, whereas granuloma with subcutaneous denosumab therapy. Journal of Oral and Maxil-
specialists in paediatrics and genetics need to be mindful of the oral lofacial Surgery 72(12): 2469e2484, 2014
and maxillofacial management of NS patients. Nakamura T, Gulick J, Colbert MC, Robbins J: Protein tyrosine phosphatase activity
in the neural crest is essential for normal heart and skull development. Pro-
ceedings of the National Academy of Sciences of the United States of America
Declarations 106(27): 11270e11275, 2009
Noonan JA: Noonan syndrome. An update and review for the primary pediatrician.
The authors declare that they have no competing interest and Clinical Pediatrics 33(9): 548e555, 1994
had no sources of funding for this research. Noonan JA, Ehkme D: Associated noncardiac malformations in children with
Ethical approval for this report was given by the Ethical com- congenital heart disease. Journal of Pediatrics 63: 468e470, 1963
Papadaki ME, Lietman SA, Levine MA, Olsen BR, Kaban LB, Reichenberger EJ: Cherub-
mittee of the University Hospital of Strasbourg, France by Pr. ism: best clinical practice. Orphanet Journal of Rare Diseases 7(Suppl. 1): S6, 2012
François CLAUSS, on May 14th, 2019, with the reference FC/file Pierpont EI, Pierpont ME, Mendelsohn NJ, Roberts AE, Tworog-Dube E,
2019-29. Seidenberg MS: Genotype differences in cognitive functioning in Noonan syn-
drome. Genes, Brain and Behavior 8(3): 275e282, 2009
Written patient consent has been obtained for publication of
Roberts AE, Allanson JE, Tartaglia M, Gelb BD: Noonan syndrome. Lancet London
this data. England 381(9863): 333e342, 2013
All authors have viewed and agreed to the submission of this Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, et al: Noonan
syndrome: clinical features, diagnosis, and management guidelines. Pediatrics
paper.
126(4): 746e759, 2010
Scully C, Langdon J, Evans J: Marathon of eponyms: 14 Noonan syndrome. Oral
Diseases 16(8): 839e840, 2010
Acknowledgements
Shaw AC, Kalidas K, Crosby AH, Jeffery S, Patton MA: The natural history of Noonan
syndrome: a long-term follow-up study. Archives of Disease in Childhood
The authors thank Pr. Joe€l FERRI, Dr. Claudine SCHWARTZ, Dr. 92(2): 128e132, 2007
Sugar AW, Ezsias A, Bloom AL, Morcos WE: Orthognathic surgery in a patient with
Elise SCHAEFER, Dr. Fabien BORNERT and Dr. Matthias SCHLUND for
Noonan's syndrome. Journal of Oral and Maxillofacial Surgery 52(4): 421e425,1994
providing clinical and radiological images.
250 J.-C. Lutz et al. / Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250

Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, et al: Gain-of- van den Berg H, Schreuder WH, Jongmans M, van Bommel-Slee D, Witsenburg B, de
Function SOS1 mutations cause a distinctive form of Noonan syndrome. Nature Lange J: Multiple giant cell lesions in a patient with Noonan syndrome with
Genetics 39(1): 75e79, 2007 multiple lentigines. European Journal of Medical Genetics 59(8): 425e428,
Turner AM: Noonan syndrome. Journal of Paediatrics and Child Health 50(10): 2016
E14eE20, 2014 Wolvius EB, de Lange J, Smeets EEJ, van der Wal KGH, van den Akker HP:
Uloopi KS, Madhuri V, Gopal AS, Vinay C, Chandrasekhar R: Multiple unerupted Noonan-like/Multiple giant cell lesion syndrome: report of a case and re-
permanent teeth associated with Noonan syndrome. Annals of Medical and view of the literature. Journal of Oral and Maxillofacial Surgery 64(8):
Health Sciences Research 5(4): 317e320, 2015 1289e1292, 2006