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 syndrome (NS) is a relatively common congenital
multiple-anomaly syndrome that is well characterized in children
* Corresponding author. Oral and Maxillofacial Surgery Department, Strasbourg
re, 67098, Strasbourg Cedex, France.
University Hospital, 1 avenue Molie
E-mail address: jean-christophe.lutz@chru-strasbourg.fr (J.-C. Lutz).
(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).
Early descriptions of this syndrome by Jacqueline Noonan
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
chromosomes.

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
heart disease, namely valvular pulmonary stenosis and hypertro-
phic cardiomyopathy (Marino et al., 1999). A large number of sys-
temic features, such as genital, kidney and lymphatic
malformations, have been thoroughly described (Noonan and
Ehkme, 1963; Papadaki et al., 2012; Roberts et al., 2013;
Bhambhani and Muenke, 2014). Vision and hearing defects,
abnormal skin pigmentation, digestive disorders, delayed puberty,
failure to thrive and low-normal intelligence have also been re-
ported (Roberts et al., 2013; Bhambhani and Muenke, 2014).
Orthopaedic deformities are often present in patients with NS.
Chest deformity (pectus carinatum or pectus excavatum) is common
(90%), in addition to hyperextensible joints and muscle hypotonia
(Noonan, 1994). Scoliosis and talipes equinovarus are reported
(10e15%) (Noonan, 1994). An increased carrying angle at the elbow
is frequent and the fifth finger is sometimes curved. Cervical spine
fusion and basilar impression may be frequently found in NS
(Miyamoto et al., 2014). Radio-ulnar synostosis and joint contrac-
tures have also been described (Noonan, 1994).
An increased risk of developing solid tumours, particularly
multiple giant-cell lesions and blood cancers, is also inherent to NS
patients (Roberts et al., 2013). Moreover, various hematologic
anomalies affecting primary and secondary haemostasis are
frequent in NS (60%) and need to be carefully considered prior to
surgery, particularly because they might not be detected through
routine screening (Morice et al., 2017).
In contrast to the comprehensive description of systemic fea-
tures in NS, only its general facial appearance has been well
established. The present article aims to provide a detailed
description of dentomaxillofacial features of NS based on a series of
10 patients. Based thereon, we also propose specific dentomax-
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
Between 2000 and 2018, 14 patients were referred for screening
of oral and maxillofacial malformations as part of NS to the
Department of Oral and Maxillofacial Surgery at the University
Hospital of Lille and Strasbourg, France. Overall, 12 patients un-
derwent genetic screening, of whom 10 were found to carry a
mutation known to be involved in NS or NS-related disorders.
Among these patients, 50% carried a mutation in PTPN11. The male
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
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. 6. Orthopantomogram of patient 6 depicting a central giant-cell granuloma
appearing as a radiolucent lesion of the left mandibular corpus around tooth #19
(yellow arrows) (Courtesy of Dr. F. BORNERT).
was 15.7 (7.1) years. The clinical and genetic features of these pa-
tients are summarized in Table 1.
General NS manifestations, such as short stature, albeit within
the normal range, were always encountered. All patients of the
present series presented with the typical extraoral features, such as
macrocephaly, hypertelorism, ptosis, triangular face shape, anti-
mongoloid slant of the palpebral fissures and low-set fleshy ears
with a posterior inclination (Figs. 1e3). Two patients had a webbed
neck (pterygium coli) (Fig. 1B).
Fig. 7. Cone beam computed tomography of patient 6 depicting a central giant-cell
granuloma appearing as a radiolucent lesion in the left mandibular corpus around
tooth #19 (yellow arrows) (Courtesy of Dr. F. BORNERT).
245
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.
F. BORNERT).
Intraoral manifestations, including malocclusion, dental anom-
alies and radiologic jaw lesions were identified in five out of 10
patients. Malocclusion was present in three out of 10 patients. This
consisted of maxillary transversal deficiency, crossbite, anterior
open-bite, as in patient 1 (Figs. 3A and 4A) and class II malocclusion,
as in patients 2 and 3. Dental anomalies were observed in five out of
10 patients. This included delayed dental eruption of teeth #7 and
10 (eruption at age 11) in patient 1, the dystrophy of tooth #10 and
agenesis of tooth #16 in patient 2 (Fig. 5). There were two
mandibular odontomas in patient 3. Patient 4 had tooth dystrophy
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
manifestations (Bezniakow et al., 2014). Molecular testing is avail-
able for the three genes primarily affected in NS: PTPN11, mutated
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.,
2017). In the present series of 10 patients, a mutation of PTPN11
was encountered in five cases (Table 1), which is consistent with
the ratio observed in the literature. However, a mutation of SOS1
was observed only in two patients in our series.
Some genotypeephenotype correlations have already been
recognized. The characteristic facial dysmorphia seems to be pre-
sent in 91% of PTPN11 mutations (Bezniakow et al., 2014; Turner,
2014). PTPN11 encodes the tyrosine phosphatase protein (SHP2
protein), involved in signalling of neural crest cells (NCCs), which
are known to participate in both skull and heart formation
(Nakamura et al., 2009). In particular, cranial NCCs are significantly
involved in the formation of mesenchymal structures in the head
and neck (Chai and Maxson, 2006). Mutations within SHP2/PTPN11
appear to be responsible for NS cases presenting with both
craniofacial anomalies and cardiac disease (Nakamura et al., 2009).
The experimental ablation of PTPN11 specifically in pre-migratory
NCCs, resulted in severe anomalies affecting large portions of the
 J.-C. Lutz et al. / Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250
Fig. 9. Guidelines for dental and orthodontics management in Noonan syndrome.
face and skull, including the mandible, the frontal and nasal bones.
The craniofacial anomalies were even more pronounced than heart
defects (Nakamura et al., 2009).
Mutation of SOS1, encountered in 10e13% of NS patients, ac-
counts for 56% of macrocephaly (Tartaglia et al., 2007; Pierpont
et al., 2009; Roberts et al., 2013). Mutations in RAF1, involved in
3e17% of NS, result in lentigines and/or caf e au lait spots and
multiple naevi (Allanson and Roberts, 2001).
Molecular genetic testing therefore seems crucial in NS. In
children, it is a helpful adjunct to clinical examination, particularly
in mildly affected patients, because it can confirm diagnosis in 70%
of cases (Bhambhani and Muenke, 2014). It is also useful to provide
specific management, namely, to consider the opportunity of
growth hormone treatment (Roberts et al., 2013). In adult NS pa-
tients, molecular genetic testing can allow prenatal counselling if
ethically accepted (Roberts et al., 2013).
3.2. Dental and maxillofacial features of NS
Few publications have focused on the oral and maxillofacial
manifestations of NS. We performed a literature review in PubMed
using “Noonan syndrome” and “maxillofacial” as keywords and
retrieved 20 articles. Adding the keyword “dental” yielded seven
results. These findings are presented in Table 2.
Based on this literature, the characteristic facies are very helpful
in diagnosis, but usually become milder over the years (Noonan,
1994), making age-based specific growth charts useful (Roberts
et al., 2013; Bhambhani and Muenke, 2014).
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
micrognathia (Mallineni et al., 2014) which was also observed in
our series. Furthermore, retroclined mandibular incisors, peri-
odontal problems, and multiple odontogenic keratocysts, as well as
progressive deformation of the lower jaw associated with tooth
displacements have been reported (Morice et al., 2017; Cao et al.,
2017), but were not present in our findings.
NS patients seem to have a higher incidence of open bite (29%)
and posterior crossbite (30%) than the general population (Cao
et al., 2017). Such a malocclusion was observed in patient 1 of the
present series (Fig. 3A). The distribution of class I occlusion and
class II malocclusion appears as normal in NS (Cao et al., 2017). The
present series is consistent with these data. Bifid uvula and occa-
sional cleft palate as well as poor tongue control have also been
described (Scully et al., 2010; Cao et al., 2017), however, these
features were not found among the patients in the present series.
All these intraoral manifestations can result in feeding difficulties
and facial growth disturbance, which may require multidisciplinary
management (Cao et al., 2017).
Giant-cell lesions histologically identical to central giant-cell
granuloma (CGCG) or multiple giant-cell lesions (MGCL) are likely
to occur in individuals with NS, as encountered in patient 6 in our
series. An orthopantomogram revealed a radiolucent lesion of the
mandible around tooth #19 (Fig. 6), which was further explored
through cone-beam computed tomography (Fig. 7) and MRI (Fig. 8),
and was diagnosed as a CGCG through biopsy. This benign lesion of
the jaws can behave aggressively or non-aggressively, as may be
differentiated using clinical and radiological criteria. MGCL have
rarely been reported in the hard and soft tissues of NS patients, but
none were found in our cases. These benign lesions are usually first
detected between ages 2 and 19 years (Romano et al., 2010; Karbach
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
jaw enlargement (Cao et al., 2017) (Table 2). Because NS can feature
bilateral, and sometimes symmetrical lesions of both jaws, it can be
easily misdiagnosed with cherubism (Dunlap et al.,1989; Edwards et
al., 2005; de Lange et al., 2007; Papadaki et al., 2012). NS with
multiple giant-cell lesions seems to be a variant within the NS
spectrum (Wolvius et al., 2006; de Lange et al., 2007) and has been
termed “Noonan/multiple giant-cell lesion syndrome” (Papadaki
et al., 2012). Among RASopathies, cardiofaciocutaneous syndrome
and Costello syndrome are the ones overlapping the most with NS
(Cao et al., 2017). Differential diagnosis of NS based on clinical ex-
amination can also be quite challenging with regard to Turner syn-
drome in females (Noonan, 1994; Roberts et al., 2013), and Aarskog
syndrome (Depeyre et al., 2018), especially in the first year of life
(Roberts et al., 2013; Cao et al., 2017).
Dental caries and gingival problems are often encountered in NS
individuals (Shaw et al., 2007; Mallineni et al., 2014). Therefore, a
first dental assessment between ages 1 and 2 years is recommended,
followed by a yearly dental assessment (Mallineni et al., 2014; Cao
et al., 2017), to facilitate oral prophylaxis (fissure sealants, preven-
tive resin restorations (Uloopi et al., 2015)), early treatment of dental
anomalies (extraction of decayed, supernumerary and submerged
teeth) and monitoring for dental crowding and malocclusion.
Thereafter, patients can be referred to an orthodontist at the
appropriate time, usually in early mixed dentition, to treat maloc-
clusion (Shaw et al., 2007; Cao et al., 2017). The rehabilitation of the
musculature of the lower third of the face, which is often impaired in
NS patients, is also crucial (Mallineni et al., 2014). Fig. 9 summarizes
these treatment guidelines (Cao et al., 2017).
NS patients may have a combination of platelet anomalies and
defects in coagulation factors (V, VII, VIII, IX, X and XI) (Morice et al.,
2017), which can lead to severe consequences in orthognathic
surgery (Sugar et al., 1994). However, no strong correlation could be
established between coagulation anomalies and the risk for
excessive perioperative bleeding in NS patients (Morice et al.,
2017). Referral to a haematologist is therefore recommended for
all NS patients considered for oral and maxillofacial surgery, to
obtain complete blood screening. Even in the case of normal results,
the haematologist must establish specific perioperative manage-
ment guidelines (Morice et al., 2017).
Differentiation between cherubism and Noonan/multiple giant-
cell lesion (N/MGCL) syndrome is important, because giant-cell le-
sions may behave aggressively, requiring appropriate treatment to
prevent morbidity (Papadaki et al., 2012). Surgical curettage was
used in patient 6 in our series, together with the extraction of tooth
#19. Surgical curettage is the most common treatment for
 J.-C. Lutz et al. / Journal of Cranio-Maxillo-Facial Surgery 48 (2020) 242e250
nonaggressive lesions (Wolvius et al., 2006; de Lange et al., 2007),
but has recurrence rates of 11e49% (de Lange et al., 2007). Surgical
treatment may therefore range from a wait-and-see policy, until
physical maturity in children and adolescents (de Lange et al., 2007;
Karbach et al., 2012), to a more extensive procedure (0.5-cm addi-
tional safety margin) in aggressive lesions, or when young males are
affected, as they have a 72% recurrence rate (de Lange et al., 2007).
The wait-and-see policy involves close monitoring of the patient
with clinical and radiologic examination and multidisciplinary
follow-up by maxillofacial surgeons and geneticists (Karbach et al.,
2012). If no further growth of the lesion is demonstrated, surgical
curettage and corrective orthodontic treatment can be conducted in
early adulthood (Karbach et al., 2012).
In cases of aggressive lesions and in adults, alternative therapies
have been reported that target either the recruitment or function of
osteoclast-like giant cells (de Lange et al., 2007): corticosteroids
(Morice et al., 2017), calcitonin (Wolvius et al., 2006; Papadaki et al.,
2012; van den Berg et al., 2016), imatinib, osteoprotegerin (de Lange
et al., 2007). Other therapies possibly impact endothelial cells
(interferon 2a) or osteoblast differentiation (interferon 2a) (Wolvius
et al., 2006). The use of a human monoclonal antibody to RANKL
(denosumab) has also been described (de Lange et al., 2007; Naidu
et al., 2014; van den Berg et al., 2016). These non-surgical thera-
pies are usually combined with contour resection or surgical
curettage (Kaban et al., 1999; Papadaki et al., 2012; Morice et al.,
2017) (Fig. 10), but none appear to be capable of eliminating CGCG
in every patient when used as a monotherapy (de Lange et al., 2007).
The facial features affecting NS patients, namely maxillary and
mandibular sagittal and transversal deficiency, high-arched palate
with open bite, and increased facial height (Macmurdo et al., 2016),
become more obvious with growth. Several cases of orthognathic
surgical procedures performed in diagnosed NS patients with
various perioperative courses (Sugar et al., 1994; Morice et al., 2017)
have been reported. Surgeons need to consider the risks of abun-
dant and life-threatening bleeding inherent to the various coagu-
lation anomalies encountered in NS, but orthognathic surgery
appears to be an acceptable treatment option after considering the
potential benefits and risks for the individual case. Accordingly, we
propose treatment guidelines in Fig. 9.
4. Conclusion
It is necessary that practitioners involved in oral and maxillo-
facial care are aware of the specific characteristics of NS, whereas
specialists in paediatrics and genetics need to be mindful of the oral
and maxillofacial management of NS patients.
Declarations
The authors declare that they have no competing interest and
had no sources of funding for this research.
Ethical approval for this report was given by the Ethical com-
mittee of the University Hospital of Strasbourg, France by Pr.
François CLAUSS, on May 14th, 2019, with the reference FC/file
2019-29.
Written patient consent has been obtained for publication of
this data.
All authors have viewed and agreed to the submission of this
paper.
Acknowledgements
The authors thank Pr. Joe€l FERRI, Dr. Claudine SCHWARTZ, Dr.
Elise SCHAEFER, Dr. Fabien BORNERT and Dr. Matthias SCHLUND for
providing clinical and radiological images.
249
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