Giant Cell Lesions of the Jaws Involving RASopathy Syndromes

Abstract

Objective

Giant cell lesions of the jaws (GCLJ) may rarely occur in the setting of RASopathy syndromes such as Noonan syndrome or neurofibromatosis I. Recently, central giant cell granulomas (CGCG), the most common of the GCLJ, have been recognized as benign neoplasms characterized by Ras/MAPK signaling pathway mutations. This provides a rational basis for understanding GCLJ in RASopathy syndromes as syndromically occurring CGCG. This review aims to summarize the clinicopathologic features of syndromic CGCG and to review the salient clinical and craniofacial features of the syndromes in which they may rarely occur.

Material and Methods

An electronic search in 3 databases was performed, looking for GCLJ/CGCG in RASopathy syndromes.

Results

124 CGCG in 56 patients were identified across 6 RASopathy syndromes. Median age at syndromic CGCG diagnosis is 11 years; 69.6% (39/56) patients developed two or more CGCG; 58.9% (33/56) presented with bilateral posterior mandibular CGCGs, mimicking cherubism. Of 88 CGCG with follow-up, 22.4% (13/58) of excised/resected CGCG recurred while 46.7% (14/30) of monitored CGCG showed continued growth.

Conclusion

Syndromic CGCG involves multiple RASopathy syndromes and may mimic cherubism or, when solitary, sporadically occurring CGCG. Familiarity with other clinical findings of RASopathy syndromes is critical for appropriate diagnosis and patient management.

INTRODUCTION

Giant cell lesions of the jaws (GCLJ) represent a group of diverse conditions occurring in the mandible or maxilla, characterized by the presence of multinucleated giant cells histopathologically (1). GCLJ may occur in sporadic or syndromic settings, or in the setting of specific metabolic alterations. Central giant cell granuloma, cherubism, brown tumor of hyperparathyroidism and aneurysmal bone cyst are the principal GCLJ.

Central giant cell granuloma (CGCG), usually occurring sporadically, accounts for the majority of GCLJ. CGCG typically occurs in the first three decades of life with a slight female predilection and is considered to have a predilection for the anterior jaws, usually mandible (2). Approximately half of cases result in cortical bone perforation and more aggressive cases show rapid growth with tooth displacement and root resorption, or may pursue a multiply recurrent clinical course (3). Histopathologically, CGCGs are characterized by a vaguely lobular proliferation of mononuclear spindle-shaped and polygonal cells with admixed multinucleated giant cells, extravasated erythrocytes, and variable osteoid production (4). Therapeutic approaches are either surgical (curettage, local excision, resection) or pharmacological (intralesional injections with steroids, interferon-α, denosumab, others), (5-7).
More recently, sporadically occurring CGCGs- in spite of their name- have been recognized as neoplasms unique to the jawbones that harbor TRPV4, KRAS or FGFR1 mutations, resulting in activation of the MAPK (mitogen activated protein kinase) pathway (Fig. 1), (8). This signaling pathway influences cell proliferation, migration and differentiation, and its dysregulation increases neoplastic behavior (9). The MAPK signaling pathway is one of the most commonly dysregulated signaling pathways in human neoplasia, benign or malignant (10).

Figure 1.

MAPK pathway alterations in sporadic CGCG and RASopathies involved by syndromic CGCG.

The identification of MAPK pathway alterations in CGCG now provides a rational basis for understanding the rare occurrence of GCLJ in Noonan syndrome, neurofibromatosis type I, and a handful of other less common syndromes. These syndromes are all characterized by germline or post-zygotic mutations in genes important in MAPK pathway signaling, and collectively are referred to as RASopathies (Fig 1), (11, 12).The fact that RASopathies are pathogenetically related explains shared clinical features of short stature, scoliosis, osteoporosis and chest wall deformities (13).

On the basis of recently discovered genomic alterations, GCLJ occurring in RASopathies can now be understood as syndromic CGCGs and this review aims to determine their incidence and clinical presentation, as well as a comprehensive review of the salient clinical features of the syndromes in which they occur. Cherubism, an autosomal dominant disorder characterized by bilateral and self-limiting maxillo-mandibular expansion and by germline SH3BP2 mutations, a gene whose function is presently unclear and with no relationship to MAPK pathway signaling, will not be reviewed (14).

MATERIAL AND METHODS

PubMed, Medline and Scopus databases were searched for articles published up to December 31, 2021. The authors screened titles and abstracts of all studies that included the terms: Noonan, neurofibromatosis, Jaffe-Campanacci, oculoectodermal, Ramon, Schimmelpenning, Costello, cardio-facio-cutaneous, osteoglophonic dysplasia and RASopathy, in combination with the term giant cell. Inclusion criteria included: primary research in the English language; adequate clinical, radiographic, histologic, and/or molecular information to confirm the diagnosis of GLCJ/CGCG as well as the parent syndrome; involvement of mandible or maxilla. Exclusion criteria included sporadically occurring GLCJ/CGCG; giant cell lesions involving bones other than the mandible/maxilla (non-ossifying fibromas); secondary research; retracted articles; non-English language.

Full-text articles screened for eligibility identified a total of 41 relevant primary research articles. Extracted data consisted of: parent syndrome, age, gender, number of CGCG, location and, when included, treatment and follow-up information. Data were presented as descriptive statistics to present, for the first time, an overview of the clinical and demographic presentation of syndromic CGCG. These findings were compared against the clinical and demographic features of sporadic CGCG, as recently reviewed in 2018, for statistical significance using a Student’s t-test or Mann-Whitney test, depending on the normality (2).

CGCG occurrence in RASopathies

Following comprehensive review of the English language literature in PubMed, a total of 124 syndromic CGCGs, in 56 patients, were identified in the following RASopathy syndromes (Table 1): Noonan syndrome /77/ (15-37), neurofibromatosis type I /22/, (38-47), oculoectodermal syndrome /11/ (48, 49), Schimmelpenning syndrome /6/ (50-52), cardio-facio-cutaneous syndrome /5/ (53), and osteoglophonic dysplasia /3/ (54, 55). In light of a recent systematic review of 2270 CGCG published in the literature by Chrcanovic et al, 5.1% (121/2391) of all published CGCG have occurred syndromically, though this presumably reflects substantial publication bias since sporadically occurring CGCG are no longer commonly reported, and the proportion is likely much smaller (2).

Table 1. Clinical features of RASopathy patients with CGCG.

	NS	NF1/JC	OES	SS	CFC	OGD	Total
Patients	34	12	2	3	3	2	56
Median age (range)	10 years (4-22 years)	12 years (7-38 years)	3.5 years (3-4 years)	11 years (5-14 years)	8 years (5-14 years)	4.5 years (3-12 years)	11 years (3-38 years)
Gender Male Female	23 11	3 9	1 1	0 3	2 1	1 1	30 26
Number of CGCG per patient 1 2+	6 28	6 6	1 1	2 1	1 2	1 1	17 (30.4%) 39 (69.6%)
Patients with: Bilateral mandibular (cherubism-like) presentation Additional CGCGs following initial CGCG diagnosis	25 3	5 2	1 1	0 1	2 0	0 0	33 (58.9%) 7 (12.5%)
Total CGCG reporteda Maxilla Anterior Posterior Unknown Mandible Anterior Posterior Unknown	77 17 (22.1%) 2 15 0 60 (77.9%) 1 56 3	22 7 (31.8%) 1 6 0 15 (68.2%) 2 13 0	11 2 (18.2%) 0 2 0 9 (81.8%) 1 4 4	6 5 (83.3%) 2 3 0 1 (16.7%) 0 1 0	5 0 (0.0%) 0 0 0 5 (100.0%) 0 4 1	3 1 (33.3%) 0 1 0 2 (66.7%) 1 1 0	124 32 (25.8%) 5 27 0 92 (74.2%) 5 79 8

NS denotes Noonan syndrome; NF1/JC denotes neurofibromatosis type 1/Jaffe-Campanacci syndrome; OES denotes oculoectodermal syndrome; SS denotes Schimmelpenning syndrome; CFC denotes cardiofaciocutaneous syndrome; OGD denotes osteoglophonic dysplasia

a Patients described as having ‘multiple’ lesions were quantified as having 3 CGCG for tabulation purposes

The median age of syndromic CGCG diagnosis is 11 years, with wider age ranges reported in Noonan syndrome (4-22 years) and neurofibromatosis type I (7-38 years) than in other syndromes where CGCGs have been reported exclusively in the first two decades of life. There is a 1.25 to 1 M:F ratio, with some variation by syndrome. Seventeen patients (30.4%) had one CGCG and 39 (69.6%) had two or more CGCGs. Mandibular involvement was noted in 92/124 (74.2%) of CGCG, with only 5 CGCGs (5.4%) occurring anterior to the canine. Anterior maxillary involvement (5/32, 15.6%) was also uncommon. Bilateral mandibular CGCGs occurred in 33/56 (58.9%) patients, leading to mischaracterization of the patient as (also) having cherubism in many instances.

Of the 88 CGCGs with follow-up information, 38 (43.2%) were conservatively excised, 20 (22.7%) were resected and 30 (34.1%) were observed (Table 2). Recurrences were noted in 8 (21.1%) excised and 5 (25%) resected CGCGs, while continued growth was noted in 14 (46.7%) CGCG managed by observation. One Noonan syndrome patient²⁴ had continued CGCG growth in spite of radiation therapy, antiangiogenic therapy and steroid therapy while one patient with osteoglophonic dysplasia had continued CGCG growth while on vinblastine and methotrexate but demonstrated response to IV bisphosphonate (54).

Table 2. Management of syndromic CGCG.

	NS	NF1/JC	OES	SS	CFC	OGD	Total
Number of CGCGs with management/ follow-up information	43	22	11	6	5	1	88
Conservative excision Recurrence	12 1	11 4	11 3	4 0	0 0	0 0	38 8 (21.1%)
Resection Recurrence	8 1	5 3	0 0	2 1	5 0	0 0	20 5 (25%)
Observation only Continued growth	23 9a	6 4	0 0	0 0	0 0	1 1b	30 14 (46.7%)

NS denotes Noonan syndrome; NF1/JC denotes neurofibromatosis type 1/Jaffe-Campanacci syndrome; OES denotes oculoectodermal syndrome; SS denotes Schimmelpenning syndrome; CFC denotes cardiofaciocutaneous syndrome; OGD denotes osteoglophonic dysplasia

a Makis, et al reported continued CGCG growth in setting of radiation therapy, antiangiogenic therapy, and steroid therapy

b White, et al reported continued CGCG growth in setting of vinblastine and methotrexate therapy but with response to IV bisphosphonate

The number of reported syndromic cases is small and precludes confident statistical comparison between syndromic and sporadic CGCG; however, certain trends are noted (Table 3). The mean age of diagnosis of syndromic CGCG was 10.5 years, which was significantly younger than the mean age of diagnosis of 25.8 years for sporadic CGCG (p < 0.001), though the wide standard deviation of ± 15.3 years for sporadic CGCG renders this clinical characteristic, in isolation, unlikely to be helpful in patient evaluaton (2). Also of statistical significance was the 1.15:1 M:F ratio in syndromic CGCG compared to 1:1.55 M:F ratio for sporadic CGCG (p = 0.03). Syndromic and sporadic CGCG share a mandibular predilection (74.2% and 69.2%, respectively), though it is noteworthy that the vast majority (91.7%) of syndromic CGCG occur posterior to the maxillary or mandibular canines. In contrast, sporadic CGCG appears to show no clear anterior or posterior predilection and only a minority of cases cross the midline of the jaws, as is often considered characteristic (2). More detailed clinical information such as size and presenting symptoms were rarely reported in syndromic cases and not amenable to comparison.

Table 3. Comparison of clinical features between syndromic and sporadic CGCG.

	Syndromic CGCG	Sporadic CGCGa	P value
Mean age ± SD (range)	10.5 ± 6.68 years (3-38 years)	25.8 ± 15.3 years (0-85 years)	< 0.001
Genderb Male Female	30/56 (53.6%) 26/56 (46.4%)	876/2233 (39.2%) 1357/2233 (60.8%)	0.030
Locationb Mandible Maxilla	92/124 (74.2%) 32/124 (25.8%)	1503/2171 (69.2%) 668/2171 (30.8%)	0.243
Recurrence following surgical treatmentc Yes No	13/58 (22.4%) 45/58 (77.6%)	232/1316 (17.6%) 1084/1316 (82.4%)	0.885

a Data derived from Chrcanovic BR, et al. J Oral Pathol Med. 2018;47:731 (reference 2).

b Cases with unknown gender or location were excluded, as in primary analysis by Chrcanovic, et al.

c Among cases with follow-up

The occurrence of multiple CGCGs, seen in approximately 70% of syndromic patients, appears strongly suggestive of an underlying syndrome as multiple CGCGs were not reported in the 2018 review (2). Of note, over half of syndromic patients (58.9%) presented with bilateral involvement of the posterior mandible, suggesting that distinction from cherubism, which also presents with giant cell-rich lesions of the posterior mandible, is critical in the pediatric setting and requires careful clinical evaluation for other syndromic features or genetic testing for correct diagnosis.

There were no statistically significant differences between recurrence rates of syndromic (22.4%) versus sporadic (17.6%) CGCG (p = 0.89). However, sporadic CGCG may present with aggressive and non-aggressive variants, and subgroup analysis of these two variants yielded recurrence rates of 22.8% and 7.8%, respectively, as reported previously (2). This suggests that syndromic CGCG may have biologic behavior more similar to aggressive CGCG and raises the interesting question as to whether underlying germline predisposition may account for more rapid growth. Definitive conclusions regarding optimal patient management are precluded by the small number of cases with follow-up information, but these findings suggest a primary role for excision/resection of syndromic CGCGs as opposed to close observation in which approximately half of cases (46.7%) demonstrated continued growth. Long-term follow-up for the development of additional CGCGs was documented infrequently (12.5% of patients), but appears prudent.

Given that syndromic CGCG occurs rarely and may have substantial overlap with sporadic CGCG or cherubism at presentation, familiarity with the clinical features of the syndromes, in particular craniofacial features, in which they may present is requisite for diagnosis and patient management.

Noonan and Noonan-like syndrome

Syndromic CGCGs have been most frequently reported in Noonan Syndrome (NS), a common RASopathy first described by Jaqueline Noonan in 1968 (56). NS presents with a variable degree of distinctive features including craniofacial dysmorphia, short stature, webbed neck and congenital heart defects (57). Individuals are usually diagnosed after birth, but certain prenatal findings can suggest the diagnosis (58). Infants frequently present with feeding difficulties (can lead to failure to thrive) and sporadic episodes of nausea/vomiting that improve or resolve by the age of 15 months. Other common early-discovered traits include scoliosis, pectus excavatum or carinatum, hematologic disorders, and cryptorchidism (60-80% of boys). Short stature typically comes to attention in puberty but adult height is not always compromised (59). Cardiac abnormalities are a main clinical manifestation of NS (50%-90%), the most frequently described being pulmonary stenosis (50-60%) followed by hypertrophic cardiomyopathy (20%) and atrial septal defect (6-10%). Other less common manifestations include auditory deficits (10-25%) and lymphatic abnormalities (less than 20%), (57, 59). Intelligence is generally within normal range, but intellectual impairment has been reported in 20% of cases (59).

The incidence of NS is estimated to be 1 in approximately every 1000-2500 births (59, 60). NS is usually inherited in an autosomal dominant fashion but can occur de novo as well (60). Germline mutations in several genes of the MAPK signaling pathway have been identified in NS: PTPN11 (50%), SOS1, RAF1 and RIT1 being responsible for 93% of the cases (61, 62). Less frequently, mutations have been found in KRAS, NRAS, BRAF, MAP2K1 and SOS2 (63). Before the advent of genetic testing definitive diagnosis was challenging due to the tremendously variable expressivity of the disease. As a result, numerous syndromic presentations emerged with an uncertain relationship to NS. However, Noonan-like syndrome, NS with multiple lentigines/LEOPARD, NS with loose anagen hair and NS with giant cell lesions are all now considered phenotypic variants of NS instead of separate entities on the basis of shared genetic findings (62, 63). Cardio-facio-cutaneous syndrome (described below) and Costello syndrome (in which CGCGs have not been reported) are two distinct, less common RASopathies with substantial clinical overlap (61-64).

Distinctive craniofacial features observed in NS include frontal bossing, low-set-posteriorly-rotated ears, ptosis, hypertelorism, epicanthal folds, down slanting palpebral fissures, and deeply grooved philtrum (59, 60). Additional characteristics include low posterior hairline, light-colored irises, and curly-coarse hair (64). The oral phenotype is significant for a high-arched palate (55%-100%), temporomandibular disorders (72%), class II malocclusion, open bite/posterior crossbite (50%-67%), and micrognathia. Multiple CGCG in NS associate with PTPN11 or SOS1 mutations (65).

Neurofibromatosis type I and Jaffe-Campanacci syndrome

Neurofibromatosis type 1 (NF1) is the most common of the three neurofibromatosis syndromes (neurofibromatosis types 1 and 2 and schwannomatosis), (66). It is has been referred to historically as von Recklinghausen’s disease as it was described by German pathologist Frederick von Recklinghausen in 1882 (66). The most recognizable features of NF1 are neurofibromas and café-au-lait macules, and diagnosis can be made clinically with two or more of the following findings: 6+ café-au-lait macules, 2+ neurofibromas or 1 plexiform neurofibroma, axillary/inguinal freckling, optic glioma, 2+ Lisch nodules (iris hamartomas), bony dysplasia, and a first degree relative with NF1(9207339). Café-au-lait macules and axillary/inguinal freckling are usually the first clinical features to present, followed by Lisch nodules and neurofibromas (66). Osseous lesions are often identified within the first year of life and optic gliomas, when symptomatic, are diagnosed by age 3.

These clinical criteria allow for a diagnosis of all NF1 patients by age 20 and 97% by age 8, but only 54% of cases by age 1 (66). Genetic testing for NF1 mutations, which results in a truncated version of the neurofibromin protein, can be performed in questionable cases or in young patients, as well as in the screening of family members (67). NF1 occurs in approximately 1:3000 live births and exhibits an autosomal dominant pattern of inheritance, but de novo mutation characterizes approximately 50% of affected individuals (68). Rarely (1:40,000) post-zygotic NF1 mutations can result in segmental mosaicism, known as segmental NF1 (68).

Complications more frequent in NF1 include macrocephaly, seizures, congenital heart disease, hypertension, and bone abnormalities (68). Plexiform neurofibromas are present in approximately 50% of NF1 patients and 8-13% of these may transform into malignant peripheral nerve sheath tumors, which have a 5-year survival rate of approximately 50% (69, 70). The median life expectancy of 59 years is somewhat lower than of the general population (67).

First reported in 1982, rare patients have presented with a characteristic triad of café-au-lait macules, non-ossifying fibromas of the long bones, and CGCG, termed Jaffe-Campanacci syndrome (47). The relationship between this presentation and NF1 has been uncertain due to overlapping features with NF1 but a uniform absence of neurofibromas, though most reported cases have been in young individuals and neurofibromas typically appear in early adolescence (71). Recently, NF1 mutations have been described near universally in patients with so-called Jaffe-Campanacci syndrome, allowing for confident recognition of this pediatric presentation as within the spectrum of NF1 and arguing against its classification as a separate syndrome (72).

Bony dysplasia most frequently affects the tibia but less commonly affects craniofacial bones and, in this setting, often presents as deformation or absence of the greater wing of the sphenoid bone, known as sphenoid wing dysplasia (41). Mucosal pigmentation and neurofibromas can occasionally involve the mucosal surfaces of the head and neck, such as the oral cavity. Neurofibromas may also involve the inferior alveolar nerve, presenting as sharply demarcated enlargement of the inferior alveolar canal (73).

Schimmelpenning syndrome

Schimmelpenning syndrome, also known as Schimmelpenning-Feuerstein-Mims syndrome and (linear) nevus sebaceous syndrome, is a rare condition originally described by Gustav Schimmelpenning in 1957 and subsequently by Feuerestein and Mims in 1962 as a classic triad of sebaceous nevi, seizures, and mental retardation (74, 75). The term epidermal nevus syndrome has often been used interchangeably with Schimmelpenning syndrome but is actually a parent term referring to a group of interrelated disorders characterized by various epidermal nevi (such as sebaceous nevi) with extra-cutaneous abnormalities, and does not refer to Schimmelpenning syndrome specifically (75, 76).

The sebaceous nevi in Schimmelpenning syndrome typically involve the scalp and face and may present at birth or become more prominent after puberty. Sporadically occurring sebaceous nevi are characterized by somatic HRAS and KRAS mutations, and Schimmelpenning syndrome is itself characterized by post-zygotic HRAS and KRAS mutations (77). The prevalence of the syndrome is less than 1 in 200,000 people, while linear sebaceous nevi are reported in roughly 1 in 1000 live births (76, 78). Other frequently reported findings in Schimmelpenning syndrome include corneal opacities, coloboma, brain abnormalities such as Dandy-Walker malformation or agenesis of the corpus callosum, and developmental delay (75).

Associated craniofacial defects are common and include frontal bossing, maxillofacial hypoplasia and macrocephaly (76). Sebaceous nevi can rarely present intraorally, where they can be mistakenly considered as squamous papillomas on account of their rough surface texture (53, 76). Patients may present with hypoplastic, misshapen or hyperpigmented dentition (52). Of note, a variety of odontogenic neoplasms, in addition to CGCG, have been reported including adenomatoid odontogenic tumor, ameloblastoma and ameloblastic fibro-odontoma (50-52, 79, 80). These rare neoplasms, interestingly, have also been shown to harbor KRAS or BRAF mutations when occurring sporadically and therefore could be expected to occur more frequently in the setting of germline MAPK signaling dysregulation (81, 82).

Cardio-facio-cutaneous syndrome

Cardio-facio-cutaneous syndrome (CFC) derives its name from the characteristic findings of congenital heart disease (commonly pulmonary stenosis, atrial septal defect or hypertrophic cardiomyopathy), distinctive facial features, and skin abnormalities (including rough/dry skin, melanocytic nevi, wrinkled palms/soles, keratosis pilaris and sparse hair), which occur in most people (83). Infants typically exhibit with hypotonia and failure to thrive; other notable features include moderate to severe growth retardation and intellectual disability (84). In adulthood, individuals may suffer from vision problems and seizures but usually lead a normal lifespan. CFC shares clinical overlap with Noonan syndrome and Costello syndrome (53, 83-85).

CFC is very rare condition that affects an estimated 200-300 people worldwide (53, 85, 86). Most mutations occur de novo in the absence of family history, though in rare cases familial inheritance has been documented (53, 87). BRAF mutations account for 75-80% of all cases and MAP2K1, MAP2K2 or KRAS account for remaining published cases (87-91).

The most commonly seen craniofacial features of individuals with CFC are telencanthic appearance, macrocephaly, high forehead with bitemporal narrowing, hypertelorism, convex facial profile, short nose and low set/posteriorly rotated ears (92-95). Intraoral findings include constricted and high-arched palate with anterior open bite and posterior crossbite (92, 93).

Oculo-ectodermal syndrome

Oculo-ectodermal syndrome (OES) is a somatic RASopathy primarily characterized by a combination of two distinctive features: focal areas of scalp lesions (aplasia cutis congenita) and unilateral or bilateral ocular lesions (epibulbar dermoids), (96). Other common findings include macrocephaly (50% of affected individuals), upper eyelid anomalies, skin hyperpigmentation, Blaschko’s lines and epidermal nevi. In addition, all described cases of OES have shown some level of multi-organ involvement that include cardiovascular (coarctation of the aorta, atrial/septal defect), CNS (arachnoid cyst, seizures) and genitourinary system abnormalities (bladder exstrophy, epispadias), (97-99). Generally, individuals present with normal growth and neurocognitive development, but intellectual disability has been reported (98, 99).

OES was first described by Toriello et al. in 1993 and is a very rare neurodevelopmental syndrome with less than 25 reported cases in the literature. All cases have occurred sporadically, and most patients have been diagnosed within the first few years of life (48, 49, 96-102). Recent studies have shown that postzygotic KRAS mutations cause OES (49-103). Two other syndromes, encephalocraniocutaneous lipomatosis (ECCL) and Schimmelpenning syndrome, share clinical features with OES, and are also classified as mosaic RASopathies. Some authors consider OES as a mild version of ECCL due to their overlapping phenotype, with the only difference being the presence of intracranial lipomas, which is characteristic of ECCL (100-102).

Osteoglophonic Dysplasia

Osteoglophonic Dysplasia (OGD) is an autosomal dominant disorder associated with FGFR1 mutations. Major clinical findings in this RASopathy include dwarfism and distinctive craniofacial features (103). The term osteoglophonic derives from the Greek word meaning “hollowed out” and refers to the characteristic occurrence of multiple non-ossifying fibromas affecting the metaphysis of long bones, resulting in radiolucent defects (104-106). OGD is a very rare skeletal disorder of unknown prevalence; less than 20 cases have been reported in the literature, the majority with de novo mutations (55, 107).

Craniosynostosis is a frequent clinical finding and typically presents as acrocephaly or mild cloverleaf skull (kleeblattschädel deformity). Other notable craniofacial features are: frontal bossing, proptosis, hypertelorism, midface hypoplasia, mandibular prognathism, and macroglossia. Hypertrophic gingiva with delayed or arrested tooth eruption, presenting clinically as anodontia, is also common (104-106).

Some individuals might present with psychomotor delay and inability to speak. However, intelligence is generally normal (106). Early features commonly seen are feeding difficulties, failure to thrive, nasal obstruction, and serious respiratory complications (54, 106, 107). Life expectancy is variable and depends on severity of the craniofacial abnormalities at birth (54, 106, 107).

CONCLUSION

In conclusion, CGCG are benign neoplasms with likely far less than 5% occurring in the setting of RASopathy syndromes. Syndromic CGCG has a predilection for the posterior mandible and may occur bilaterally or even multifocally and can be confused with cherubism in this context, particularly if the possibility of an underlying syndromic predisposition is not considered. Considering the rarity of syndromic CGCG, recognition of the underlying syndrome in previously undiagnosed individuals rests on awareness of this uncommon association and identification of other more characteristic syndromic features. It is possible that increased awareness of the association between CGCG and RASopathy syndromes may lead to early diagnosis in patients for whom an underlying syndromic disorder has not yet been diagnosed.