Cherubism

SH3BP2-related cherubism (autosomal dominant), OGFRL1-related cherubism (autosomal recessive) and Ramon syndrome

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

Cherubism is an autoinflammatory bone disease of childhood in which fibro-osseous lesions rich in multinucleated giant cells replace the bone of the mandible and maxilla, bilaterally and usually symmetrically, growing until puberty and regressing in the second and third decades [1, 2]. The table brings together the classic form, the recessive form described in 2024, Ramon syndrome, which Orphanet associates with cherubism, with the TBC1D2B form, and primary intraosseous vascular malformation due to ELMO2; the giant cell lesions of the RASopathies and fibrous dysplasia enter the differential diagnosis.

Table sources: [1–29].

1. Introduction

1.1. Founding description and origin of the name

William A. Jones described in 1933 a family with several members affected by a «familial multilocular cystic disease of the jaws» and, shortly afterwards, proposed the name «cherubism», because the full, round cheeks and upturned gaze gave the children the appearance of the cherubs of Renaissance painting [1, 2, 30]. The upward gaze results from expansion of the maxillary masses into the orbital floor, which elevates the globe and retracts the lower eyelid, leaving a band of sclera visible below the iris [2]. The descriptive designation became the current nomenclature and was retained in subsequent classifications [2]. Other historical names were «familial benign giant cell tumour of the jaws» and «familial multilocular cystic disease of the jaws»; in 1965, Jones stressed that the absence of signs or history in the parents does not exclude one of them being a carrier, because the disease may only be detected by radiographs taken for that purpose [13]. Among the first large pedigrees are a family with 20 cases (Peters, 1979) and a Brazilian family described in 1966 by Salzano and Ebling [13].

1.2. From «familial fibrous dysplasia» to an autonomous entity

For decades, cherubism was treated as a familial and symmetrical form of fibrous dysplasia of the jaws, and the term «familial fibrous dysplasia of the jaws» still appears in databases and in the very condition associated with the variants in ClinVar [31, 32]. The skeletal dysplasia atlas records that cherubism with symmetrical lesions of the facial bones is now recognised as an entity separate from fibrous dysplasia, which is a mosaic GNAS disorder [31]. The distinction has practical consequences: fibrous dysplasia is not familial, is rarely symmetrical, does not regress after puberty and has a «ground-glass» radiological pattern, whereas cherubism is hereditary, bilateral, multilocular and self-limiting [1, 6].

1.3. Molecular discovery

The locus was mapped to 4p16 in 1999 by two groups, by linkage study in families (maximum lod scores of 4.21 and 5.64), and haplotype analysis of 12 families narrowed the interval to 1.5 Mb [13]. In 2001, Ueki and colleagues identified missense variants in the SH3BP2 gene, which encodes the adaptor protein 3BP2, in 12 of 15 families studied (80%); the variants were concentrated in exon 9 and affected residues 418 (eight families), 415 (two) and 420 (two) [10, 33]. In 2007, the same group created a knock-in mouse with the most frequent variant and showed that the disease results from a gain of function, with an exaggerated response of myeloid cells to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL), hyperactive osteoclasts and inflammation dependent on tumour necrosis factor α (TNF-α), which led to cherubism being classified as an autoinflammatory bone disease [1, 34]. In 2011, Levaot and colleagues showed that variants in the RSPPDG hexapeptide prevent tankyrase- and RNF146 ubiquitin ligase-mediated destruction of 3BP2, stabilising the protein [35]. In 2024, exome sequencing of two consanguineous families without an SH3BP2 variant, one Syrian and the other Indian, identified homozygous loss-of-function variants in OGFRL1, the first gene associated with an autosomal recessive form [1, 8]. GeneReviews has incorporated OGFRL1 into the molecular criteria, whereas OMIM keeps the association as «awaiting confirmation» [1, 15].

1.4. Current nomenclature and classifications

The 2023 revision of the Nosology of Genetic Skeletal Disorders designates the entity «SH3BP2-related cherubism» and includes it in the group of disorders of disorganised development of skeletal components [1, 7]. The 5th edition of the World Health Organization (WHO) classification of head and neck tumours places giant cell lesions of the jaws in a section on odontogenic and maxillofacial bone tumours; in that group, sporadic granulomas have mutually exclusive somatic variants of TRPV4, KRAS or FGFR1, brown tumours KRAS variants and cherubism germline SH3BP2 variants [36].

Severity is described by successive radiological systems. Seward and Hankey proposed three grades in 1957 (mandibular rami; rami, body and maxillary tuberosities; entire maxilla and mandible) [2, 37]. Motamedi proposed in 1998 a system of grades, classes and subclasses that Raposo-Amaral simplified in 2007, adding a sixth grade for orbital involvement [2, 38, 39]. A more recent proposal adds a seventh grade for cherubism associated with another syndrome [40].

Source: [2], after [38, 39].

Besides extent, biological behaviour and histological profile matter. The 2012 consensus distinguishes quiescent lesions (older patients, no growth), non-aggressive lesions (more frequent in adolescence) and aggressive lesions (young children, large rapidly growing lesions, tooth displacement, root resorption and cortical perforation) [2]. The Necker Hospital team proposed in 2016 an aggressiveness classification based on the course one year after surgery (mild A, moderate B, severe C), which correlates with tartrate-resistant acid phosphatase (TRAP) activity and with nuclear localisation of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) in giant cells; in grade C lesions all giant cells were TRAP-positive and had nuclear NFATc1 [1, 41]. In the 2026 series from the same centre, the NFATc1 scale was applied as A no detection, B cytoplasmic only and C nuclear and cytoplasmic [42].

1.5. Entities in this article

SH3BP2-related cherubism is the classic form and accounts for about 80% of clinically diagnosed cases; diagnosis rests on the clinical, radiological, histological and family picture, or on identification of a heterozygous gain-of-function SH3BP2 variant [1]. OGFRL1-related cherubism is defined by the presence of biallelic loss-of-function variants in that gene in a cherubism-like picture, so far in two families [1, 8]. Ramon syndrome combines a cherubism-like phenotype with gingival fibromatosis, epilepsy and intellectual disability. It is genetically heterogeneous: biallelic variants have been described in TBC1D2B, the gene for neurodevelopmental disorder with seizures and gingival overgrowth, and in ELMO2, the gene for primary intraosseous vascular malformation, and the boundary between these entities is under discussion [4, 11, 12, 24, 25]. Primary intraosseous vascular malformation due to ELMO2 is treated as a related entity because it mimics cherubism in young children and because the risk of massive haemorrhage changes the diagnostic approach [20, 21]. The multiple giant cell lesions of the RASopathies, formerly called «Noonan-like» syndrome with giant cell lesions, belong to the Noonan spectrum; fibrous dysplasia and McCune-Albright syndrome also enter the differential diagnosis [2].

2. Molecular Genetics and Pathophysiology

2.1. The SH3BP2 gene and the 3BP2 protein

SH3BP2 is located at 4p16.3 and encodes the cytoplasmic adaptor protein 3BP2 (SH3 domain-binding protein 2), ubiquitously expressed and with well-characterised functions in haematopoietic and bone cells [1, 5]. The protein has an N-terminal pleckstrin homology (PH) domain, a proline-rich region that binds proteins with SH3 domains and a C-terminal SH2 domain that binds phosphotyrosine residues; it participates in tyrosine kinase-dependent pathways (c-Abl, SYK, SRC) and binds VAV exchange factors, positively regulating the transcription factor NFAT, which is central to osteoclastogenesis [1, 5]. It is also required for B-cell receptor signalling, but in the mouse model the lesions develop without the participation of B or T lymphocytes [2].

2.2. Molecular mechanism: stabilisation of 3BP2 and gain of function

Pathogenic variants are concentrated in the RSPPDG hexapeptide (residues 415 to 420), located between the PH and SH2 domains, which is the tankyrase-binding motif [1, 8]. Tankyrase, an enzyme of the poly(ADP-ribose) polymerase family, ADP-ribosylates 3BP2 and marks it for ubiquitination by the RNF146 ligase and proteasomal degradation; cherubism variants uncouple 3BP2 from this pathway, the protein accumulates in the cytoplasm and hyperactivates the SRC, SYK and VAV pathways [35, 43]. The result is an exaggerated response of myeloid precursors to M-CSF and RANKL: RANKL-induced phosphorylation of phospholipase Cγ increases nuclear translocation of NFATc1, which induces osteoclastic genes and fusion into multinucleated giant cells [1]. In the mouse, TNF-α produced by hyperreactive macrophages stimulates stromal production of M-CSF and RANKL, in a cycle that sustains macrophage and osteoclast differentiation; hence the classification as an autoinflammatory bone disease [1, 34].

2.3. From the mouse model to human disease

The mouse model does not reproduce the human disease in a linear way. Mice heterozygous for the equivalent variant (P416R, corresponding to human p.Pro418Arg) have no phenotype; only homozygotes develop facial swelling, mandibular bone destruction and, in addition, systemic osteopenia and inflammatory infiltration of internal organs [1, 8, 43]. In the mouse, the toll-like receptor (TLR) 2 and 4 pathway with the adaptor protein MYD88 in haematopoietic cells is necessary for the phenotype; pathogen-associated molecular patterns lead to phosphorylation of 3BP2 by SYK, NF-κB activation and TNF-α production, but germ-free mice still become ill [43]. This gave rise to the hypothesis that human cherubism is a latent predisposition, activated in the jaws by the oral flora or by tissue damage signals released during tooth eruption and chewing, which would explain the location and the temporal coincidence with the mixed dentition and with the development of the second and third molars [1, 10, 43]. The mechanism of post-pubertal regression has not been clarified; involvement of the TLR–MYD88 pathway has been proposed [1].

Recent human data qualify the role of TNF-α. In the French series of 11 patients, TNF-α and interleukin 1β were raised in few patients and unrelated to severity, unlike bone resorption markers [42]. Osteoclasts obtained from peripheral blood mononuclear cells of two symptomatic carriers and one asymptomatic carrier of the same variant were larger and resorbed more bone than those of controls, with a weaker effect of TNF-α than of RANKL, and did not differ between symptomatic and asymptomatic carriers; the authors conclude that severity depends on microenvironmental factors external to the osteoclasts and that this explains the reduction in giant cells without clinical benefit observed with TNF-α inhibitors [44]. In the mouse, deletion of caspase-1 corrected neither the bone nor the inflammatory phenotype, which rules out the caspase-1-dependent inflammasome as a necessary mechanism [45].

2.4. Inheritance and penetrance

SH3BP2-related cherubism is transmitted in an autosomal dominant manner [1]. The proportion of cases without a family history varies with the mode of ascertainment: about 50% of cases with an identified variant in a United States reference laboratory, 32% in the systematic review of 513 cases (family history in 310 of 458) and 15% in the review of 92 individuals with a confirmed variant [2, 10, 46]. Expressivity is highly variable, even within the same family, and there are asymptomatic carriers [1, 10, 44].

Penetrance by sex is the main divergence between sources. The skeletal dysplasia atlas and OMIM give a penetrance of 100% in males and 50–70% in females, with twice as many males affected, figures that go back to descriptions prior to identification of the gene [6, 13]. In a three-generation family, the mandible was more affected in males and the maxilla in females, and clinical onset was earlier in females (5.5 versus 10.6 years) [13]. Later sources do not support this difference: the 2012 consensus considers it a historical artefact, explained by late diagnosis and failure to identify adults with mild forms, whose lesions fill in with bone and are no longer visible [2]; in the Norwegian cohort of 24 individuals there was no evidence of non-penetrance and females were, on average, more severely affected [47]; the review of 92 individuals found an equal distribution between sexes [46]; and the 2025 GeneReviews update considers penetrance equivalent in both sexes, with no ethnic predilection [1]. The review of 513 cases found 57.2% male patients and notes that some authors have described lower penetrance in females and others have not [10]. In practice, penetrance is incomplete, but the difference between sexes should be read as historical data.

The OGFRL1-related form is autosomal recessive: in both families, affected individuals were homozygous and heterozygotes had no disease [1, 8]. The same clinical picture can thus have two inheritance patterns depending on the gene.

2.5. Spectrum of SH3BP2 variants

The MANE Select transcript is NM_001122681.2 (protein NP_001116153.1); GeneReviews and several series use NM_003023.4 (NP_003014.3), and the c. and p. numbering of exon 9 variants is the same in both transcripts (for example, NC_000004.12:g.2831573G>A corresponds to c.1244G>A p.(Arg415Gln) in both) [9]. All recurrent variants are heterozygous missense variants in exon 9, between c.1243 and c.1259, and affect residues 415, 418, 419 and 420; in the 2021 review, 94 of 101 cases with a variant (93.1%) had a variant in this interval, and c.1244G>A p.(Arg415Gln) was the most frequent in familial (24/80) and sporadic (4/14) cases [10]. GeneReviews gives p.Pro418Arg as the most common variant, based on the mouse model [1].

Sources: [9, 10, 32]. The abbreviated protein notation of the review was expanded to the three-letter format; variants c.1244G>A, c.1253C>G and c.1255G>A were confirmed in VariantValidator with the MANE transcript.

Outside exon 9, variants are rare and have seldom been sought, because many laboratories sequenced only exon 9 [10]. A missense variant in exon 4, in the PH domain, NM_001122681.2:c.320C>T p.(Thr107Met), was found in the blood and lesional tissue of a patient with cherubism; the same Brazilian study found a variant in exon 11, NM_001122681.2:c.1442A>T p.(Gln481Leu), in a sporadic central giant cell granuloma [48]. A variant NM_001122681.2:c.1258G>A p.(Gly420Arg), by G>A transition, was described in a family, after the G>C transversion known for the same amino acid [49]. Intragenic deletions and duplications have not been described and are unlikely as a cause, since this is gain of function; 4p16.3 deletions that remove SH3BP2, such as those of Wolf-Hirschhorn syndrome, do not cause cherubism, which, together with the clustering of missense variants, supports a gain-of-function mechanism [1, 13, 32]. OMIM records seven reference allelic variants: p.Pro418Leu, p.Pro418Arg, p.Pro418His, p.Arg415Pro, p.Arg415Gln, p.Gly420Arg and p.Gly420Glu [14].

In gnomAD, five pathogenic variants of the RSPPDG motif (published protein designations: p.Arg415Gln and p.Pro418Arg with two counts each; p.Pro418Thr, p.Pro418Leu and p.Pro418His with one) totalled seven counts in about 1,435,000 alleles, which the authors interpret as an indication that cherubism is more frequent than the number of published cases suggests; these data do not constitute a prevalence estimate [8].

2.6. OGFRL1 and the recessive form

OGFRL1 encodes a protein similar to the opioid growth factor receptor (OGFR), with 36.1% homology, of poorly understood function, expressed mainly in the brain, bone marrow and spleen, and in cells of the myeloid lineage [8]. In the Syrian family, exome sequencing of two affected individuals and homozygosity mapping identified NM_024576.5:c.75del p.(Asp26ThrfsTer93), in exon 1, absent from gnomAD v4.0.0, which eliminates the conserved OGFR domain; the variant segregated in the homozygous state in the two affected individuals, while six heterozygous relatives were healthy [8, 9]. In the Indian family, the affected individual was homozygous for c.337C>T p.(Arg113Ter), in exon 3; this variant has 24 alleles out of 1,612,002 in gnomAD v4.0.0 (21 in non-Finnish Europeans), with no homozygotes [8, 9]. Mice lacking Ogfrl1 or carrying the Syrian variant did not reproduce cherubism, and their macrophages showed no increase in inflammatory response or osteoclastogenesis; the authors acknowledge that they cannot exclude another cause in the regions of homozygosity [8]. OMIM classifies this association as awaiting confirmation and records that the authors themselves admit that the finding may be coincidental [15]. GeneReviews included OGFRL1 in the molecular diagnosis in 2025, noting that this gene will not explain all the heterogeneity, since 10–20% of patients have no identified variant [1].

2.7. Genotype–phenotype correlations, allelic disorders and modifiers

There is no clinically useful genotype–phenotype correlation: in the review of 513 cases, neither the presence nor the type of substitution in SH3BP2 was associated with clinical grade, and intrafamilial variability is marked [1, 10, 47]. The only factor associated with grade was tooth agenesis, more frequent in advanced grades [10]. There are no known germline allelic disorders of SH3BP2 or OGFRL1 other than cherubism [1]. The observation that symptomatic and asymptomatic carriers produce equally hyperactive osteoclasts points to local modifiers, such as the dental and inflammatory microenvironment of the jaws [43, 44].

2.8. Tissue pathophysiology

The lesions are non-neoplastic fibrous granulomas with spindle-shaped stromal cells, osteoclast-like multinucleated giant cells, abundant vessels and sometimes cysts; at the periphery there is osteoid and newly formed bone [1, 2]. Three histological phases have been described: osteolytic, with many TRAP-positive giant cells, intense vascularisation and haemosiderin; reparative, with proliferation of spindle cells and fibroblastic nodules; and bone-forming, with alkaline phosphatase-positive cells and more collagen [2]. In aggressive lesions, giant cells have nuclear NFATc1 and TRAP activity, behaving as osteoclasts; in non-aggressive lesions, CD68-positive giant cells appear to differentiate more towards macrophages [41, 43]. Osteolysis is deeper than in chronic recurrent multifocal osteomyelitis, another autoinflammatory bone disease [1]. In severe forms, the process may extend beyond the jaws, with systemic increase in bone resorption and low bone mass [42, 43].

2.9. ELMO2, TBC1D2B and the related entities

ELMO2 encodes a 722-amino-acid cytoplasmic adaptor protein, homologous to Caenorhabditis elegans Ced-12, without enzymatic activity of its own [17]. Bound to active RhoG, it forms with DOCK1 (DOCK180) a ternary complex that activates the GTPase RAC1 and drives the cytoskeletal rearrangement required for cell migration, integrin-mediated adhesion and phagocytosis of apoptotic cells [17]. The Armadillo repeats of the N-terminal region bind RhoG and ILK, and the pleckstrin homology domain and the C-terminal proline-rich motif mediate binding to DOCK proteins [17, 21]. The MANE Select transcript is NM_133171.5, with 22 exons; variants published with NM_133171.4 keep the same numbering [9, 21].

In fibroblasts from a patient with primary intraosseous vascular malformation, the ELMO2 protein was undetectable, DOCK1 was markedly decreased and RAC1-dependent cell migration was twice as slow as in controls, with partial correction by expression of normal ELMO2 [17, 20]. The vessels of the lesions lacked a mature vascular smooth muscle layer, which makes them unable to withstand arterial pressure [18, 20]. Zebrafish lacking elmo2 had no phenotype, and phylogenetic analysis placed the appearance of the gene at the time when intramembranous bones and the jaw arose in ancestral vertebrates, which could explain the restriction of lesions to these bones [20]. In the mouse, global inactivation of Elmo2 is lethal in mid-gestation owing to dilatation of the third pharyngeal arch arteries and common carotid aneurysms, with disorganisation of smooth muscle cells; deletion limited to the neural crest reproduces the phenotype, and in vitro ELMO2 regulates the adhesion, spreading and contractility of these cells through RAC1 [50]. The Cologne team, which found abundant de novo bone formation in the resection specimens, hypothesised that loss of ELMO2 also causes a primary disturbance of the craniofacial bones [21].

ClinVar also records NM_133171.5:c.311dup, NM_133171.5:c.1447C>T p.(Arg483Ter) and NM_133171.5:c.1525C>T p.(Arg509Ter) as pathogenic or likely pathogenic for primary intraosseous venous malformation [51]. All known ELMO2 variants, except the Lebanese one, are predicted loss-of-function; the number of patients with molecular study does not allow genotype–phenotype correlations to be established [12, 21].

TBC1D2B (15q24.3-q25.1; MANE NM_144572.2) encodes a member of the family of TBC domain-containing proteins that activate the GTPase of RAB proteins (TBC/RABGAP), regulators of endolysosomal membrane trafficking [9, 23, 24]. The protein binds several RABs, including RAB31, and colocalises with vesicles positive for RAB5, the GTPase that directs early endocytosis [23, 24]. In fibroblasts from two patients, mRNA was reduced to 10–20% and the protein was undetectable; in HeLa cells lacking TBC1D2B, internalisation of epidermal growth factor decreased and serum deprivation increased apoptosis [23, 24]. The protein positively regulates autophagy, and the authors relate the neurodegenerative disease to defects in autophagy and the endolysosomal system [24]. Gingival overgrowth has been attributed to epithelial–mesenchymal transition and internalisation of E-cadherin, which depend on RAB5, RAB7 and RAB22 [25, 27]. By 2024, 12 variants had been described in ten patients: seven nonsense, three frameshift, one splicing and one missense [24].

Variability is great and there is no genotype–phenotype correlation: a 35-year-old man homozygous for an early nonsense variant, p.(Glu9Ter) (published protein designation), had a mild phenotype, whereas a female patient compound heterozygous for a nonsense and a missense variant had severe deterioration and died at 26 years [24].

3. Clinical Spectrum and Manifestations by System

3.1. Natural course: expansion, stabilisation and regression

Children with cherubism appear normal at birth [1, 2]. Swelling of the jaws appears, according to GeneReviews and the 2012 consensus, between 2 and 7 years, with a phase of rapid enlargement up to 7–8 years, followed by stability or slow growth until puberty [1, 2]. The skeletal dysplasia atlas places the manifestation between 12 and 24 months, with most cases before 5 years, and OMIM between 14 months and 4 years, with progression until the end of adolescence and radiographic changes persisting into the fourth decade [6, 13]. In the systematic review of 513 cases, the mean age at which symptoms were noticed was 5.6 ± 3.8 years (range 0–30; n = 279) and the mean age at first consultation 12.4 ± 11.0 years (1–84; n = 488), with a mean interval of 82.6 months between first symptoms and consultation [10]. From puberty onwards, lesions stabilise, fill with bone and remodel; by 30 years facial changes are generally no longer evident, although bone changes persist on imaging [1, 2].

Follow-up of 18 patients from six Danish families, for up to 36 years, documented the radiological sequence of regression: new bone formation in radiolucent areas after 20 years, normal bone with residual multilocular outlines between 32 and 39 years and completely normal structure after 41 years, including in seven of seven carriers over 32 years [2, 53]. In a Brazilian series of eight patients, lesions stabilised at 12 years in seven and regressed afterwards; one more severe patient still had signs at 20 years, and bone filling appeared between two years after stabilisation and the third decade [2]. In a Norwegian cross-sectional study of 15 adults aged 29 to 84 years with confirmed familial cherubism, 11 (73%) had mandibular changes, from subtle to severe, most often unilocular and exclusively in the anterior mandible [54]. The expected facial improvement does not occur in all patients, and late reactivations in adults have been described, one of them after local inflammation [1]. There are no reports of spontaneous fracture of the jaws, even in severe forms [2].

3.2. Maxillomandibular lesions

The disease begins with progressive bone degradation, rapid in severe forms, which produces multiple, bilateral and symmetrical cystic changes, first in the mandible and then in the maxilla [1]. The first radiological signs usually appear at the angle of the mandible; the rami and coronoid processes are frequently affected, the condyles rarely; mandibular lesions are usually symmetrical and maxillary lesions may be asymmetrical [1, 2]. In progressive forms, resorption leaves only a fenestrated cortical shell, and the fibrous masses expand the cortex and deform the face [2]. In the systematic review, 95.3% of cases had bone expansion, 98.4% multilocular lesions, 92.6% radiolucent lesions, 95.3% well-defined margins, 35.3% cortical destruction and only 2.9% (10/347) pain [10]. The distribution by Motamedi grade, possible in 175 cases, was: grade I 33.7%, II 24.6%, III 7.4%, IV 25.7% and V 8.6% [10]. In the review of 92 individuals with a confirmed variant, lesions were limited to the mandible in 36% and affected mandible and maxilla in 54% [46].

Lesions are usually painless, but massive enlargement may cause severe pain, and mouth pain and discomfort when eating are frequent complaints [1, 2]. Severe malformation may prevent chewing and swallowing [1]. Recurrence after surgery is possible [1].

3.3. Lymphadenopathy and the inflammatory component

Submandibular and cervical lymphadenopathy accompanies the early phases and may precede the bone lesions; it contributes to the fullness of the face [1, 2]. Submandibular nodes are associated with swelling of the lower face and upper cervical nodes with maxillary swelling, but their natural history has not been studied systematically [2]. In the patient treated with tacrolimus, lymph nodes of 21 and 19 mm regressed in parallel with stabilisation of the lesions [55].

3.4. Dentition

Dental changes are the most constant sequelae. Teeth become displaced, impacted, hypoplastic or absent, or appear to «float» in cystic spaces; there is malocclusion, early exfoliation of deciduous teeth and root resorption [1]. The second and third molars, whose development coincides with the active phase of the disease, are the teeth most often missing [1, 10]. In the review of 513 cases, there was tooth displacement in 94.5%, agenesis in 62.0% (114/184) and root resorption in 40.1%; agenesis increased with grade (34.0% in grade I, 63.2% in II, 25.0% in III, 88.2% in IV and 85.7% in V; p < 0.001) [10]. In the review of 92 individuals with a variant, teeth were missing in 38% [46]. In the Norwegian cohort, adults had on average 13 fewer teeth (2 to 28); 13 of 17 individuals aged 16 or over wore removable or fixed prostheses, five had implants and implant survival was 79% [47]. A high «V»-shaped palate, supernumerary teeth and ectopic eruption are also described [2].

3.5. Orbit and vision

Orbital involvement depends on maxillary extent [1]. The fibro-osseous mass may invade the floor and the lateral and inferior walls of the orbit, displace the globe and retract the lower eyelid; in severe cases it invades the retrobulbar space and displaces the optic nerve, with proptosis [2]. The effects are due to displacement and compression, not to invasion of the globe or extraocular muscles [2]. Eyelid retraction, proptosis, strabismus, diplopia, globe displacement and visual loss due to optic atrophy, retinal vein occlusion and macular folds with scarring have been described [1]. The age at which orbital mass effect occurred ranged from 7 to 27 years [1]. There are cases of orbital masses after post-pubertal regression of the maxillary lesions: at 27 years, with reduced ocular motility; in a 27-year-old woman, with optic nerve dysfunction; and at 31 years, with visual loss due to optic neuropathy, macular striae and scarring [2]. The 2012 consensus concludes that ophthalmological surveillance should continue long after maxillary regression [2].

3.6. Airway and sleep

Respiratory problems are uncommon but may be severe: posterior displacement of the tongue by the mandibular mass and obliteration of the nasal fossae by the maxillary mass cause mouth breathing, snoring, chronic nasal infection and obstructive sleep apnoea (OSA) [1, 2]. OSA has been described in an adult, and a child with severe OSA was treated with nocturnal mouthpiece ventilation and medical hypnosis [1]. An 8-year-old boy with airway obstruction died of pulmonary infections, aspiration and septicaemia [2]. The pharmacological systematic review also records the existence of fatal cases [40].

3.7. Speech, swallowing, feeding and growth

Difficulty with pronunciation was not relevant in the Norwegian cohort, but physical obstruction may affect speech and swallowing [1]. Dysphagia with weight loss and failure to thrive prompted treatment in some reports [40, 56]. In the Gabonese girl described in 2020, height (−1.7 standard deviations) and weight (−2 standard deviations) deviated from the onset of the lesions and again when these worsened [43]. In the 2026 French series, with 11 patients, weight and height were within normal limits at a single assessment point [42].

3.8. Extramaxillary and systemic manifestations

Cherubism has been described as a disease limited to the jaws, and the skeletal dysplasia atlas states that there are no systemic manifestations [6]. There are, however, exceptions. Lesions of the temporal bone, ribs and humerus are rare; asymptomatic lesions of the anterior ends of the ribs have been described in three patients (a 17-year-old girl from a family with three affected members, an 8-year-old boy with bilateral invasion of the zygomatic bones and a 6-year-old child), without published follow-up and, in most cases, without genetic confirmation [1, 2]; OMIM also mentions two cases with multilocular rib lesions in which biopsy showed the same fibrous tissue with giant cells [13]. A spondyloarthropathy has been described in one patient, and the association with craniosynostosis and digital clubbing in one family is of uncertain relationship [1, 2].

In 2020, the Paris team described in a child with grade VI cherubism very low bone mass (whole-body Z-score of −4.6 unadjusted and −3.2 adjusted for ethnic origin), raised turnover markers and increased inflammatory cytokines, reproducing the systemic phenotype of the mouse [43]. In the series of 11 patients assessed in 2026, eight had a low Z-score at at least one site and five at all three sites measured (whole body, femoral neck and lumbar spine); C-terminal telopeptide of type I collagen (CTx) was raised in eight, N-terminal propeptide of type I procollagen (P1NP) in four, bone alkaline phosphatase in two and osteocalcin in one; patients with nuclear NFATc1 (grade C) had three or four raised markers, and the three with normal markers had grades A or B and appeared to be in an inactive phase [42]. Half of the patients with a low Z-score had whole-body values above −1.5 [42]. These data come from a cross-sectional assessment in a reference centre and do not establish the frequency of osteopenia in cherubism in general [42].

3.9. Biochemistry

Mineral metabolism is usually normal: calcium, parathyroid hormone (PTH), PTH-related peptide, calcitonin and alkaline phosphatase within reference values; urinary turnover markers may be at the upper limit and alkaline phosphatase and phosphate may rise in the active phase [2, 40]. In the 2026 series, three patients had raised PTH (two at the time of surgery, with subsequent normalisation) and nine had low 25-hydroxyvitamin D, without a characteristic calcium-phosphate profile [42].

3.10. Quality of life and psychosocial dimension

Facial disfigurement may affect self-esteem and lead to bullying; even so, the Norwegian cohort of 24 individuals aged 5 to 84 years reported good psychosocial adjustment and good quality of life in adulthood, despite dental sequelae [1, 47]. The cultural impact may be great: a woman from Ghana with onset at 12 years only sought care at 21, after resorting to traditional medicine, and reported stigma, loss of employment and of relationships [57]. In a review of 20 African cases, the median age at presentation was 13.75 years, suggesting delayed access to care [58]. In the Amsterdam protocol, one of the indications for treatment was impaired psychosocial development due to bullying [59].

3.11. Recessive form and Ramon syndrome

The two families with OGFRL1-related cherubism were clinically diagnosed as cherubism, with expansile dysplasia of the mandible; the publication does not describe the natural history in detail [8]. Ramon syndrome combines cherubism, gingival fibromatosis that may conceal the teeth, epilepsy and intellectual disability, with variable hypertrichosis, short stature, juvenile rheumatoid arthritis and ocular anomalies (pigmentary retinopathy, optic disc pallor, Axenfeld anomaly); radiology shows bilateral multifocal radiolucencies of the body, angle, ramus and coronoid process of the mandible [4]. In the Lebanese family with a homozygous ELMO2 variant, there were also repeated gingival bleeding, a high narrow palate and adenoid hypertrophy; the affected brother died at 8 years from pulmonary infection and haemorrhage [11]. In patients with biallelic TBC1D2B variants, gingival overgrowth begins in early childhood and is the most constant sign (12 of 14 patients summarised in 2026), and seizures appear in 11 of 14 [27]. In the 2024 series of ten patients, half had developmental delay, six had progressive mental deterioration with onset between 10 and 20 years, accompanied by cerebral or cerebellar atrophy, with or without dilatation of the lateral ventricles, and flexion contractures were frequent; half had visual loss and half cytopenias (pancytopenia in two patients) [24]. Mandibular prognathism was common, three patients had fibrous dysplasia of the mandible and two had a diagnosis of cherubism; three died between 21 and 39 years [24]. The 2026 Indian series added gait ataxia, dysarthria, dystonia, perioral and lingual myoclonus, optic atrophy, retinal cavitation, pigmentary retinopathy, posterior subcapsular cataract operated on at 5 years and facial freckling [27]. In the two Brazilian siblings, gingival overgrowth and bilateral enlargement of the malar soft tissues began at 3 years and progressed to marked maxillary hypertrophy, with brainstem compression by fibrous dysplasia of the facial bones, mental deterioration, limb tremor and ataxia; one of them had seizures [52]. The Thai girl had gingival fibromatosis from 4 years, recurrence three years after gingivectomy, a persistent anterior fontanelle, cherubism-like mandibular lesions with osteoclast-like multinucleated giant cells on CT and histology at 7 years, focal epilepsy from 5 years and amblyopia [25]. The authors of the 2024 series stress that cognitive regression, the hallmark of this form, has not been described in classic Ramon syndrome, and that their patients lacked the hypertrichosis and hypoplasia of the distal phalanges of Zimmermann-Laband syndrome [24].

3.12. Natural history and treated disease

Almost all natural history data come from uncontrolled series and reports, many of operated patients [2, 10]. In the systematic review, the first approach was observation in 52.4% of 431 cases with information, and the mean duration of published follow-up was 70.7 months [10]. Effects attributed to drugs or surgery during childhood must be read against a natural course that includes spontaneous stabilisation and regression [40, 55].

3.13. Primary intraosseous vascular malformation due to ELMO2

The entity was described in 2002 in two consanguineous Turkish families with four affected individuals: severe vascular expansions in the craniofacial bones, limited to the mandible and maxilla before puberty, with rapid expansion from 12 or 13 years, and midline anomalies (diastasis recti, supraumbilical raphe and hiatus hernia) [60]. The 15-year follow-up of one patient showed involvement of almost all skull bones without extension beyond the craniofacial region and without soft tissue malformation, which indicated a primary bone alteration [60]. In 2016, eight children from five consanguineous families (Turkish, Saudi, Iraqi and North American) were normal at birth and developed in early childhood a painless swelling of the mandible, with acceleration at the onset of puberty and severe facial asymmetry [18, 20]. The mandible and maxilla were always affected; next came the nasal bones, calvaria, sphenoid and clivus and, less often, the clavicles, ribs and vertebrae [18]. All had ectopic tooth eruption and gingival bleeding requiring endovascular embolisation or percutaneous sclerotherapy, and five had chronic anaemia [18]. Compression by the lesions caused exophthalmos in seven patients (with visual loss in five), spinal cord compression with paraplegia in one and intracranial hypertension in three, with brain herniation and death in one of them; another patient died at 27 years from spontaneous massive haemorrhage [18]. In the review of 25 years of experience at the Turkish centre, the calvaria and skull base were involved in 62.5% of patients, the clavicles in 50% and the ribs and vertebrae in 25%; three of the five patients with long follow-up died, on average at 27 years [21, 61].

The 2025 Cologne series brought together four children from three families (Bulgarian and Egyptian), with first symptoms between 6 and 16 months: gingival bleeding in three and massive tooth eruption in one [21]. All had swelling of the facial bones and ectopic eruption; three had facial asymmetry, two exophthalmos, three congenital heart disease (muscular ventricular septal defect, atrial septal defect, patent foramen ovale and patent ductus arteriosus) and two diastasis recti, one of them with umbilical hernia [21]. An Egyptian child had four haemangioma-like skin lesions of 2–4 mm, appearing in the first year and stable; gingival bleeding brought haemoglobin down to 5 g/dL, with transient thrombocytopenia that reversed with intravenous immunoglobulin, and the patient died at 3.5 years after repeated haemorrhages, the earliest age at death described [21]. The other Egyptian patient, with epistaxis and gingival bleeding from 6 months, lost bone and teeth and expelled a bone fragment through the mouth [21]. None of the four patients, like none of the five described previously, had signs of neurodevelopmental delay, and the team considers it unresolved whether the neurological features of the Ramon cases with ELMO2 are due to another variant in the consanguineous families or to a genotype–phenotype effect [21]. The Bulgarian family had lost two late pregnancies (at 35 and 25 weeks) with brain cysts and heart disease, without a molecular study described [21, 22].

Imaging divides the sources. In the 2016 series, five of six angiographies showed abnormal vessel organisation and late capillary accumulation, typical of slow-flow lesions of capillary or venous origin, and Orphanet describes the entity as a venous malformation [18, 19]. In the 2025 series, CT and MR angiography showed fast-flow malformations, one of them arteriovenous arising from the lingual artery with hypertrophied feeders, and feeders from branches of the external carotid, especially the maxillary artery; dynamic MR angiography showed tortuous intramedullary vascular channels with enhancing tufts in the arterial phase and early venous filling [21]. Internal carotid aneurysms are also part of the picture described [50]. CT showed ground-glass expansion of the facial bones and skull base with osteolytic foci, an appearance that led to suspicion of fibrous dysplasia [21].

Histology also diverges. In the Turkish families, the vessels were irregular, dilated, thin-walled channels lined by a single layer of Ki-67-negative endothelium, with abundant adipose tissue between the trabeculae and no markers of mature vascular smooth muscle; the fibula harvested for reconstruction was normal [18, 60]. The 25-year review describes positivity for CD31 and smooth muscle actin and negativity for Ki-67, desmin and h-caldesmon [61]. In the Cologne specimens, the capillaries were positive for CD31 and smooth muscle actin, negative for D2-40 and desmin, without criteria for arteriovenous malformation, with de novo woven bone formation, pseudocystic areas and multinucleated giant cells suggesting aneurysmal bone cyst, without USP6 rearrangement and without variants in the fibrous dysplasia genes; before the genetic diagnosis, the lesion was classified as reactive granulation tissue [21]. The multinucleated giant cells and the mandibular expansion explain the confusion with cherubism.

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Cherubism should be considered in a child, usually between 2 and 7 years, with bilateral, symmetrical, progressive and painless enlargement of the mandible, with or without maxillary enlargement, especially if there is submandibular or cervical lymphadenopathy in the early phase [1, 2]. The classic face combines full cheeks, effacement of the mandibular angle and an apparently upturned gaze with visible lower sclera, but it is often absent; many children are identified by bilateral multilocular lesions found on radiographs taken for trauma or at a dental appointment [2]. At the dental visit, the warning signs are early loss of deciduous teeth, delayed or ectopic eruption of permanent teeth, absence of the second and third molars, malocclusion and expansion of the posterior alveolar ridge [1, 2]. On the lateral radiograph, absence of the posterior maxillary molars leaves much of the hard palate visible («hard palate sign») [6].

The family history should be actively sought, including adults with early tooth loss or with old radiographs, because adult carriers may have complete regression and mild forms go unnoticed [1, 53]. A history compatible with dominant inheritance (several individuals of both sexes in several generations) or recessive inheritance (affected siblings, consanguinity) supports the diagnosis, but its absence does not exclude it [1].

4.2. Contexts that call for another explanation

Lesions that appear after adolescence, are unilateral, unilocular, located in the anterior mandible or accompanied by disproportionate pain require exclusion of other giant cell lesions [1, 6]. A face suggestive of Noonan syndrome, heart disease, short stature, café-au-lait spots or lentigines point to a RASopathy; café-au-lait spots with irregular borders, endocrinopathy or lesions in other bones point to fibrous dysplasia or McCune-Albright syndrome; hypercalcaemia or raised PTH point to hyperparathyroidism; and gingival fibromatosis with epilepsy and intellectual disability points to Ramon syndrome [1, 2, 4].

4.3. Warning and emergency signs

Sources: [1, 2, 21, 59, 62].

4.4. Newborn screening

There is no newborn screening, and the disease is not expressed at birth [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no published consensus clinical criteria [1]. The diagnosis is established in a proband with typical clinical, radiological and histological findings and a compatible family history, and/or with a heterozygous pathogenic or likely pathogenic gain-of-function variant in SH3BP2, or with biallelic loss-of-function variants in OGFRL1 [1]. The 2012 consensus bases the diagnosis on age, family history, examination, radiology, biochemistry and molecular analysis, and considers that biopsy is not necessary in most cases [2].

Source: [1].

5.2. Imaging

Orthopantomography shows the bilateral multilocular radiolucent lesions and displaced or absent teeth [2, 6]. CT defines the extent and the relationship with the orbits, nasal fossae and floor of the mouth, and should use the lowest possible radiation dose; magnetic resonance imaging shows signal changes in areas apparently normal on radiography and CT and is useful for assessing orbital involvement and the relationship with neurovascular structures [1, 6]. Typical images describe multilocular «soap bubble» radiolucent lesions with expansion and cortical thinning [1, 10]. In the Amsterdam cohort, lesion volume was measured on three-dimensional reconstructions of CT or cone-beam tomography, a method that allows objective comparison of progression; the authors recommend reserving three-dimensional imaging for when it is strictly necessary [59]. The radiological grade defined at diagnosis should be reassessed during follow-up: in one patient, a low grade at 7 years progressed to grade VI at 16 [42].

5.3. Histology

Histology shows osteoclast-like multinucleated giant cells in a moderately loose fibrous stroma, with ovoid to spindle-shaped cells, small vessels with large endothelial cells and sometimes haemosiderin and cysts [1, 2]. Perivascular eosinophilic deposition («cuffing») is suggestive of cherubism, but appeared in only 28.1% (63/224) of the cases described and is not associated with grade [2, 10]. Histology does not distinguish cherubism from central giant cell granuloma, brown tumour of hyperparathyroidism, aneurysmal bone cyst or other giant cell lesions; the distinguishing feature is bilaterality [1, 2]. Aspiration cytology identifies stromal and giant cells, but its diagnostic usefulness is doubtful if not combined with molecular analysis [2]. NFATc1 immunohistochemistry and TRAP activity in giant cells help to define aggressiveness (grade C with nuclear NFATc1) and have been proposed as a prognostic factor; they are not required for diagnosis [1, 41, 42].

5.4. Biochemistry

Biochemistry serves mainly to exclude hyperparathyroidism: calcium, phosphorus, PTH and alkaline phosphatase [1, 2]. In cherubism, calcium and PTH are usually normal, and alkaline phosphatase and phosphate may rise in the active phase [2]. Hyperparathyroidism is rare in children outside chronic kidney disease [2]. Turnover markers (CTx, P1NP, bone alkaline phosphatase, osteocalcin) and densitometry have been proposed by the Paris team to characterise the activity and systemic extent of the disease; CTx was the most frequently raised marker and was associated with severity, but this assessment has not yet been prospectively validated [42].

5.5. Genetic tests: order and yield

Testing generally begins with SH3BP2 sequencing, in particular of exon 9, where almost all variants lie; if negative, OGFRL1 is sequenced [1]. A multigene panel that includes SH3BP2, OGFRL1 and the genes of the differential diagnosis (RASopathies, CDC73, GNAS) avoids sequential testing and reduces findings in genes unrelated to the phenotype [1]. Exome (or genome) sequencing is the option when the phenotype is atypical or indistinguishable from other jaw lesions; the known SH3BP2 and OGFRL1 variants are in coding regions and are detectable by exome [1]. In consanguineous families without an SH3BP2 variant, exome sequencing with homozygosity mapping identified OGFRL1 [8].

Source: [1].

The proportion of patients with a variant depends on selection: 80% of families in the original study, 93.5% (101/108) of tested cases described in the literature up to 2019, all 22 familial cases and none of the 2 sporadic cases in the Norwegian cohort, 10 of 11 in the French series and 2 of 3 in an Iranian series in which only exon 9 was sequenced [10, 42, 47, 63]. The yield is higher in familial cases, partly because these are tested more often [10].

5.6. Limitations of testing

Sequencing limited to exon 9 does not detect the rare variants in other exons, such as those described in exons 3 and 4 [10, 48]. Deletion and duplication techniques add no yield in SH3BP2, but may be relevant in OGFRL1, where a deletion of one or more exons could mimic homozygosity [1]. Testing of parental leucocyte DNA may not detect low-level somatic mosaicism and does not detect exclusively gonadal mosaicism [1]. A negative result does not exclude the diagnosis, given the genetic heterogeneity [1, 2]. A variant of uncertain significance neither establishes nor excludes the diagnosis; GeneReviews, following the recommendations of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), considers pathogenic and likely pathogenic variants diagnostic [1]. The presence of pathogenic SH3BP2 variants in the general population (gnomAD) and the existence of asymptomatic carriers show that the variant alone does not predict severity [8, 44]. Molecular testing of lesional tissue may be useful to separate entities in multifocal lesions without an evident syndrome, as in a 14-year-old boy with multiple granulomas without an SH3BP2 variant and with a somatic TRPV4 variant in one of the lesions (germline TRPV4 disorders include skeletal dysplasias and motor neuropathies) [64].

The report should state the gene, the transcript with version (for SH3BP2, NM_001122681.2, MANE Select; many publications use NM_003023.4, with the same numbering in exon 9), the variant in HGVS at the c. and p. levels, the zygosity and the classification according to ACMG/AMP criteria [1, 9].

5.7. Diagnosis in adults and relatives

In adults, lesions filled with bone may no longer be visible, and the diagnosis of mild forms not recognised in childhood becomes difficult; genetic testing is the way to clarify the status of adult relatives [2, 53]. Siblings of a proband should be assessed by clinical examination, orthopantomography and genetic testing when the familial variant is known [1, 2].

5.8. Algorithm

1. Child with painless bilateral maxillomandibular swelling or incidental bilateral multilocular lesions: targeted family history, dental and ocular examination and orthopantomography [1, 2].
2. Low-dose CT to define extent and grade; magnetic resonance imaging if orbital or neurovascular involvement is suspected [1].
3. Calcium, phosphorus, PTH and alkaline phosphatase to exclude hyperparathyroidism [2].
4. SH3BP2 sequencing (or a panel with SH3BP2, OGFRL1, RASopathies, CDC73 and GNAS); if negative and the picture is typical, OGFRL1 and exome, especially in consanguineous families [1, 8].
5. Biopsy when the picture is atypical (unilateral, unilocular, anterior, late-onset, painful or rapidly growing lesion) or when surgery is indicated; consider NFATc1 and TRAP for aggressiveness [1, 41].
6. Multidisciplinary assessment for decision: observation, surgery or pharmacological treatment in the context of an experienced team [1, 63].

A 2026 Iranian series proposed a similar diagnostic and treatment algorithm, derived from expert consensus and not from comparative evidence [63].

5.9. Prenatal and preimplantation diagnosis

When the familial variant (or variants) has been identified, prenatal diagnosis and preimplantation genetic testing are possible [1]. The disease has no prenatal ultrasound expression described in the sources consulted.

5.10. Forms with gingival fibromatosis, bleeding or neurological signs

A child with a cherubism-like picture and gingival bleeding, gingival overgrowth, rapid growth, congenital heart disease or midline anomalies should have CT or MR angiography before any biopsy, curettage or extraction; in the two Bulgarian children with ELMO2 malformation in whom biopsy was performed without vascular imaging, near-fatal intraoperative haemorrhage required emergency coil embolisation [21, 22]. Dynamic MR angiography distinguishes the vascular malformation, with tortuous intramedullary channels and early venous filling, from the non-vascular multilocular lesions of cherubism; ground-glass CT may mimic fibrous dysplasia [21]. Histology may be misleading, because the specimen shows giant cells, pseudocystic areas and granulation tissue [21].

The exome should include ELMO2 and TBC1D2B in addition to SH3BP2 and OGFRL1 [21, 24]. One of the ELMO2 alleles described is a complex rearrangement that eliminates exon 1 and the promoter, so that, faced with a single allele or none in a typical picture, structural variants must be sought by copy number analysis or genome sequencing [17, 20]. In the Bulgarian family, prenatal diagnosis by Sanger sequencing of amniotic fluid at 18 weeks identified the homozygous sibling [21].

Faced with gingival fibromatosis with seizures, developmental delay or regression, ataxia or low vision, the assessment includes EEG, brain MRI (cerebellar or cerebral atrophy, ventricular dilatation, white matter changes), ophthalmological examination with fundoscopy and full blood count [24, 27]. In the Indian series, spinocerebellar ataxia panels, testing for Friedreich ataxia and chromosomal microarray were normal before exome sequencing [27].

6. Differential Diagnosis

6.1. Principle

The differential of cherubism is that of giant cell and fibro-osseous lesions of the jaws in children. Since the histology is similar in almost all of them, the distinction relies on distribution (bilateral and symmetrical in cherubism), age at onset, family history, extramaxillary findings, biochemistry and genetics [1, 2, 6]. Once hyperparathyroidism has been excluded, multifocal giant cell lesions of the jaws almost always appear before 20 years and are associated with a syndrome, especially RASopathies or cherubism [65].

Sources: [1, 2, 6, 11, 12, 20, 21, 24, 25, 27, 31, 36, 65–69].

6.2. RASopathies with giant cell lesions

Chuong and colleagues described in 1986, in a series of 17 patients with giant cell lesions of the jaws, two patients with Noonan syndrome and bilateral lesions; Dunlap described four children aged 4 to 8 years with both entities; in 1991, Cohen and Gorlin brought together 15 cases and proposed the name «Noonan-like/multiple giant cell lesion syndrome» [2]. The identification of PTPN11 and SOS1 variants in these patients showed that the lesions are part of the Noonan spectrum and not of cherubism; the 2012 consensus recommends abandoning the «Noonan-like» designation [2]. PTPN11 variants have also been described in patients initially diagnosed with cherubism, and an individual with confirmed Noonan syndrome was excluded from the Norwegian cherubism cohort [47, 70]. Giant cell lesions in Noonan syndrome may be aggressive and are easily confused with cherubism when they are symmetrical in the maxilla and mandible; the consensus illustrates the case of a 20-year-old woman with an SOS1 variant, treated with contour resection in two sessions and four cycles of zoledronic acid at six-week intervals [2]. A 2025 series used imatinib for multifocal lesions in one patient with Noonan syndrome and two with cherubism [71]. GeneReviews includes in the differential Noonan syndrome, cardiofaciocutaneous syndrome, neurofibromatosis type 1 and Noonan syndrome with multiple lentigines [1].

6.3. Hyperparathyroidism and brown tumours

Brown tumours are giant cell lesions caused by excess PTH; in the jaws they are rare, lack the symmetry of cherubism and are accompanied by other radiological signs of hyperparathyroidism and by raised calcium, PTH and alkaline phosphatase [1, 6]. In hyperparathyroidism–jaw tumour syndrome, autosomal dominant due to CDC73 variants (parafibromin, 1q31), the lesions are ossifying fibromas, sometimes bilateral or multifocal and recurrent, and are associated with primary hyperparathyroidism, renal and uterine tumours and a risk of parathyroid carcinoma [1, 67]. In familial isolated hyperparathyroidism, germline MEN1 variants have been found in 20% to 57% of families, depending on the series [1]. Brown tumours may have somatic KRAS variants [36]. In children, hyperparathyroidism is rare outside chronic kidney disease, but biochemistry should always be requested [2].

6.4. Fibrous dysplasia and McCune-Albright syndrome

Craniofacial fibrous dysplasia may overlap clinically and radiologically with cherubism [1]. It is distinguished by being asymmetrical, non-familial, of later onset, without a cherubic appearance and without regression after puberty; it has a ground-glass pattern, frequently affects the frontal and sphenoid bones and may involve other bones (femur, tibia, ribs); in McCune-Albright syndrome there are café-au-lait spots and endocrinopathies [1, 6, 31]. Molecular diagnosis is made by testing for the post-zygotic GNAS variant, preferably in lesional tissue [31].

6.5. Central giant cell granuloma

Central giant cell granuloma is histologically indistinguishable from cherubism, but appears later, is rarely bilateral or symmetrical, is usually unilocular and mainly affects the anterior mandible [1, 6]. Sporadic granulomas have mutually exclusive somatic variants of TRPV4, KRAS or FGFR1; a somatic SH3BP2 variant has been described in one case [1, 36, 48]. The multifocal form without a syndrome is rare and may be clarified by tissue genetics [64, 65].

6.6. Ramon syndrome and primary intraosseous vascular malformation due to ELMO2

Ramon syndrome (OMIM 266270) was described in 1967 in two siblings with cherubism, gingival fibromatosis, epilepsy, intellectual disability, hypertrichosis and short stature; about eight cases had been described by 2012 [2, 4, 16]. In 1986, Pina-Neto described four patients in a consanguineous Brazilian family, three of whom had juvenile rheumatoid arthritis; during follow-up, retinal pigmentary changes, optic disc pallor and fibromatous hypertrophy of the labia minora appeared; two other siblings had Axenfeld anomaly [16]. The OMIM entry has no gene assigned, and the ELMO2 entry does not include Ramon syndrome among its phenotypes [17]. Since 2020, biallelic loss-of-function variants of TBC1D2B have been known to cause a neurodevelopmental disorder with seizures and gingival overgrowth (OMIM 619323), and in 2024 a Thai girl with the full picture of Ramon syndrome had a homozygous TBC1D2B variant; the authors consider that TBC1D2B and ELMO2 are both linked to the syndrome, whereas the series of ten patients with TBC1D2B treats the two entities as overlapping but distinct, owing to the neurological deterioration [23–26]. The entry for the syndrome also notes that phenytoin reproduces some features of the syndrome and that gingival hyperplasia exists in other syndromes (Rutherfurd, Laband, Jones) [16]. In 2018, a homozygous missense variant in ELMO2, p.(Ile606Ser) (published protein designation), was found in two Lebanese siblings, children of first cousins, with the clinical picture of the syndrome [11]. Biallelic loss-of-function variants of ELMO2 (20q13.12) cause primary intraosseous vascular malformation (OMIM 606893), autosomal recessive, formerly called intraosseous haemangioma [17, 18]. In the consanguineous families described, the children were normal at birth and developed in early childhood a painless, progressive swelling of the mandible, with acceleration at the onset of puberty, ectopic tooth eruption and gingival bleeding; the maxilla was always affected and, less frequently, the nasal bones, calvaria, sphenoid, clivus, clavicles, ribs and vertebrae, sometimes with midline anomalies; potentially fatal haemorrhage after a simple tooth extraction is frequent, and histology shows a venous malformation and not a neoplasm [18]. In the 2025 series, the malformations were fast-flow, compressed the facial bones and could cause massive haemorrhage and intracranial herniation; in these four new patients, propranolol and sirolimus brought no significant improvement, sirolimus caused severe infections and one patient died from haemorrhage [18, 21]. In 2024, a Brazilian team described a patient with gingival overgrowth, neurodevelopmental delay and a cherubism-like phenotype, with a homozygous loss-of-function ELMO2 variant and familial recurrence, and argued that the two entities may not be distinct [12]. In practice, a child with a cherubism-like picture, gingival overgrowth and gingival bleeding should have vascular imaging before any biopsy or curettage and testing of ELMO2 [12, 21].

6.7. Cemento-osseous lesions and gnathodiaphyseal dysplasia

Familial gigantiform cementoma affects the mandible and maxilla, but with focal lesions, more maxillary than mandibular, which frequently extend to the orbits and nasal septum [6]. It is autosomal dominant, begins in adolescence and progresses through three radiological phases (osteolytic, cementoblastic and mature, with radiopaque masses in all four quadrants); OMIM does not yet assign it an established molecular basis [69]. Gnathodiaphyseal dysplasia, autosomal dominant due to ANO5 variants (11p14.3), combines mixed radiopaque and radiolucent cemento-osseous lesions in the tooth-bearing segments from adolescence with bone fragility, fractures and diaphyseal cortical thickening; the jaws are susceptible to infection [66, 68]. Cherubism, Ramon syndrome and RASopathies with giant cell lesions lack the long bone changes [66]. The two entities and familial florid cemento-osseous dysplasia share ANO5 variants [36, 69].

6.8. Other associations described

Cases of cherubism associated with fragile X syndrome, gingival fibromatosis with psychomotor delay, neurofibromatosis type 1 and craniosynostosis, and bilateral mandibular lesions with an NF1 variant have been described [2]. In Jaffe-Campanacci syndrome, the jaw lesions are eccentric or unilateral [2]. Histologically similar lesions include aneurysmal bone cyst, myxoma and haemangioma [2]. OMIM also includes Caffey disease, with different radiology and more extensive skeletal involvement [13]. The review of 513 cases excluded patients with Noonan, Ramon, fragile X, Dandy-Walker and polycystic ovary syndromes, which shows the frequency of these associations in the reports [10].

7. Treatments and Risk Management Strategies

7.1. Framework and reference documents

There are no clinical practice guidelines for cherubism, and no drug has an approved indication for the disease [1, 5]. The available recommendations are GeneReviews, updated in 2025 by authors from the Paris reference centre on the basis of their experience, and the 2012 good clinical practice document, resulting from the international meeting on fibrous dysplasia, McCune-Albright syndrome and cherubism [1, 2]. Two systematic reviews of pharmacological treatment concluded that the evidence is of very low certainty, consisting of case reports and small series [40, 72]. Since the disease is self-limiting and improves with time, treatment is individualised according to presentation and course [1].

7.2. Initial evaluation

After diagnosis, GeneReviews recommends assessment in a craniofacial clinic (oral and maxillofacial surgery, plastic surgery, dentistry and orthodontics, otorhinolaryngology, child psychology or social work), imaging of extent by low-dose CT and, when lesions approach neurovascular or ocular structures, magnetic resonance imaging [1]. It also includes swallowing assessment by a speech and language therapist, orthodontic assessment, respiratory assessment (mouth breathing, snoring, chronic nasal infection, OSA) with overnight polysomnography if sleep-disordered breathing is suspected, ophthalmological examination, genetics clinic consultation and assessment of family support needs [1].

7.3. Observation

In mild forms, without dysmorphism, without relevant dental involvement and without ocular involvement, the approach is longitudinal observation, because spontaneous regression is expected after puberty [2]. Observation was the first approach in 52.4% of 431 published cases, mainly in the less aggressive grades [10]. In the 2026 Iranian series, seven of nine patients treated conservatively (observation or intralesional triamcinolone) stabilised or regressed [63].

7.4. Surgery

Indications and timing. Surgery is indicated when there is functional or aesthetic concern: nasal obstruction, displacement of the tongue with airway compromise, difficulty swallowing, proptosis, major facial deformity or locally aggressive lesions [1, 2]. GeneReviews estimates that, in patients with disfiguring enlargement or complications, surgery takes place between 5 and 15 years [1]. The 2012 consensus recommends operating, whenever possible, after puberty and with quiescent lesions, accepting earlier surgery for severe aesthetic or functional problems; aggressive lesions with airway obstruction justify early intervention [2]. Orbital surgery is rare and is reserved for globe displacement or suspected visual loss due to optic atrophy [2].

Techniques. Options include curettage with or without bone grafting, contour resection, partial resection or combinations; liposuction has been used to recontour the jaws [1, 2]. In the review of 431 cases, the first approach was curettage in 20.2%, debridement or osteoplasty in 19.7%, marginal resection in 1.4%, enucleation in 0.7% and resection with continuity in 0.5%; grades IV and V were operated on more often [10].

Results. Results vary. In some studies, recontouring during the growth phase was followed by rapid regrowth, and a malignant mesenchymal tumour (leiomyosarcoma) was described in the mandible of a 10-year-old child after two recontourings [2]. Other reports showed favourable results with curettage and recontouring during the growth phase; in the Danish follow-up, biopsy with or without autotransplantation of ectopic teeth did not provoke lesion growth in 22 of 22 interventions [2, 53]. Raposo-Amaral operated in two stages on eight children aged 6 to 15 years (mean 11) with severe cherubism, between 1987 and 2005, in Campinas: first the maxilla and orbits (osteotomy and removal of the anterior wall of the maxilla, curettage and recontouring with refixation, in five; cortical windows, curettage and infracture with in situ recontouring, in three), and six months later the mandible, through bone windows with curettage and manual infracture; with follow-up of 2 to 18 years (mean 5.1), all had a satisfactory aesthetic result and none had clinical or radiological recurrence; the only relevant complication was bilateral ectropion, corrected with a full-thickness skin graft [39]. In a series of nine patients from 2010 to 2024, seven were debrided; the two with grade VI required several procedures and one received adjuvant denosumab; there was improvement in symmetry in all and in proptosis and breathing in the severe cases [73]. The 2021 review notes that early surgery appears to predispose to recurrence, but that it is unclear whether surgery induces growth or merely coincides with the phase of rapid growth [10]. GeneReviews advises planning surgery individually and avoiding unrealistic expectations, because recurrence is possible and surgery may not halt progression [1]. The 2023 review records that surgery may cause irreversible damage [40].

Radiotherapy. Radiotherapy is contraindicated in this benign disease, because of the risk of delayed maxillary growth, osteoradionecrosis and induced neoplasia [2]; even so, it was the first approach in 2.3% of published cases [10].

7.5. Dental treatment and oral rehabilitation

Development of the dentition should be closely monitored [2]. The problems of early loss of deciduous teeth and absent and delayed eruption of permanent teeth have no satisfactory solution; space maintainers are used while awaiting eruption and, sometimes, surgical exposure of impacted teeth; extraction may be necessary when teeth «float» in the lesions or become ectopically impacted [2]. In severe forms, children may need prostheses, adjusted to growth, which improve chewing and self-esteem [2]. Orthodontics is generally done after the end of growth and in the regression phase, although it may be needed earlier with fixed appliances [1, 2]. In adults, rehabilitation with implants is possible: in the Norwegian cohort, implant survival was 79%, and a case followed for 23 years received implants by guided surgery, without grafting, after stabilisation had been confirmed, with stable osseointegration and prosthetic outcome [47, 74].

7.6. Airway, swallowing and eyes

OSA and airway obstruction are managed with otorhinolaryngology and sleep medicine [1]. Continuous positive airway pressure (CPAP) ventilation may be difficult because of the anatomy; nasal clearance surgery, correction of tongue displacement or tracheotomy may be necessary [2]. A child with severe OSA was treated with nocturnal mouthpiece ventilation combined with medical hypnosis [1]. Speech and language therapy is needed in rare cases of physical obstruction to speech or swallowing [1]. Ocular complications (eyelid retraction, proptosis, diplopia, globe displacement, visual loss) follow ophthalmology guidance [1].

7.7. Pharmacological treatment: principles

GeneReviews lists the drugs used, mainly in severe forms — calcitonin, anti-TNF-α agents, a calcineurin inhibitor (tacrolimus), a tyrosine kinase inhibitor (imatinib) and denosumab — and stresses that the mechanisms are not fully understood, that some are not authorised in children and that there is no standard treatment or consensus [1]. The 2023 systematic review (PROSPERO registration CRD42022351044) identified 621 studies and included 14, all case reports or letters, with 18 patients (seven female; mean age 9.6 years, range 4 to 19): six received denosumab, seven immunomodulators or bisphosphonates and five calcitonin; five studies had low risk of bias, four unclear risk and five high risk; the certainty of evidence according to GRADE was very low and no conclusion could be drawn on the efficacy of any drug [40]. Adverse effects (nausea, hypophosphataemia and hypocalcaemia, sometimes severe) occurred in eight patients, and in only nine of the 18 did the decision involve a multidisciplinary team or an ethics committee [40]. The 2026 review (18 studies from 2015 to 2025, 36 patients, 25 of them with grade V–VI) describes better results with the combination of surgery and drug in advanced grades, but rests on heterogeneous reports and contains inaccuracies in the transcribed routes of administration; the data should be read in the original studies [72]. Before any systemic treatment, the 2023 review recommends recording the severity grade, the biological assessment (including bone markers) before, during and after treatment, the planned duration and adverse effects, and reminds that improvement may correspond to the natural regression of the disease [40].

All uses described below are off-label. There is no guideline-established dose for any drug in cherubism; the doses indicated are those of the published studies and are compared with the labels for the approved indications of the same drug, stating the extrapolation.

7.8. Salmon calcitonin

Mechanism and rationale. Calcitonin inhibits osteoclastic resorption and was used in central giant cell granuloma, from which it passed to cherubism [2, 59].

Evidence. The largest series is the Amsterdam retrospective cohort: between 2012 and 2022, nine of the 19 children with DNA-confirmed cherubism in the jaw giant cell lesion registry received calcitonin (11 courses); the Motamedi-Raposo grades were III-5 (one) and IV-1 or IV-3 (eight); the mean age at start was 8.2 years (2.1 to 14.3) and the mean duration 17.9 months (<1 to 35) [59]. Mean cumulative lesion volume, measured on three-dimensional reconstructions, fell from 80.85 cm³ (n = 8) to 42.53 cm³ at 6 months, 31.03 cm³ at one year (n = 7) and 24.53 cm³ at 2 years (n = 6), a reduction of more than 70% in the six courses with 2 years (p < 0.01), greatest in the first six months [59]. After stopping, volume increased again in six of seven courses with follow-up imaging (28% at 6 months; 41%, 88% and 121% at 1 year; 151% and 172% at 2 years), without returning to baseline; the only patient with reduction after stopping was completing tooth eruption [59]. Adverse effects occurred in 73% of courses, almost all mild: nausea (45%), vomiting (27%), injection site reaction (27%), flushing (18%), headache or fatigue (18%); one child had grade 3 symptomatic hypocalcaemia after the first injection, with hospital admission and discontinuation of treatment [59]. Daily injections were experienced as burdensome, which reduced adherence; the authors propose shorter, repeated courses [59]. In isolated reports with nasal calcitonin 200 IU per day, for 12 to 30 months, improvement or resolution was described; with 100 IU subcutaneously for 6 months in a 7-year-old boy there was no improvement; the effect on giant cell granuloma may take up to 18 months, so calcitonin is not preferred for rapidly growing lesions [2, 40]. In a 2026 series, nasal calcitonin 200 IU per day, started after surgical recurrences and denosumab, caused severe nausea [63].

Published doses and comparison with the label. In the Amsterdam protocol, 100 IU subcutaneously once a day (50 IU under 4 years), for 2 years, prescribed by a paediatric oncologist, with CT or cone-beam tomography at 0, 6 and 12 months and then annually [59]. In case reports, 200 IU nasally once a day [40]. The US label for Miacalcin® injection states, for symptomatic Paget disease, «100 USP Units (0.5 mL) per day administered subcutaneously or intramuscularly» and, for hypercalcaemia, 4 IU/kg every 12 hours, increasable to 8 IU/kg every 6 hours; safety and efficacy in paediatrics have not been established [75]. The Amsterdam subcutaneous dose matches the label dose for Paget disease in adults; its application to children and the 2-year duration fall outside the label conditions.

Safety. The US label warns of serious hypersensitivity with fatal anaphylaxis, hypocalcaemia (ensure calcium and vitamin D), antibodies with loss of response and risk of malignancy: in a meta-analysis of 21 trials with nasal or oral calcitonin, the incidence of malignancies was 4.1% versus 2.9% with placebo [75]. In 2012, the European Medicines Agency (EMA) concluded that long-term use is associated with a small increase in the risk of cancer, restricted calcitonin to short-term use in Paget disease, acute bone loss due to sudden immobilisation and hypercalcaemia of malignancy, and withdrew the osteoporosis indication [76]. The Amsterdam authors consider the oncological risk of little relevance in children, because the malignancies were described in adults over 50 years [59].

Availability. In Portugal, a search of Infomed (INFARMED) on 31 October 2026 returned no authorised and marketed calcitonin medicines; the authorisations of Miacalcic® have been revoked and those of Calcimon®, Calsyn® and a generic nasal calcitonin have lapsed [77]. The Dutch cohort used an injectable salmon calcitonin from a Maltese marketing authorisation holder [59].

7.9. Denosumab

Mechanism and rationale. Denosumab is a monoclonal antibody that binds RANKL and inhibits osteoclast formation and function; its use in cherubism was extrapolated from giant cell tumour of bone and central giant cell granuloma [62, 78].

Evidence. Reports describe a rapid and consistent response: relief of pain and oral bleeding in the first month and sclerosis of the lytic lesions, regardless of dose, duration and age [40, 62]. In a prepubertal boy, eight injections of 120 mg over 6 months suppressed expansion and ossified the lesions, at the cost of a transient reduction in growth velocity and asymptomatic rebound hypercalcaemia [79]. In two sisters aged 15 and 19 years, ten doses made the bone denser, and serum CTx rose after stopping [40, 78]. The 2023 review questions the aim of transforming cavities into sclerotic bone in a disease that regresses spontaneously, notes that the 120 mg dose is the one used in adults with malignant disease and that the long-term effects in children are poorly known [40]. In 2026, the team that had reported a first success described, in the same patient, multiple fragility fractures of long bones and severe rebound hypercalcaemia during prolonged treatment, and adjusted the dose and metabolic surveillance in a second patient [80, 81]. In an Iranian series, 120 mg every two weeks for 14 months was followed by severe pain in the spine and lower limbs [63].

Published doses and comparison with the label. Adult regimen for giant cell tumour, with 120 mg subcutaneously on days 1, 8 and 15 and then every 4 weeks, in patients over 40 kg, with calcium carbonate 500 mg and vitamin D3 1000 IU per day [62]. Reduced regimens: 60 mg monthly after severe hypocalcaemia; 60 mg calculated by body surface area on days 1, 8, 15 and 28 and then monthly (19 doses) in a 6-year-old child [62, 82]. Other paediatric regimens described for giant cell lesions: start at 1.2 mg/kg up to 1.6 mg/kg monthly; 1 mg/kg with increases of 0.25 mg/kg every 3 months up to 1.75 mg/kg; 70 mg/m²; some teams eliminated loading doses to reduce initial hypocalcaemia [62]. To avoid rebound hypercalcaemia, the Los Angeles team progressively spaced the doses (2, 2, 3 and 4 months) before stopping [62]. The US label for Xgeva® approves, in unresectable giant cell tumour of bone in adults and skeletally mature adolescents, «120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy», with calcium and vitamin D; safety and efficacy in paediatrics have not been established outside skeletally mature adolescents aged 12 to 16 years [83]. In the European Union, Xgeva® has the same regimen in the same indication («120 mg … once a week for 3 weeks, and then once every 4 weeks») [84]. In cherubism, which mainly affects children with an immature skeleton, all use falls outside the conditions of both labels.

Safety. The Xgeva® label warns of severe symptomatic hypocalcaemia, with fatal cases (correct beforehand, monitor in the first weeks and supplement), osteonecrosis of the jaw (prior oral examination, avoid invasive dental procedures), atypical femoral fracture, multiple vertebral fractures after discontinuation, embryo-fetal toxicity and clinically significant hypercalcaemia after discontinuation in paediatric patients with a growing skeleton; in animals, RANKL inhibition impaired bone growth and tooth eruption [83]. The Prolia® label states that, in 153 children with osteogenesis imperfecta, denosumab had no efficacy and caused hypercalcaemia with hospital admission and acute kidney injury, leading to early termination of the paediatric studies [85]. In cherubism, severe hypocalcaemia at the first injection, hypophosphataemia, reduced growth, rebound hypercalcaemia and fragility fractures have been described [62, 79, 80, 82].

7.10. Tacrolimus

Rationale. The presence of nuclear NFATc1 in the giant cells of aggressive forms led the Necker Hospital team to use a calcineurin inhibitor, which prevents nuclear translocation of NFATc1 [41, 55].

Evidence. A boy with the NM_001122681.2:c.1253C>G p.(Pro418Arg) variant and grade IV cherubism had recurrence after surgery at 2 and 3 years, with nasal obstruction, glossoptosis and severe apnoea on CPAP; at 4 years he started tacrolimus for one year, at the end of which the lymphadenopathy regressed, the permanent incisors erupted, the maxillary swelling partially regressed, nasal breathing was recovered without CPAP and imaging showed osteogenesis and stabilisation; there were no clinical or biological adverse effects [55]. In curettage specimens before and after, TRAP-positive osteoclasts fell from 15.4 to 1.6 per field (p = 0.0003), cells with nuclear NFATc1 from 14.7 to 1.8 per field (p = 0.0006) and the RANKL/osteoprotegerin ratio fell by 70% [55]. This is a single patient, compared with himself, in a disease that regresses spontaneously [40, 55].

Published dose and comparison with the label. 0.15 mg/kg/day orally in two divided doses, with a target trough concentration of 5 ng/mL; creatinine, full blood count, liver function and blood pressure before, at 2 weeks and every 3 months [55]. The US label for Prograf® indicates, in paediatric liver transplantation, an initial oral dose of 0.15–0.2 mg/kg/day in two divided doses every 12 hours, with concentration monitoring; the Kadlub dose corresponds to the lower limit of that range and the target trough is lower than those used in transplantation [86]. The label has a boxed warning for malignancies and serious infections [86].

7.11. Imatinib

Imatinib, a tyrosine kinase inhibitor, was used in three children aged 4, 6 and 8 years with reductions of 65%, 22% and 75% in lesion volume over 10 to 12 months, with nausea as an adverse effect; in the two patients with higher grades it was combined with debridement [40, 72, 87]. Doses were 200 to 300 mg per day orally (about 300 mg/m²) [40]. Histology did not change in the patient with the greatest reduction, and in the mouse model imatinib suppressed osteoclastogenesis in vitro but not inflammation or osteopenia in vivo [40, 88]. The US label for Gleevec® indicates 340 mg/m²/day in paediatric chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia and warns of fluid retention, cytopenias and growth retardation in children and preadolescents, with a recommendation to monitor growth [89].

7.12. TNF-α inhibitors and bisphosphonates

Two Finnish children treated with adalimumab 40 mg subcutaneously every two weeks for about 2.5 years had a histological reduction in giant cells and TNF-α staining, but the lesions increased or remained stable, bone markers did not change and one required surgery; there were respiratory infections and one pneumonia [40, 90]. The combination of adalimumab (24 mg/m² fortnightly) with alendronate (35 mg weekly) in a 5-year-old child was ineffective [40]. Alendronate 70 mg per week, as an adjunct to anterior maxillectomy in a 13-year-old boy, was associated with absence of progression, with new lesions after stopping [40, 56]. These results are compatible with the in vitro observation that TNF-α has little effect on resorption by cherubism osteoclasts [44].

7.13. Other options

Intralesional corticosteroids (triamcinolone 40 mg/mL, at intervals of two weeks to three months) were used in non-aggressive forms in an Iranian series, with stabilisation or regression [63]. Interferon α has been used in aggressive giant cell lesions and, once, in cherubism, in a patient who no longer had deformity when treatment started [2, 10].

7.14. Regimens described

Sources: [40, 55, 56, 59, 62, 75, 76, 82–84, 86, 87, 89, 90]. SC, subcutaneous; IM, intramuscular; GCTB, giant cell tumour of bone; CML, chronic myeloid leukaemia; ALL, acute lymphoblastic leukaemia; Ph+, Philadelphia chromosome-positive.

7.15. Regulatory status

Sources: [5, 75–77, 83–86, 89].

7.16. Registered trials and studies

Sources: [59, 91].

There is no interventional clinical trial targeting cherubism on ClinicalTrials.gov [91]. All therapeutic evidence comes from studies without a control group, with patients of different grades, ages and disease phases, non-standardised outcomes and short follow-up; drugs cannot be compared across studies, and the improvement observed may reflect natural regression [40, 72]. The negative results (subcutaneous calcitonin for 6 months, adalimumab, adalimumab with alendronate) show that not all patients respond and that a reduction of giant cells on histology does not equate to clinical benefit [40, 90]. Regrowth after stopping calcitonin and rebound hypercalcaemia after denosumab indicate that the duration and mode of discontinuation matter as much as the drug chosen [59, 62].

7.17. Developments between November 2025 and October 2026

Outside the window, but recent: a 2025 in vitro study with osteoclasts from symptomatic carriers and an asymptomatic carrier [44], a surgical series of nine cases [73], the use of imatinib in multifocal lesions [71] and a preclinical study on caspase-1 [45]. No marketing authorisation application, Committee for Medicinal Products for Human Use (CHMP) opinion or regulatory authorisation for cherubism was found in the sources consulted.

7.18. Preclinical research

In the cherubism mouse, etanercept started in the neonatal period prevented the disease, but was not effective in adult mice with established lesions or in patients [93]. The second-generation SYK inhibitor entospletinib, administered intraperitoneally for six weeks to 10-week-old mice, reduced facial swelling, inflammatory infiltrates, serum TNF-α and bone erosion; clinical trials of this drug were conducted in adults with haematological malignancies, and its use in cherubism is only preclinical [40, 93]. NFATc1 has been identified as a target, and the hypothesis of a microbial trigger or of damage during tooth eruption opens the possibility of preventive strategies in carriers, still without data [2].

7.19. Agents and procedures to avoid

Radiotherapy is contraindicated [2]. In a child with a cherubism-like picture, gingival overgrowth and bleeding, biopsy or curettage without prior vascular imaging exposes to the risk of haemorrhage from an ELMO2 vascular malformation [12, 21]. During treatment with denosumab, invasive dental procedures should be avoided because of the risk of osteonecrosis of the jaw, and abrupt discontinuation exposes to rebound hypercalcaemia [62, 83].

7.20. Special populations

Growing children. Denosumab may affect bone growth and tooth eruption and causes rebound hypercalcaemia in immature skeletons; imatinib is associated with growth retardation; calcitonin has no established paediatric safety [75, 79, 83, 89]. Since most treated patients are children, the 2023 review recommends limiting the radiation of follow-up imaging [40].

Pregnancy. Denosumab has embryo-fetal toxicity and requires effective contraception in women of childbearing potential [83]. The sources consulted do not describe the course of cherubism during pregnancy; for fibrous dysplasia, the atlas records reactivation in pregnancy, a finding that cannot be transposed to cherubism [31]. Among the references of the 2026 review is a report of late reactivation of cherubism in a patient with recent-onset polycystic ovary syndrome [72].

Perioperative care. The lesions are highly vascularised; two-stage surgery was planned to limit blood loss [2, 39]. The airway may be difficult because of glossoptosis and nasal obstruction, and should be assessed before anaesthesia [1, 2]. In the Paris series, PTH was transiently raised at the time of surgery in two patients [42].

Transition to adulthood. Surveillance should continue into young adulthood, with particular attention to the orbit, because ophthalmological complications may arise after maxillary regression, and to definitive dental rehabilitation, which takes place after stabilisation [2, 59, 74].

7.21. Intraosseous vascular malformation due to ELMO2 and TBC1D2B forms

There is no causal treatment or guideline for primary intraosseous vascular malformation; the data come from little more than a dozen patients described in series and reports [21, 22]. Haemorrhages are treated with endovascular coil embolisation and percutaneous sclerotherapy, followed, when possible, by partial resection of the embolised bone; in the 2016 series, extraction of all teeth, excision of calvarial bone and mandibulectomy were described, and removal of teeth and facial bone gave temporary symptomatic relief and delayed progression [18, 21]. Interferon alfa-2a and radiotherapy did not alter the course [21]. As the lesions progress with growth, the Turkish team advocates surgery before complications arise [61]. In extensive forms, surgery, even after preparatory embolisation, carries a high risk of fatal haemorrhage, and the malformations recur and appear in new bones (maxilla, zygomatic, sphenoid) after embolisation [21]. In a massive gingival haemorrhage, intravenous activated factor VII had no effect, the patient went into cardiac arrest and required urgent embolisation of the internal maxillary artery; she died shortly afterwards [21].

Sirolimus. It was used in three children, with no published dose [21]. In the Bulgarian patient, with troughs between 6.7 and 8.6 µg/L, it was discontinued after three months because of recurrent fevers and gingival bleeding; shortly after stopping, multiple brain abscesses due to Streptococcus intermedius appeared, drained surgically, without demonstrated immunodeficiency [21]. In the Egyptian girl, with troughs of 4.3–5 ng/mL, there were dental abscesses and frequent interruptions; in the Egyptian boy, started at 8 years, gingival bleeding decreased and haemoglobin stabilised, without reduction of the lesions [21]. The authors did not move on to everolimus because of the infections [21]. For comparison, in a similar condition treated with the same drug, the phase II trial in 61 patients with complicated vascular anomalies used 0.8 mg/m² per dose, twice a day, adjusted to troughs of 10–15 ng/mL, for 12 cycles of 28 days; 47 of 57 evaluable patients had a partial response after six cycles, with no complete responses, and 27% had grade 3 or higher haematological toxicity [94]. This dose is an extrapolation, because no patient with an ELMO2 malformation entered the trial [21, 94].

Propranolol. Used in two children, with no published dose: it was stopped after four months because of nightmares in one patient, resumed and then stopped by the parents because of no effect on the frequency of haemorrhages; in the other child there was initial improvement followed by worsening [21]. The FDA label for proliferating infantile haemangioma, a vascular tumour and not a malformation, provides for initiation between 5 weeks and 5 months of age with 0.6 mg/kg twice a day, at least 9 hours apart, increased to 1.1 mg/kg twice a day after one week and to 1.7 mg/kg twice a day after two weeks, maintained for 6 months, with no higher dose provided in the label; it is taken during or right after a meal, because of the risk of hypoglycaemia, with monitoring of heart rate and blood pressure for 2 hours after initiation or each increase [95]. Transposition to intraosseous malformation is an extrapolation without demonstrated efficacy [21].

Bisphosphonates. Zoledronic acid, started on suspicion of fibrous dysplasia, coincided with an increase in haemorrhages and lesion size and with the loss of a bone fragment through the mouth after four months; it was stopped at eight months for lack of response, and the authors consider drug-related osteonecrosis unlikely given the short interval [21]. Bevacizumab, thalidomide and mTOR, PI3K, AKT and MEK inhibitors, used in other vascular malformations, have no data in this disease [21].

Supportive measures. Oral iron supplementation prevents the iron deficiency of chronic bleeding [21]. Brain abscesses of odontogenic origin (Streptococcus intermedius, Staphylococcus epidermidis and Escherichia coli) required prolonged intravenous antibiotic therapy [22]. The preventive dental protocol includes quarterly appointments, topical fluoride and age-appropriate fluoridated toothpaste, fissure sealants, soft toothbrushes and parent-supervised interdental cleaning, sugar restriction, a soft diet and a written plan for bleeding and trauma agreed with paediatrics and haematology; restorations are performed in a minimally invasive way, and partial prostheses and orthodontics were contraindicated because of the bleeding risk [22]. The parents' fear of causing bleeding led to insufficient oral hygiene, corrected with targeted instruction [22].

Forms due to TBC1D2B. There is no targeted treatment. Gingivectomy improves gingival overgrowth, but in the Thai girl there was recurrence after three years; in the Cambodian men with gingival fibromatosis, gingivectomy with extraction of all permanent teeth had no recurrence in seven years [25]. Seizures were treated with valproate, levetiracetam and clobazam [25, 27]. Phenytoin reproduces some features of Ramon syndrome, including gingival hyperplasia, and was replaced by valproate in the Thai girl [16, 25].

8. Reproductive Options and Family Counselling

8.1. Modes of inheritance

In most families, cherubism is transmitted in an autosomal dominant manner by SH3BP2 variants, responsible for about 80% of cases; in the two families with OGFRL1 variants, transmission is autosomal recessive [1, 8]. Counselling therefore depends on the gene identified in the proband.

8.2. Autosomal dominant form

Parents of the proband. Some probands have an affected parent; many simplex cases result from a de novo variant [1]. A case may appear isolated because the disease was not recognised in relatives, because penetrance is incomplete or because the parent had a mild form that regressed; therefore, when the proband's variant is known, testing of the parents is recommended [1, 2]. In adults, complete regression often prevents radiological diagnosis: in the Danish follow-up, seven of seven carriers over 32 years had completely normal bone structure [53]. In the Amsterdam cohort, all nine treated children had inherited the variant from their father [59]. If the variant is not found in the leucocyte DNA of either parent, with confirmed parentage, the variant is de novo in the proband or there is gonadal (or somatic and gonadal) mosaicism in a parent, who may have a minimal form [1]. The 2012 consensus considers germline mosaicism rare [2].

Siblings. The risk is 50% if a parent is affected or a carrier, with the caveat that expressivity varies and penetrance is incomplete [1]. If the variant is not present in the parents, the risk is slightly higher than that of the general population, because of the possibility of gonadal mosaicism [1]. If the parents' status is unknown and they are clinically healthy, the risk is low but higher than in the population, owing to incomplete penetrance and mosaicism [1].

Offspring. Each child of an affected individual has a 50% probability of inheriting the variant [1]. Severity in the child cannot be predicted from severity in the parent, given intrafamilial variability and the absence of genotype–phenotype correlation; in the Norwegian cohort, females were on average more severely affected [10, 47].

8.3. Autosomal recessive form

The parents of a child with OGFRL1-related cherubism are presumed to be heterozygous and should be tested; if the variant is found in only one of them, a de novo variant or parental mosaicism is considered; if the proband appears homozygous, a deletion of one or more exons not detected by sequencing and uniparental isodisomy must be excluded [1]. Heterozygotes are asymptomatic, as observed in the six heterozygous relatives of the Syrian family [1, 8]. Each sibling has, at conception, a 25% probability of being affected, 50% of being an asymptomatic carrier and 25% of not being a carrier; the children of an affected individual are obligate carriers, and each sibling of the parents has a 50% probability of being a carrier [1]. Carrier testing requires prior identification of the familial variants [1]. The OGFRL1 c.337C>T variant exists in the heterozygous state in the European population (21 alleles in non-Finnish Europeans in gnomAD), which is relevant in consanguineous couples and in populations with marriages between relatives [8].

The same rules apply to intraosseous vascular malformation due to ELMO2 and to the TBC1D2B forms, both autosomal recessive [18, 24]. The heterozygous parents and siblings tested for ELMO2 were healthy, as were the heterozygous parents of the siblings with TBC1D2B [17, 21, 24]. In the Bulgarian family with ELMO2, prenatal diagnosis identified the second affected child, the family continued the pregnancy and the child has been followed since birth, with a course so far milder than that of his brother [21]. Given the severity and mortality of the malformation, prenatal diagnosis and preimplantation genetic testing are options to discuss when the family's variants have been identified [21]. TBC1D2B heterozygosity was associated with non-syndromic gingival fibromatosis in a Cambodian family, together with a KREMEN2 variant; this isolated finding does not allow risk to be attributed to carriers [25].

8.4. Assessment of at-risk relatives

Asymptomatic at-risk relatives should be assessed to identify early those who benefit from surveillance: molecular testing when the familial variant is known; otherwise, clinical and radiological examination [1]. The 2012 consensus recommends assessing siblings by clinical examination, orthopantomography and genetic testing [2]. Identification of a carrier without symptoms does not allow prediction of whether disease will develop, because there are asymptomatic carriers with osteoclasts as hyperactive as those of patients [44].

8.5. Minors

Testing of asymptomatic minors is justified by the direct benefit: the disease manifests in childhood and early dental and radiological surveillance allows planning of orthodontics, airway and eye surveillance and, in aggressive forms, intervention [1, 2]. Counselling of affected or at-risk young adults on the risks to offspring and reproductive options should be offered [1].

8.6. Reproductive options

The appropriate time to discuss risk and options is before pregnancy [1]. With the familial variant identified, prenatal diagnosis and preimplantation genetic testing are possible; their use in a self-limiting disease, with highly variable expressivity and good quality of life described in adults, is a personal decision, and perspectives may differ among professionals and within families [1, 47]. When there is no molecular diagnosis, storing DNA from the proband for future studies is recommended [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

The prevalence of cherubism is unknown [1, 2]. The sources count published cases, not patients in the population: about 300 cases in 2012, about 400 in 2020, about 500 in 2023 and about 600 in 2025–2026; the systematic review with strict inclusion criteria brought together 513 cases in 260 publications up to September 2019 [1, 2, 10, 40, 42, 43]. Orphanet classifies the disease in the «cases/families» category [3, 5]. Underdiagnosis is likely, because mild or asymptomatic forms go unnoticed and regression in adults erases the radiological signs [1]. The presence of several pathogenic variants of the RSPPDG motif in gnomAD reinforces this hypothesis, without allowing prevalence to be calculated [8].

9.2. Geographical and population distribution

The disease has been described in all ethnic groups, with no ethnic predilection [1, 2]. The available data come from centre series:

Sources: [1, 2, 8, 11, 12, 20, 21, 24–27, 42, 43, 47, 52–54, 57–59, 62, 63, 90, 91].

The two families with OGFRL1 were consanguineous, as was the Lebanese family with Ramon syndrome due to ELMO2 [8, 11]. The ELMO2 variant NM_133171.5:c.1065+1G>A appeared in two Turkish families with a common intragenic haplotype, compatible with a distant founder, and NM_133171.5:c.1065+1G>T in two Egyptian families from distant regions [17, 21]. In the African review, only two of 20 cases had molecular testing, and the features observed reflect gaps in reporting and access, not population patterns [58].

9.3. Brazil and Portugal

In Brazil, one of the first families with cherubism was described in 1966, and a consanguineous family with Ramon syndrome was described in 1986 and followed until 1998 [13, 16]. Raposo-Amaral described in Campinas eight patients with severe cherubism operated on between 1987 and 2005 [39]; researchers from Belo Horizonte published the systematic review of 513 cases and described new SH3BP2 variants in giant cell lesions and in cherubism [10, 48]; and a team from Bahia described a patient with a biallelic ELMO2 variant and a cherubism-like phenotype [12]. Another Brazilian team described two siblings with progressive gingival overgrowth, fibrous dysplasia of the face and mental deterioration, homozygous for a TBC1D2B variant, the fourth family described worldwide with biallelic loss of function of this gene [52]. The sources consulted contain no data from Portugal, which does not demonstrate their absence.

9.4. Special populations

Diagnostic delay is greater where access to specialised care and genetic testing is limited, and the stigma associated with facial disfigurement may be severe in some cultural contexts [57, 58]. Densitometry Z-scores in children of African origin use reference curves not validated for these populations, which limits interpretation [43]. In the Gabonese child with severe cherubism, hepatosplenomegaly and hypochromic anaemia led to the exclusion of tropical, infectious, parasitic and haematological causes before they were attributed to the disease [43].

9.5. Reference networks and patient organisations

In Europe, cherubism falls within ERN BOND (rare bone diseases) and ERN CRANIO (craniofacial anomalies and rare ear, nose and throat disorders) [96, 97]. Intraosseous vascular malformation due to ELMO2 falls within the scope of VASCERN, the European network for rare multisystemic vascular diseases, and the TBC1D2B forms with epilepsy within that of ERN EpiCARE (rare and complex epilepsies) [28, 29]. GeneReviews lists MedlinePlus, the Children's Craniofacial Association (United States), Face Equality International (United Kingdom) and the FD/MAS Alliance as resources for patients and families [1, 98–100]. The 2012 consensus also listed AboutFace International and the Fibrous Dysplasia Foundation [2]. The authors of the 2023 calcitonin study argue that selection of the drug, dose and protocol requires collaboration within rare disease networks [59].

10. Illustrative Clinical Case

10.1. Grade VI cherubism with systemic manifestations

A 6-year-old Gabonese girl was seen at the reference centre of Necker Hospital, in Paris, for rapid and progressive swelling of the maxilla and mandible, beginning at 3 years [43]. Her mother, grandmother and an uncle had mild forms of cherubism, and a cousin, followed at another centre, had an aggressive form without skeletal or inflammatory changes [43]. She measured 109 cm (−1.7 standard deviations) and weighed 15.2 kg (−2 standard deviations); the weight curve had been normal until 3 years and showed a new inflection at 6, when the lesions became more aggressive, without clinical signs of malnutrition [43].

Examination showed symmetrical, painless enlargement of the maxilla, with complete bilateral nasal obstruction and proptosis, and enlargement of the mandible with glossoptosis, without fever or arthritis [43]. Polysomnography was almost normal (one obstructive apnoea per hour) [43]. There was exophthalmos with visible sclera and bilateral limitation of ocular motility; the fundus was normal and visual acuity 3/10 in both eyes [43]. CT showed multilocular expansion of the maxilla and mandible with osteolysis, cortical thinning and expansion, tooth displacement, root resorption, extension to the floor of the mouth and the nasal fossae and elevation of the orbital floors, corresponding to Motamedi and Raposo-Amaral grade VI [43]. Because of the nasal obstruction and proptosis, partial resection of the granuloma was performed, without complications [43].

SH3BP2 sequencing identified the heterozygous variant c.1244G>A p.(Arg415Gln) in exon 9 (described on NM_003023.4; the same numbering on the MANE transcript NM_001122681.2), a recurrent variant classified as pathogenic [9, 32, 43]. Histology showed ovoid to spindle-shaped fibroblasts and numerous osteoclast-like multinucleated giant cells, vessels with perivascular hyalinosis, CD68- and TRAP-positive giant cells and nuclear and cytoplasmic NFATc1, compatible with an aggressive form [43].

Systemic assessment revealed hypochromic anaemia with thrombocytosis (normal haemoglobin electrophoresis), phosphate 2.10 mmol/L (reference 1.3–1.85), normal calcium (2.37 mmol/L), PTH 54 ng/mL (10–50), CTx 18,678 pmol/L (3875–14,260 for age 6), P1NP 1480 ng/mL (324–895), bone alkaline phosphatase 126.6 ng/mL (39.6–98.9), normal 25-hydroxyvitamin D and normal C-reactive protein; interleukin 1β (75.2 pg/mL; reference 0–15) and TNF-α (38.8 pg/mL; 0–20) were raised [43]. Ultrasound showed a slightly enlarged (+1 standard deviation), homogeneous liver and spleen [43]. Densitometry gave Z-scores of −4.6 for the whole body and −2.8 for the lumbar spine unadjusted (−3.2 and −2.6 adjusted for ethnic origin) and −1.0 at the hip [43]. Viral and parasitic infections and malaria were excluded, and a 50-gene bone mass panel found no pathogenic variants [43].

The authors concluded that this was the first case of cherubism with systemic bone loss and inflammation and that, if confirmed, this phenotype would reduce reservations about the use of systemic treatments [43]. They acknowledge that the Z-scores were calculated with curves not validated for African children [43]. The series of 11 patients published by the same group in 2026 confirmed raised turnover markers in several patients and low bone mass mainly in the more severe forms, but none had a systemic picture as marked as this patient, which the authors interpret as a phase of particularly intense activity [42]. The partial resection was indicated for functional complications and is consistent with the recommendations; the extensive systemic assessment is research and not routine [1, 2, 42].

Figures consulted: clinical features, coronal CT, electropherogram and histology at https://pmc.ncbi.nlm.nih.gov/articles/PMC7441549/figure/Fig1/; densitometry at https://pmc.ncbi.nlm.nih.gov/articles/PMC7441549/figure/Fig2/ [43].

10.2. Complementary case: treatment with tacrolimus

A boy with a family history of cherubism was referred at 2 years for rapid bilateral swelling of the jaws, with complete nasal obstruction, mandibular lymphadenopathy and orbital compression; he had the c.1253C>G p.(Pro418Arg) variant and grade IV cherubism [55]. After maxillary enucleation and mandibular surgery at 3 years, the disease recurred, with glossoptosis and severe apnoea requiring CPAP [55]. Biopsy showed giant cells with nuclear NFATc1, and at 4 years he started tacrolimus 0.15 mg/kg/day in two divided doses, with a trough of 5 ng/mL; one year later he was breathing without CPAP, the lymphadenopathy had regressed and imaging showed osteogenesis, which allowed conservative curettage at 5 years [55]. The case does not establish efficacy: it is a single patient, in a disease with spontaneous regression, and tacrolimus has no indication in this disease [40, 55].

10.3. Complementary case: intraosseous vascular malformation due to ELMO2 followed from early childhood

A boy, the second child of healthy, distantly related Bulgarian parents, was born after two late fetal losses with brain cysts and heart disease; he had a muscular ventricular septal defect, patent ductus arteriosus and patent foramen ovale and umbilical hernia with diastasis recti, not requiring intervention [21]. The lower incisors erupted without problems at 6 months, but the first molars, at around 11 months, came with swelling and gingival bleeding, followed by gingival overgrowth throughout the mandible, facial asymmetry, recurrent mucositis, loss of appetite and poor weight gain [21]. At 16 months, during a scheduled biopsy of the mandibular lesion, there was a near-fatal massive haemorrhage; CT angiography showed an extensive, hyperperfused arteriovenous malformation arising from the lingual artery, the feeders were occluded with coils and the embolised region was curetted the next day [21]. The exome, analysed first for ELMO2 given the specificity of the picture, identified the homozygous 25 bp duplication NM_133171.5:c.579_603dup p.(Leu202ProfsTer47), with heterozygous parents [9, 21].

Embolisation was repeated twice in branches of the maxillary artery, followed by partial resection of the maxilla, and new malformations appeared in the zygomatic and sphenoid bones [21]. Propranolol, started at 2.5 years, was stopped after four months because of nightmares; sirolimus was discontinued after three months because of fevers without a focus, and at 3 years, shortly after stopping, the patient had fever, neurological deterioration and signs of herniation due to multiple Streptococcus intermedius brain abscesses, drained surgically; immunological assessment was normal [21]. MRI at 4.5 years showed progression; surgery was considered too risky, propranolol was resumed for five months and stopped by the parents, and at 5.5 years MRI showed slow progression without new lesions, on oral iron only [21]. The histology of two mandibular resections and one maxillary resection showed mature capillary vessels and de novo bone formation in granulation tissue, without criteria for arteriovenous malformation [21].

A paediatric dentistry report from Sofia describes a Bulgarian boy with the same course (biopsy with haemorrhage in 2019, bilateral coil embolisation, three brain abscesses and a family with two fetal losses), followed between 2022 and 2025 [22]. At 4 years he had haemangiomatous lesions in the maxilla and mandible, firm gingival overgrowth, abundant subgingival plaque and cervical caries; at 6–7 years, the central incisors and first permanent molars erupted with enamel hypoplasia and hypomineralisation, restored with composite, and neurological development was normal [22]. The brother diagnosed prenatally had his first gingival bleed at 2 years and a possible mandibular malformation on MRI at 2.5 years, without progression one year later and without further haemorrhages [21]. The case shows the cost of a biopsy performed without vascular imaging, recurrence after embolisation, the severe infections that limit sirolimus and the importance of dental prevention throughout the mixed dentition.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Cherubism is self-limiting in most patients: lesions stabilise around puberty (at 12 years in seven of eight patients in a Brazilian series), fill with bone in the second and third decades and, by 30 years, facial changes are generally no longer evident; in the Danish follow-up, bone structure was completely normal after 41 years [1, 2, 53]. However, bone changes persist on imaging in many adults (73% of 15 Norwegian adults) as do major dental sequelae (mean of 13 missing teeth) [47, 54]. The adult quality of life described is good [47]. A minority have aggressive forms with orbital, visual or respiratory compromise; deaths from airway obstruction with infection, visual loss in adults and late reactivations have been described [1, 2, 40]. There is no validated prognostic marker; nuclear localisation of NFATc1, a high radiological grade and raised CTx are associated with more severe forms in centre series [41, 42]. The grade may change during childhood and should be reassessed [42]. The related entities have a very different prognosis: intraosseous vascular malformation due to ELMO2 does not regress, progresses with growth and caused the death of three of five patients with long follow-up, on average at 27 years, and of one child at 3.5 years [21, 61]; in the TBC1D2B form, six of ten patients had progressive neurological deterioration and three died between 21 and 39 years, while the oldest living were 31 and 35 years [24].

11.2. Surveillance

The intervals for lesion surveillance after quiescence diverge between the two reference sources (2–3 years in GeneReviews, 2–5 years in the 2012 consensus); GeneReviews is the more recent version and cites the consensus as a source [1, 2]. The 2012 consensus recommends that clinical and radiological observation continue into adulthood [2].

12. Summary and Final Considerations

Cherubism is an autoinflammatory bone disease of the jaws, with onset in childhood, caused in the vast majority of families by heterozygous gain-of-function variants in exon 9 of SH3BP2, which prevent degradation of the adaptor protein 3BP2 and make osteoclast precursors hyperreactive to RANKL and M-CSF. An autosomal recessive form due to loss of function of OGFRL1 has been described in two consanguineous families, and 10–20% of patients remain without an identified molecular cause. Ramon syndrome is genetically heterogeneous, with biallelic variants of TBC1D2B, the gene of a progressive neurological disease with gingival overgrowth, and of ELMO2, the gene of primary intraosseous vascular malformation. This malformation mimics cherubism in young children, progresses with growth, causes potentially fatal haemorrhages and requires vascular imaging before any biopsy or extraction.

The typical picture is a child aged 2 to 7 years with bilateral, symmetrical and painless swelling of the mandible and, often, the maxilla, with early lymphadenopathy, multilocular radiolucent lesions in the angles and rami and dental changes, especially agenesis and displacement of the molars. The lesions grow until puberty and regress afterwards, leaving dental sequelae and residual bone changes on imaging in many adults. Penetrance is incomplete and expressivity varies within families; the difference in penetrance between sexes described in the past is not confirmed by recent studies.

Diagnosis combines clinical features, low-dose imaging, biochemistry to exclude hyperparathyroidism and SH3BP2 sequencing, followed by OGFRL1 and exome when necessary; histology does not distinguish cherubism from other giant cell lesions, and the bilateral distribution is the decisive finding. The main differential is with the giant cell lesions of the RASopathies, tumours of hyperparathyroidism, fibrous dysplasia and central giant cell granuloma.

Management takes place within a craniofacial team with paediatric experience. Most patients need only observation, dental and orthodontic care and surveillance of the airway and orbit; surgery is reserved for functional or aesthetic complications and, when possible, for after puberty. There are no guidelines or approved drugs: calcitonin, denosumab, tacrolimus and imatinib have been used off-label in severe forms, with results described in small series and case reports, regrowth after stopping and relevant adverse effects, especially calcium disturbances, rebound hypercalcaemia and fractures with denosumab in children. Radiotherapy is contraindicated. Genetic counselling distinguishes dominant inheritance, with a 50% risk for offspring and the possibility of minimally symptomatic carriers, from the recessive inheritance of the OGFRL1 form, and should include assessment of siblings and parents with molecular testing.

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