DNA methylation profile discriminates sporadic giant cell granulomas of the jaws and cherubism from their giant cell-rich histological mimics.

Sporadic giant cell granulomas (GCGs) of the jaws and cherubism-associated giant cell lesions share histopathological features and microscopic diagnosis alone can be challenging. Additionally, GCG can morphologically closely resemble other giant cell-rich lesions, including non-ossifying fibroma (NOF), aneurysmal bone cyst (ABC), giant cell tumour of bone (GCTB), and chondroblastoma. The epigenetic basis of these giant cell-rich tumours is unclear and DNA methylation profiling has been shown to be clinically useful for the diagnosis of other tumour types. Therefore, we aimed to assess the DNA methylation profile of central and peripheral sporadic GCG and cherubism to test whether DNA methylation patterns can help to distinguish them. Additionally, we compared the DNA methylation profile of these lesions with those of other giant cell-rich mimics to investigate if the microscopic similarities extend to the epigenetic level. DNA methylation analysis was performed for central (n = 10) and peripheral (n = 10) GCG, cherubism (n = 6), NOF (n = 10), ABC (n = 16), GCTB (n = 9), and chondroblastoma (n = 10) using the Infinium Human Methylation EPIC Chip. Central and peripheral sporadic GCG and cherubism share a related DNA methylation pattern, with those of peripheral GCG and cherubism appearing slightly distinct, while central GCG shows overlap with both of the former. NOF, ABC, GCTB, and chondroblastoma, on the other hand, have distinct methylation patterns. The global and enhancer-associated CpG DNA methylation values showed a similar distribution pattern among central and peripheral GCG and cherubism, with cherubism showing the lowest and peripheral GCG having the highest median values. By contrast, promoter regions showed a different methylation distribution pattern, with cherubism showing the highest median values. In conclusion, DNA methylation profiling is currently not capable of clearly distinguishing sporadic and cherubism-associated giant cell lesions. Conversely, it could discriminate sporadic GCG of the jaws from their giant cell-rich mimics (NOF, ABC, GCTB, and chondroblastoma).

Response of Central Giant Cell Granuloma of the Jaw to Imatinib.

Central giant cell granuloma of the jaw (CGCJ) can be locally aggressive and result in facial and dental deformity. A child with CGCJ was treated surgically and with denosumab with a response but life-threatening toxicity. Imatinib, a tyrosine kinase inhibitor, was prescribed based on clinical similarities between CGCJ and cherubism, for which Imatinib has been effective. Within 2 months, a computed tomographic scan showed significant ossification, which increased over the following 8 months. This case suggests that tyrosine kinase inhibitors may be an effective option, and one with limited toxicity, for CGCJ.

Cherubism in three siblings. / A cherubismus elofordulása három testvérben.

Összefoglaló. A cherubismus ritka, autoszomális dominánsan öröklodo megbetegedés. A fibroossealis elváltozások csoportjába tartozik. Jellemzoje az állcsontok szimmetrikus duzzanata, a típusos radiológiai elváltozások és az SH3BP2-gén mutációja. Szövettanilag nem különül el az óriássejtes granulomától. A csontelváltozások és a fibroticus szövet felszaporodása pubertás elott kezdodik, ezután stagnálás vagy visszafejlodés következik be. A magyar orvosi irodalomban a szerzok elsoként tárgyalják három testvér kórtörténete alapján a cherubismust. A diagnózist a hasonló klinikai tünetek, a típusos kórlefolyás, a szinte azonos radiológiai kép, a szövettan és a genetikai elváltozások biztosítják. A testvérek és az anya csíravonalában kimutatott azonos mutáció akkor is megfelel egy dominánsan öröklodo szindrómának (például cherubismusnak), ha a betegség az anyában klinikailag nem manifesztálódott, de genetikailag igen. A szerzok összefoglalják a kórkép kezelési lehetoségeit: a sebészi (excochleatio, ,,decountouring", esetleg reszekció) és a gyógyszeres (biszfoszfonát, kalcitonin, szteroid stb.) terápiát. Egyezik a véleményük azokéval, akik azon az állásponton vannak, hogy a beavatkozásokkal várni kell, és meg kell figyelni a betegeket a várható regresszió miatt. Saját eseteikben csak a növekvo tumorrész excochleatióját végezték, foleg kozmetikai okok és a szövettan biztosítása érdekében. Orv Hetil. 2022; 163(11): 446-452. Summary. Cherubism is a rare autosomal, dominant bone disorder, characterised by symmetrical expansion of the jaws along the typical radiological and genetic (SH3BP2 mutation) features. It belongs to the heterogenous group of fibro-osseous lesions. Its histology is the same as that of giant-cell granuloma. The bone lesions and fibrous tissue expansion increase before puberty and regress thereafter. For the first time in Hungarian medical literature, the authors discuss the condition of cherubism in the case of three siblings. The diagnosis of these three siblings is supported by the clinical, radiological, microscopic and genetic data. In all three, the bone lesions and fibrous tissue expansion increased before puberty and stabilized thereafter. The radiological results and the molecular findings were nearly identical. The identical mutation shown in the germ lines of the three siblings and the mother correspond to a dominantly inherited syndrome (e.g., cherubism) even if the condition did not manifest in the mother. The authors summarize the treatment options of the disease: surgical (excochleation, decountouring, in rare case resection) and drug (bisphosphonate, calcitonin, steroid, etc.) therapy. They agree with those who are of the opinion that interventions should wait and the patients should be observed ("wait and see") for the expected regression. In their own cases, only excochleation of the growing tumor was performed, mainly for cosmetic reasons and to secure the tissue. Orv Hetil. 2022; 163(11): 446-452.

Late reactivation of cherubism in an adult further to local inflammation.

Cherubism is a rare pediatric disease affecting the jaw. It appears among children between 2 and 5 years old. Maximum growth is observed at 7-8 years old, then lesions remain unchanged or increase slowly until puberty. Only 2 cases of later growth have been reported. We describe a case of cherubism reactivation in a 46-year-old woman. Appearance of a new lesion occurs in a context of local inflammation due to repeated friction of the dental prosthesis on the mandible. No article in the literature describes a similar case. This case shows the determining role of inflammation (local or general) in the pathophysiology of cherubism.

Early detection of cherubism with eventual bilateral progression: a literature review and case report.

Cherubism is a rare familial disease of childhood that commonly affects the bilateral mandible and maxilla and typically resolves in adulthood. It has been shown to have a male predilection and has been mapped to the SH3 BP2 gene. Only 2 cases of unilateral cherubism have been documented in the literature; in the first case, the contralateral side was eventually affected. Although rare, unilateral cherubism presents a diagnostic dilemma. This case report describes a unique presentation of unilateral cherubism that progressed to affect the contralateral side and describes some of the considerations in the diagnosis and treatment of unilateral benign giant cell lesions of the jaws.

Homozygous mutation in ELMO2 may cause Ramon syndrome.

We report on a girl, born to first cousin Lebanese parents, with intellectual disability, seizures, repeated gingivorrhagia, enlarged lower and upper jaws, overgrowth of the gums, high arched and narrow palate, crowded teeth, hirsutism of the back, large abdomen and a small umbilical hernia. Cysts of the mandible, fibrous dysplasia of bones, and enlarged adenoids causing around 60% narrowing of the nasopharyngeal airways were noted at radiographic examination. Her brother presented with the same features in addition to a short stature, an ostium secundum, and more pronounced intellectual disability. He died at the age of 8 years from a severe pulmonary infection and repeated bleeding episodes. A clinical diagnosis of Ramon syndrome was made. Whole exome sequencing studies performed on the family revealed the presence of a novel homozygous missense mutation in ELMO2 gene, p.I606S in the affected individuals. Loss of function mutations in ELMO2 have been recently described in another clinically distinct condition: primary intraosseous vascular malformation or intraosseous hemangioma, called VMOS. Review of the literature and differential diagnoses are discussed.

Clinical factors in prosthodontic treatment of children with genetic defects.

BACKGROUND: Prosthodontic treatment of children with genetic disorders is an area that is rarely examined in the current specialist literature. Few prosthodontists will undertake treatment of such patients, who will more often be referred to an orthodontic specialist. After examining the 4 cases of children with genetic disorders described in this paper, it can be concluded that when a prosthodontist includes a few additional procedures in the treatment process, he or she can successfully help such patients. OBJECTIVES: The aim of this paper is to indicate the clinical difficulties faced by prosthodontists who undertake prosthodontic rehabilitation of children with genetic disorders. MATERIAL AND METHODS: The paper is based on data collected during the prosthodontic treatment of 4 children, aged 5-12 years with genetic defects, and analysis of the body of work concerning these defects and their treatment. RESULTS: Presentation of guidelines for the prosthodontic treatment process and creation of dentures for treated children based on extended procedures. CONCLUSIONS: A prosthodontist is a crucial person in a team of specialists treating disorders within the face among children with a genetic predisposition. A basic knowledge of orthodontics and psychology facilitates the treatment. Prosthetic restoration in the treatment group does not always require complicated operations. Individualization of the tools for downloading orthodontic impressions, designing denture elements and an increased number of checkups are the additional procedures. For the clinician, the emotional aspect of the treatment is the main impediment. Maintaining a good relationship with a patient and his or her caregivers requires interpersonal skills.

Bone-Related Lesions of the Jaws.

The jaws combine several unique properties that mainly result from their distinct embryonic development and their role in providing anchorage for the teeth and their supporting structures. As a consequence, several bone-related lesions almost exclusively develop in the jaws (eg, osseous dysplasias, ossifying fibromas), have distinct clinical features (eg, osteosarcoma), or hardly ever occur at this location (eg, osteochondroma, enchondroma). The specific characteristics of these tumors and tumorlike lesions are outlined in this article.

Cherubism. A case report.

Cherubism is a rare disorder with autosomal dominant inheritance. It is classified as a benign fibro-osseous lesions and may involve either facial bone. Its typical dentofacial deformities are caused by mutations in the SH3BP2 gene. The protein encoded by SH3BP2 had a significant role in the regulation of osteoblasts and osteoclasts. Accordingly with the radiological findings, differential diagnoses includes fibrous dysplasia, giant cell granuloma, osteosarcoma, juvenile ossifying fibroma, fibrous osteoma, odontogenic cyst and hyperparathyroidism. The aim of the present report is twofold. First, we examine the importance of the proper management of these cases. Second, we describe this rare syndrome with the goal of proposing suitable treatments.

Defining a new aggressiveness classification and using NFATc1 localization as a prognostic factor in cherubism.

Cherubism is a rare genetic disease characterized by bilateral giant cell reparative granuloma of the jaws consisting of a fibrotic stroma with giant multinucleated cells (GMCs) and osteoclastic features. Cherubism severity is highly variable, and recurrence after surgery is the most important risk. Currently, there are no prognostic indicators. The aims of this study were to evaluate the osteoclastogenesis phenotype by histologic examination of nuclear factor of activated T cells 1 (NFATc1) localization and tartrate-resistant acid phosphatase (TRAP) activity and to correlate the results to disease aggressiveness to define prognostic indicators. Based on cherubism evolution 1 year after surgery, 3 classes of cherubism aggressiveness were identified: mild (group A), moderate (group B), and severe (group C). Histologically, in grade A and B cherubism lesions, GMCs were negative for both TRAP activity and NFATc1 nuclear localization. In contrast, in grade C cherubism lesions, GMCs were all positive for TRAP activity and NFATc1 nuclear localization and displayed osteoclast-like features. Other histopathologic findings were not different among the 3 groups. Our results establish that TRAP activity and NFTAc1 nuclear localization are associated with aggressive cherubism and therefore could be added to routine pathologic examination to aid in prognosis and management of the disease. The finding of NFATc1 nuclear localization in aggressive tumors supports the addition of anticalcineurin treatment to the therapeutic arsenal for cherubism.

Cherubism With Bilateral Mandible and Maxilla Involvement: A Case Report.

Cherubism is a rare, nonneoplastic, self-limiting fibro-osseous that occurs in children. Affected children usually appear normal at birth. Lesions are characterized by the replacement of bone with fibrovascular tissue containing many multinucleated giant cells. Most studies have reported cherubism to be familial and with bilateral involvement of the mandibles. The authors describe a nonfamilial case of cherubism, involving both the mandible and the maxilla, in a 4-year-old female child with slowly enlarging, painless, symmetrical swelling of both cheeks.Cherubism is a rare disease that is usually limited to the mandible, but the maxilla may be involved. Computed tomography scan and biopsy are helpful for early diagnosis.

Bone markers in craniofacial bone deformations and dysplasias.

Various forms of bony deformations and dysplasias are often present in the facial skeleton. Bone defects can be either localized or general. Quite often they are not only present in the skull but also can be found in other parts of the skeleton. In many cases the presence and levels of specific bone markers should be measured in order to fully describe their activity and presence in the skeleton. Fibrous dysplasia (FD) is the most common one in the facial skeleton; however, other bone deformations regarding bone growth and activity can also be present. Every clinician should be aware of all common, rare and uncommon bony diseases and conditions such as cherubism, Paget's disease, osteogenesis imperfecta and others related to genetic conditions. We present standard (calcium, parathyroid hormone, calcitonin, alkaline phosphatase, vitamin D) and specialized bone markers (pyridinium, deoxypyridinium, hydroxyproline, RANKL/RANK/OPG pathway, growth hormone, insulin-like growth hormone-1) that can be used to evaluate, measure or describe the processes occurring in craniofacial bones.

Ophthalmic manifestations of cherubism.

Cherubism is a rare craniofacial disorder characterized by progressive replacement of mandibular and maxillary bone with multicystic fibro-osseous tissue, potentially resulting in significant deformity and morbidity. The severity of the disorder is variable; more advanced disease may affect the orbit and impact vision. We detail the ophthalmological findings in 2 patients, 7 and 8 years of age, with cherubism.

Cherubism: report of three cases and literature review.

PURPOSE: To report 3 cases of cherubism, one of whom underwent surgery for orbital manifestations, and to provide a literature review. CASE REPORTS: Our patients were normal at birth and developed painless enlarging of the cheeks and jaws when they were 4-5 years old. Ophthalmologic examinations showed mild proptosis, superior globe displacement and inferior scleral show in all cases. Cases 2 and 3 had lower lid skin discoloration. Computed tomography (CT) scans demonstrated bilateral multicystic lesions in the maxilla and mandible with cortical thinning in all cases. In Case 3, left eye hyperglobus and anisometropic amblyopia was seen. In this case, the CT scan showed a round, well-defined and homogeneous mass, involving the anterior and superior walls of the maxillary sinus on the left side, extending into inferior orbit. Debulking of the mass was performed at the surgery. The pathologic findings were compatible with the diagnosis of giant cell reparative granuloma. He returned 1 year after surgery with recurrence of the mass. DISCUSSION: A few cases were reported in the literature with histopathologically proven orbital cherubism. To our knowledge, lower lid skin discoloration in Cases 2 and 3 and anisometropic amblyopia in case 3 were not described elsewhere in cherubism cases. We recommend that all cases with cherubism must be examined by an ophthalmologist to diagnose and treat possible orbital manifestations.