Genetically confirmed coexistence of neurofibromatosis type 1 and Cherubism in a pediatric patient.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder typified by various combination of numerous Café-au-lait macules, cutaneous and plexiform neurofibromas, freckling of inguinal or axillary region, optic glioma, Lisch nodules and osseous lesions. Cherubism is a rare genetic syndrome described by progressive swelling of the lower and/or upper jaw due to replacement of bone by fibrous connective tissue. Patients are reported in the literature with NF1 and cherubism-like phenotype due to the NF1 osseous lesions in the jaws. The purpose of this case report is the description of a young male genetically diagnosed with both NF1 and cherubism. METHODS AND RESULTS: A 9 years and six month old patient with clinical findings of NF1 and cherubism in whom both diseases were genetically confirmed, is presented. The patient was evaluated by a pediatrician, a pediatric endocrinologist, an ophthalmologist, and an oral and maxillofacial surgeon. A laboratory and hormonal screening, a histological examination, a chest X-ray, a magnetic resonance imaging (MRI) of the orbit and a digital panoramic radiography were performed. Genetic testing applying Whole Exome Sequencing was conducted. CONCLUSIONS: A novel and an already reported pathogenic variants were detected in NF1 and SH3BP2 genes, respectively. This is the first described patient with coexistence of NF1 and cherubism. The contribution of Next Generation Sequencing (NGS) in gene variant identification as well as the importance of close collaboration between laboratory scientists and clinicians, is highlighted. Both are essential for optimizing the diagnostic approach of patients with a complex phenotype.

Efficacy and Toxicity of Calcitonin Treatment in Children with Cherubism: A Single-Center Cohort Study.

Cherubism is a rare autosomal dominant disease characterized by expansile osteolytic jawbone lesions. The effect and safety of off-label calcitonin treatment during the progressive phase of the disease are not well described. In this retrospective study, we present data on the radiological response and adverse effects of subcutaneously administered calcitonin in a cohort of nine cherubism children (three female, six male). Two of the nine patients underwent two separate treatment courses with a significant off-treatment interval in between; therefore, a total of 11 treatment courses with a mean duration of 17.9 months (range <1 to 35, SD 10.8) were studied. To measure the response, the cumulative volume of cherubism lesions was calculated from available three-dimensional imaging. The primary outcome was the change in the volume of lesions during calcitonin treatment and only assessed for the eight treatment courses with a minimal duration of 6 months. A statistically significant reduction in the mean cumulative volume of lesions was seen regardless of treatment duration. Average volume reduction was highest in the first half year of treatment, with a gradual, ongoing reduction thereafter. For the secondary outcome, the change in the cumulative volume of lesions after treatment cessation was assessed for the seven treatment courses with follow-up imaging available. After six of these seven treatment courses, the cumulative volume increased again but remained undoubtedly smaller than the initial volume at the start of therapy. Adverse effects were assessed for all 11 treatment courses and occurred in 73% of them. Most adverse effects were mild and low grade, with the most severe being one grade 3 symptomatic hypocalcemia requiring hospitalization and early treatment termination. Calcitonin treatment seems effective and tolerable in treating actively progressing cherubism in children. However, further research is required to better understand the pharmacological treatment of cherubism, including also other drugs, dosing, and protocols. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Current concepts in targeted therapies for benign tumors of the jaw - A review of the literature.

The aim of our study was to review current concepts in targeted therapies for benign tumors of the jaw. Benign odontogenic and maxillofacial bone tumors often require radical surgery, with consequent morbidity that impacts patients' postsurgical quality of life. Currently, targeted therapies and novel nonsurgical therapeutics are being explored for management of non-resectable tumors, with the aim of avoiding surgery or minimizing surgical scope. However, data on clinical applications of targeted therapies for benign tumors of the jaw remain sparse. Therefore, a literature review was conducted, based on the PubMed database, which included in vivo human clinical studies describing clinical application of targeted therapy for benign tumor of the jaw. The review assessed the outcomes of BRAF and MEK inhibitors for treatment of ameloblastoma, RANKL monoclonal antibody for treatment of giant cell tumor, cherubism, aneurysmal bone cyst, and fibrous dysplasia, and tyrosine kinase inhibitor for treatment of odontogenic myxoma and cherubism. Targeted therapies decreased tumor size, slowed down tumor progression, and reduced bone pain. Surgery remains the gold standard, but targeted therapies are promising adjuvant or alternative treatment options for reducing tumor progression and morbidity of tumor surgery.

Surgical management of mandibular cherubism in an adolescent: integration of virtual surgical planning.

Cherubism, also known as familial fibrodysplasia of the jaw, is an autosomal dominant disorder with variable penetrance. The disease process is characterised by painless and progressive bilateral enlargement of the maxillofacial skeleton. We present an adolescent female with a family history of cherubism who presented to the Oral and Maxillofacial Surgery clinic with progressive bilateral swelling of the mandible. The diagnosis of cherubism was established through a thorough history which was confirmed with an incisional biopsy. The progressive swelling negatively affected her appearance and psychosocial well-being. The patient opted for surgical intervention after a course of conservative management. Although there is often resolution of these lesions into adulthood, surgical intervention may be considered when managing this condition in adolescence. Integration with virtual surgical planning can aid in obtaining desired postoperative outcomes.

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).

E3-ubiquitin ligases and recent progress in osteoimmunology.

Ubiquitin-mediated proteasomal degradation is a post-transcriptional protein modification that is comprised of various components including the 76-amino acid protein ubiquitin (Ub), Ub-activating enzyme (E1), Ub-conjugating enzyme (E2), ubiquitin ligase (E3), deubiquitinating enzyme (DUB) and proteasome. We and others have recently provided genetic evidence showing that E3-ubiquitin ligases are associated with bone metabolism, the immune system and inflammation through ubiquitylation and subsequent degradation of their substrates. Dysregulation of the E3-ubiquitin ligase RNF146-mediated degradation of the adaptor protein 3BP2 (SH3 domain-binding protein 2) causes cherubism, an autosomal dominant disorder associated with severe inflammatory craniofacial dysmorphia syndrome in children. In this review, on the basis of our discoveries in cherubism, we summarize new insights into the roles of E3-ubiquitin ligases in the development of human disorders caused by an abnormal osteoimmune system by highlighting recent genetic evidence obtained in both human and animal model studies.

PARsylation-mediated ubiquitylation: lessons from rare hereditary disease Cherubism.

Modification of proteins by ADP-ribose (PARsylation) is catalyzed by the poly(ADP-ribose) polymerase (PARP) family of enzymes exemplified by PARP1, which controls chromatin organization and DNA repair. Additionally, PARsylation induces ubiquitylation and proteasomal degradation of its substrates because PARsylation creates a recognition site for E3-ubiquitin ligase. The steady-state levels of the adaptor protein SH3-domain binding protein 2 (3BP2) is negatively regulated by tankyrase (PARP5), which coordinates ubiquitylation of 3BP2 by the E3-ligase ring finger protein 146 (RNF146). 3BP2 missense mutations uncouple 3BP2 from tankyrase-mediated negative regulation and cause Cherubism, an autosomal dominant autoinflammatory disorder associated with craniofacial dysmorphia. In this review, we summarize the diverse biological processes, including bone dynamics, metabolism, and Toll-like receptor (TLR) signaling controlled by tankyrase-mediated PARsylation of 3BP2, and highlight the therapeutic potential of this pathway.

Pharmacological management of cherubism: A systematic review.

Objective: The aim of this systematic review was to determine if there exists an efficacious drug treatment for cherubism, based on published studies. Methods: This systematic review included observational case studies reporting pharmacological management of cherubism. We developed specific search strategies for PubMed (including Medline), ScienceDirect, Web of Science. We evaluated the methodological quality of the included studies using criteria from the Joanna Briggs Institute's critical appraisal tools. Results: Among the 621 studies initially identified by our search script, 14 were selected for inclusion, of which five were classified as having a low risk of bias, four as having an unclear risk, and five a high risk. Overall, 18 cherubism patients were treated. The sample size in each case study ranged from one to three subjects. This review identified three types of drugs used for cherubism management: calcitonin, immunomodulators and anti-resorptive agents. However, the high heterogeneity in case reports and the lack of standardized outcomes precluded a definitive conclusion regarding the efficacy of any treatment for cherubism. Conclusions: The present systematic review could not identify an effective treatment for cherubism due to the heterogeneity and limitations of the included studies. However, in response to these shortcomings, we devised a checklist of items that we recommend authors consider in order to standardize the reporting of cherubism cases and specifically when a treatment is given toward identification of an efficacious cherubism therapy. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022351044, identifier CRD42022351044.

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.

Imatinib has minimal effects on inflammatory and osteopenic phenotypes in a murine cherubism model.

OBJECTIVE: Cherubism is a genetic disorder characterised by bilateral jawbone deformation. The associated jawbone lesions regress after puberty, whereas severe cases require surgical treatment. Although several drugs have been tested, fundamental treatment strategies for cherubism have not been established. The effectiveness of imatinib has recently been reported; however, its pharmaceutical mechanism remains unclear. In this study, we tested the effects of imatinib using a cherubism mouse model. METHODS: We used Sh3bp2 P416R cherubism mutant mice, which exhibit systemic organ inflammation and osteopenia. The effects of imatinib were determined using primary bone marrow-derived macrophages. Imatinib was administered intraperitoneally to the mice, and serum tumour necrosis factor-α (TNFα), organ inflammation and bone properties were examined. RESULTS: The cherubism mutant macrophages produced higher levels of TNFα in response to lipopolysaccharide compared to wild-type macrophages, and imatinib did not significantly suppress TNFα production. Although imatinib suppressed osteoclast formation in vitro, administering it in vivo did not suppress organ inflammation and osteopenia. CONCLUSION: The in vivo administration of imatinib had a minimal therapeutic impact in cherubism mutant mice. To establish better pharmaceutical interventions, it is necessary to integrate new findings from murine models with clinical data from patients with a definitive diagnosis of cherubism.

Denosumab Therapy in Cherubism.

Cherubism is a rare disorder characterized by proliferative fibro-osseous lesions that result in bilateral bony hyperplasia of the face. Management varies based on symptom severity and includes longitudinal follow-up, pharmacotherapy, and/or surgical debulking. Off-label treatment with denosumab, a human monoclonal antibody that binds RANKL and inhibits osteoclast function to reduce bone resorption, can be beneficial in suppressing the proliferation of bone to minimize the need for surgery and to control postoperative reproliferation. Close follow-up is needed to maintain appropriate electrolyte levels. The present case demonstrates the achievement of symptomatic control with denosumab in a child with severe refractory cherubism.

Cherubism in Saudi population: a rare case report / Querubismo na população Saudi: relato de um caso raro

Cherubism is a rare hereditary benign fibro-osseous disorder characterised by bilateral swelling of the mandible and/or maxilla with varying severity of involvement. It occurs because of dominant mutations in SH3BP2 gene on the chromosome 4p16.3. On radiography cherubic lesions appear as multilocular cystic radiolucencies in the jaw bones giving a soap bubble appearance. These lesions usually heal by themselves by the time the patient attains puberty. Treatment is necessary only in aggressive cases where there is severe facial deformity or vital functions are hampered. Surgical corrections are preferred when the lesion is in its dormant phase. The aim of the present case report is to illustrate a case of cherubism in a 9-year-old Saudi boy which is a very rare occurrence as only 1 case of cherubism has been reported so far in the Saudi Arabian population (AU)

Querubismo é uma desordem fibro-óssea hereditária rara caracterizada por aumento de volume bilateral da mandíbula e/ou maxila com graus variáveis de severidade. Ocorre devido a mutação dominante no gene SH3BP2 no cromossomo 4p16.3. Radiograficamente as lesões de querubismo aparecem como radiolucência multilocular semelhantes a bolhas de sabão nos ossos maxilares. Geralmente as lesões involuem espontaneamente quando o paciente atinge a puberdade. O tratamento se faz necessário apenas nos casos mais agressivos que demonstram deformidade facial severa ou comprometimento de funções vitais. Correções cirúrgicas são preferíveis quando a lesão está na fase dormente. O objetivo do presente relato é ilustrar um caso de querubismo em um paciente de 9 anos da Arábia Saudita, sendo este um evento raríssimo com apenas um outro caso relatado na população da Arábia Saudita (AU)

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.

[Bilateral giant cell central granuloma of the jaws in a Noonan syndrome: About one case with emphasizing on bone giant cell lesions of the jaws]. / Granulome central à cellules géantes des maxillaires bilatéral dans le cadre d'un syndrome de Noonan : à propos d'un cas avec mise au point sur les lésions osseuses riches en cellules géantes des maxillaires.

We report the case of a 10-year-old child with bilateral mandibular localization of a central giant cell granuloma occurring in the setting of Noonan syndrome. The histological appearance was classic with two intermigled components, one fibrous with non-atypical mononuclear cells, the other consisting of numerous osteoclast-like giant cells. This aspect is similar to that observed in the brown tumor as well as that of cherubism, which can also give multiple bone lesions. We will discuss the other lesions to consider in case of benign giant cell bone lesions affecting the jawbones, sometimes multiple and part of which falls within the scope of RASopathies.

Surgical Treatment of Cherubism With the Use of ThreeDimensional Virtual Planning and CAD-CAM Resection Guides: A Case Report and Systematic Literature Review.

ABSTRACT: We report the use of a three-dimensional virtual surgical planning technique including both fusion and superimposition to obtain harmony and symmetry of the face in an 18-year-old woman suffering from cherubism. The treatment contained several threedimensional techniques that allowed precise planning and a predictable surgical outcome. The reduction plasty was successful, and the postoperative healing was uneventful. No relapse of the disease occurred after the surgical treatment and the sensation of the mentalis area recovered. The patient was satisfied with the aesthetic result and no additional surgery was needed. The surgical planning techniques described, and the CAD/CAM patient-specific resection guides seems to be safe and reliable in a one-step surgical treatment of cherubism patients after the disease has clearly ceased based on radiological findings. A systematic review of the literature on surgical correction of deformities due to cherubism was conducted. The systematic review of the existing literature was performed on the available studies from PubMed and Ovid Medline published before June 9, 2020. The search term was ''Cherubism.'' The inclusion criteria were: 1) full article published in English and 2) the patient had surgical treatment. We excluded the cases that included only minor surgery as biopsy or only treatment of unerupted teeth. The database identified 638 citations of which 50 met the eligibility criteria. The systematic review revealed no earlier use of surgical 3D planning in the treatment of cherubism.

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.

SH3BP2-related fibro-osseous disorders of the maxilla and mandible: A systematic review.

Cherubism is a disorder of bony overgrowth of the jaws that manifests in childhood. SH3BP2 gene variants have been associated with cherubism; this gene plays a major role in bone homeostasis. Due to its rare occurrence, there is as yet no comprehensive understanding of the natural history and clinical course of the disease. The aim of this review was to compile and analyze all cases of SH3BP2-related cherubism and cherubism-like disorders. Thirty publications were identified, including 92 individuals from 34 families, who were diagnosed with SH3BP2-related fibro-osseous lesions of the jaw. Only 15% of cases included in this review had no known family history of the disease. The distribution of cherubism was equal with respect to biological sex. Missing teeth were reported in 38% of cases. Lesions were restricted to the mandible in 36% of cases and involved both the maxilla and mandible in 54% of cases. The clinical phenotypes reported in the articles analyzed varied greatly in detail, making comparisons between studies and conclusive analysis difficult. Further work is necessary to describe the connection between SH3BP2 gene variants and cherubism in order to advance its diagnosis and treatment.

Crecimiento mandibular bilateral: un caso de querubismo / Bilateral swelling of the jaws: a case of querubism

El querubismo es una displasia ósea benigna de la infancia caracterizada por un crecimiento mandibular bilateral progresivo. Presenta herencia autosómica dominante y es más frecuente en varones. Las primeras manifestaciones aparecen en torno a los dos años de edad, con un crecimiento óseo acelerado a los 8-9 años e interrupción espontánea tras la pubertad. El diagnóstico se basa en la clínica, radiología y anatomía patológica. El tratamiento es controvertido, incluyendo tratamiento médico o quirúrgico. Presentamos el caso de un varón de nueve años que consultó por crecimiento mandibular bilateral, requiriendo finalmente extirpación quirúrgica de las lesiones (AU)

Cherubism is a benign bone dysplasia characterized by bilateral progressive enlargement of the jaws. It is an autosomal dominant disease and boys are more affected than girls. The first signs of manifestation of the disease are generally observed at about two years of age, followed by accelerated growth from 8-9 years of age and spontaneous interruption after puberty. The diagnosis is based on clinical, radiographic and histopathologic findings. Treatment is a controversial issue and therapy strategies include surgical treatment and medical treatment. We describe the case of a nine-year-old boy with bilateral swelling of the jaws who required surgical treatment. (AU)

Cherubism and anaesthesia.

Respiratory complications are one of the main problems in paediatric anaesthesia. Cherubism is a rare fami-lial disease causing enlargement of the mandible that may be associated with difficult intubation [1, 2]. A 5-year-old, 20 kg, ASA 1, healthy girl was evaluated for anaesthesia requested for the removal of mandibular lesions (Figure 1). She had a positive family history of cherubism; her father and cousins were affected. Radiogra-phically, the lesions demonstrated multilocular, expansile radiolucencies with mandibular enlargement. The preoperative examination was unremarkable: normal neck flexion, no trismus, and a Mallampati score of 1. A venous catheter was inserted peripherally under N2O inhalation and transdermic lidocaine and prilocaine patch. The general anaesthesia combined sevoflurane and IV sufentanil. Nasotracheal intubation under direct laryngoscopy was uneventful. After the surgery, which lasted 120 minutes, she was admitted to the post anaesthesia care unit for 1 night and discharged the next day without any sequelae.