Structural basis and sequence rules for substrate recognition by Tankyrase explain the basis for cherubism disease.

The poly(ADP-ribose)polymerases Tankyrase 1/2 (TNKS/TNKS2) catalyze the covalent linkage of ADP-ribose polymer chains onto target proteins, regulating their ubiquitylation, stability, and function. Dysregulation of substrate recognition by Tankyrases underlies the human disease cherubism. Tankyrases recruit specific motifs (often called RxxPDG "hexapeptides") in their substrates via an N-terminal region of ankyrin repeats. These ankyrin repeats form five domains termed ankyrin repeat clusters (ARCs), each predicted to bind substrate. Here we report crystal structures of a representative ARC of TNKS2 bound to targeting peptides from six substrates. Using a solution-based peptide library screen, we derive a rule-based consensus for Tankyrase substrates common to four functionally conserved ARCs. This 8-residue consensus allows us to rationalize all known Tankyrase substrates and explains the basis for cherubism-causing mutations in the Tankyrase substrate 3BP2. Structural and sequence information allows us to also predict and validate other Tankyrase targets, including Disc1, Striatin, Fat4, RAD54, BCR, and MERIT40.

Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism.

Cherubism is an autosomal-dominant syndrome characterized by inflammatory destructive bony lesions resulting in symmetrical deformities of the facial bones. Cherubism is caused by mutations in Sh3bp2, the gene that encodes the adaptor protein 3BP2. Most identified mutations in 3BP2 lie within the peptide sequence RSPPDG. A mouse model of cherubism develops hyperactive bone-remodeling osteoclasts and systemic inflammation characterized by expansion of the myelomonocytic lineage. The mechanism by which cherubism mutations alter 3BP2 function has remained obscure. Here we show that Tankyrase, a member of the poly(ADP-ribose)polymerase (PARP) family, regulates 3BP2 stability through ADP-ribosylation and subsequent ubiquitylation by the E3-ubiquitin ligase RNF146 in osteoclasts. Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the SRC, SYK, and VAV signaling pathways.

New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs.

Poly(ADP-ribose) polymerases (PARPs) are enzymes that transfer ADP-ribose groups to target proteins and thereby affect various nuclear and cytoplasmic processes. The activity of PARP family members, such as PARP1 and PARP2, is tied to cellular signalling pathways, and through poly(ADP-ribosyl)ation (PARylation) they ultimately promote changes in gene expression, RNA and protein abundance, and the location and activity of proteins that mediate signalling responses. PARPs act in a complex response network that is driven by the cellular, molecular and chemical biology of poly(ADP-ribose) (PAR). This PAR-dependent response network is crucial for a broad array of physiological and pathological responses and thus is a good target for chemical therapeutics for several diseases.

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.

Nonfamilial cherubism in a 6-month-old infant: a case report.

BACKGROUND: Cherubism is known as a very rare autosomal dominant familial disorder of childhood caused by a mutation in the SH3BP2 gene on 4p16.3. It has not yet been observed at birth and is usually diagnosed in children aged 2-7. Here, we present a non-hereditary case of cherubism at a very early age. CASE PRESENTATION: A 6-month-old girl presented with bilateral progressive jaw enlargement. On physical examination, bilateral asymmetrical jaw enlargement, predominantly on the left side, and some enlarged, non-tender, mobile submandibular lymph nodes were detected. No other abnormality was observed. Further investigations with radiology suggested cherubism and Burkitt's lymphoma as differential diagnoses. Later on, histopathologic evaluations were suggestive of cherubism. No surgical interventions were indicated, and the child is on regular follow-ups. CONCLUSION: Non-hereditary Cherubism, despite scarcity, can present in children below two years of age, even as early as the beginning of primary dentition. Accurate and swift diagnosis is essential to avert physical and psychological complications. Our case report shows the importance of keeping cherubism in mind as a differential diagnosis of bone disease, even in children under a year old, and the value of interdisciplinary collaboration in dealing with rare genetic disorders.

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.

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.

[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.

Adjuvant Alendronic Acid in the Management of Severe Cherubism: A Case Report and Literature Review.

Cherubism is a rare disease of the jaws characterized by bilateral symmetrical painless expansion of the mandible and maxilla. In extreme cases, larger lesions can become exophytic and have profound functional and esthetic implications. Several pharmacologic agents have been trialed in the treatment of cherubism with variable success reported. Bisphosphonates have not been significantly studied in this setting. We present a case where oral alendronic acid was used as an adjuvant treatment after surgical debulking of the maxilla in a 13-year-old boy with a severe case of cherubism.

An Overview of the Derivation and Function of Multinucleated Giant Cells and Their Role in Pathologic Processes.

Monocyte lineage cells play important roles in health and disease. Their differentiation into macrophages is crucial for a broad array of immunologic processes that regulate inflammation, neoplasia, and infection. In certain pathologic conditions, such as foreign body reactions and peripheral inflammatory lesions, monocytes fuse to form large, multinucleated giant cells (MGCs). Currently, our knowledge of the fusion mechanisms of monocytes and the regulation of MGC formation and function in discrete pathologies is limited. Herein, we consider the types and function of MGCs in disease and assess the mechanisms by which monocyte fusion contributes to the formation of MGCs. An improved understanding of the cellular origins and metabolic functions of MGCs will facilitate their identification and ultimately the treatment of diseases and disorders that involve MGCs.

Positive Outcomes of Denosumab Treatment in 2 Patients With Cherubism.

Cherubism is a rare autosomal dominant disease whose severity ranges widely, from asymptomatic to life-threatening. Bilateral symmetrical painless expansion of the mandible and maxilla resulting in a typical appearance of the face resembling a cherub, are the highlighted features of the condition. In most cases, cherubism-induced lesions in the jaws appear around the age of 3 years and tend to expand and increase in numbers until puberty. Treatment options for cherubism range from observation to surgical correction and various pharmacologic therapies. Given the excess sensitivity of cherubism osteoclasts to RANKL (receptor activator of nuclear factor κB ligand) and the positive effects of denosumab (XGEVA; Amgen, Thousand Oaks, CA) treatment in patients with giant cell granuloma, we have designed a treatment based on denosumab for 2 cherubism patients that achieves what we consider promising results.

True Unilateral Mandibular Cherubism: A Literature Review and Case Report.

Cherubism is a self-limiting fibro-osseous disorder that is classically characterized by bilateral mandibular swelling in the first or second decade of life. Three cases of unilateral cherubism have been described in the literature; however, bilateral involvement did not eventually develop in only 1 case. Histopathologic variation and genetic heterogeneity complicate the diagnosis and treatment of a unilateral benign giant cell lesion of the jaws. Our case report presents a 13-year-old male patient with unilateral posterior mandibular swelling that proved to be histologically and clinically consistent with unilateral cherubism. Involution of the unilateral lesion with no bilateral involvement occurred during 8 years of serial examination.

Cherubism as a systemic skeletal disease: evidence from an aggressive case.

BACKGROUND: Cherubism is a rare autosomal dominant genetic condition caused by mutations in the SH3BP2 gene. This disease is characterized by osteolysis of the jaws, with the bone replaced by soft tissue rich in fibroblasts and multinuclear giant cells. SH3BP2 is a ubiquitous adaptor protein yet the consequences of SH3BP2 mutation have so far been described as impacting only face. Cherubism mouse models have been generated and unlike human patients, the knock-in mice exhibit systemic bone loss together with a systemic inflammation. CASE PRESENTATION: In light of these observations, we decided to search for a systemic cherubism phenotype in a 6-year-old girl with an aggressive cherubism. We report here the first case of cherubism with systemic manifestations. Bone densitometry showed low overall bone density (total body Z-score = - 4.6 SD). Several markers of bone remodelling (CTx, BALP, P1NP) as well as inflammation (TNFα and IL-1) were elevated. A causative second-site mutation in other genes known to influence bone density was ruled out by sequencing a panel of such genes. CONCLUSIONS: If this systemic skeletal cherubism phenotype should be confirmed, it would simplify the treatment of severe cherubism patients and allay reservations about applying a systemic treatment such as those recently published (tacrolimus or imatinib) to a disease heretofore believed to be localised to the jaws.

A Paradigm Shift in the Management of Cherubism? A Preliminary Report Using Imatinib.

Cherubism is an autosomal-dominant inherited mutation in the SH3BP2 gene on chromosome 4p16.3. It is characterized by bilateral symmetric fibro-osseous lesions that are limited to the maxilla and mandible. The lesions present in early childhood and typically spontaneously involute after puberty. Current standard practice is to reserve surgery for symptomatic or severely disfiguring cases. This report presents 3 patients with cherubism who exhibited marked reduction in tumor size with imatinib, a tyrosine kinase inhibitor. Treatment was well tolerated, with few side effects.

Innovative Surgical Treatment of Severe Cherubism.

BACKGROUND: Cherubism is an autosomal dominant syndrome characterized by excessive bilateral maxillomandibular bony degeneration and fibrous tissue hyperplasia. Conservative management is the preferred treatment as cherubism has a self-limiting course. Functional or emotional disturbances may, however, demand surgical intervention. We report a patient who underwent surgical intervention. METHOD/DESCRIPTION: He had significant enlargement of lower cheeks and bilateral lower lid scleral show. On computed tomography of the face, the patient had significant fibrous tissue involving bilateral maxilla and mandible. The mandibular tumor was excised. Given normal inferior border, bilateral sagittal split osteotomy was performed to infracture and inset the outer cortex. During the procedure, patient required blood transfusion intraoperatively, so the maxillary portion of the procedure was delayed until 6 months later. For the maxilla, bilateral transconjunctival approach was used to resect parts of the orbital floors that were concave, resulting in 1 × 2 cm defects bilaterally which were reconstructed using resorbable plates. Then the anterior maxillary tumor was excised. RESULTS: The patient and his parents were satisfied with his appearance after surgery. The patient was noted to have improvement in contour and decreased scleral show. He has most recently followed up 15 months after the initial surgery. There were no long-term complications. CONCLUSIONS: Severity of cherubism influences the type of surgical intervention. The present case is innovative because this is the first reported case of recontouring orbital floors with resorbable plates and infracturing of the mandible using sagittal split osteotomies for surgical treatment of cherubism.

[Unique Experience of Cherubism Targeted Therapy].

The family form of giant cell reparative granuloma or cherubism is a rare benign lesion of the jaws which causes face deformation reminiscent of the cherubs portrayed in Renaissance art. Radical surgery, especially in children before puberty, is impossible or irrational, because it leads to disablement. For four years, a child with cherubism was undergoing an outpatient supervision in the Department of Maxillofacial Surgery in Russian Children Clinical Hospital. During the observation period it was noted that tumor masses were slowly progressing leading to exoorbitism. The child had a diagnosis histological verification; a treatment using human monoclonal antibodies to RANKL was developed, adapted and approved by the ethical committee. The clinical effect was observed from the third month of therapy - jaws corners sharpened, the volume reduced. The control biopsy material taken at the end of the 6-month course did not reveal any giant cells which meant complete pathomorphism. Computed tomography showed that at the end of the therapy bone density increased by 6-7 times in the affected zones and was additionally growing over the next 6 months of observation. Such dynamics allowed making effective contouring surgery of excessive bone tissues. Inoperable and early stages of cherubism require a combined treatment which includes a course of monoclonal antibodies followed by alendronic acid therapy that increases osteoblasts survival. After the treatment, if it is necessary to improve the appearance, contouring surgery of excessive bone tissue is performed.

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.

Orthodontic management of a patient with cherubism: A case report.

INTRODUCTION: The aim of this case report was to present the successful orthodontic treatment of an adolescent girl with cherubism. METHODS: The patient began treatment after puberty. Necessary extractions were performed, and she had full-arch treatment of the maxillary and mandibular anterior teeth. A series of archwires was used in a timely manner to create an adequate arch form and close the interdental spaces. Once treatment was completed, retention was ensured with a maxillary spring aligner and mandibular fixed retainer. RESULTS: Maxillary alignment and an adequate arch form were achieved, and mandibular treatment was limited to the anterior segment. The patient finished treatment with an esthetically pleasing smile. CONCLUSIONS: There have been few reports of orthodontic treatment for a patient with cherubism. This case report provides evidence that complete or limited orthodontic treatment can be provided to these patients to improve facial esthetics and bolster their self-esteem.