ABSTRACT
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.
Subject(s)
Cherubism , Humans , Cherubism/genetics , Cherubism/diagnosis , Female , Infant , Diagnosis, DifferentialABSTRACT
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.
Subject(s)
Cherubism , Neurofibromatosis 1 , Child , Humans , Male , Cafe-au-Lait Spots/complications , Cafe-au-Lait Spots/genetics , Cherubism/complications , Cherubism/genetics , Genetic Testing , Neurofibromatosis 1/complications , Neurofibromatosis 1/genetics , Neurofibromatosis 1/diagnosis , PhenotypeABSTRACT
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).
Subject(s)
Bone Neoplasms , Cherubism , Chondroblastoma , Giant Cell Tumor of Bone , Granuloma, Giant Cell , Humans , Cherubism/diagnosis , Cherubism/genetics , Cherubism/pathology , Granuloma, Giant Cell/diagnosis , Granuloma, Giant Cell/genetics , Granuloma, Giant Cell/pathology , Chondroblastoma/diagnosis , Chondroblastoma/genetics , Chondroblastoma/pathology , DNA Methylation , Giant Cells/pathology , Giant Cell Tumor of Bone/diagnosis , Giant Cell Tumor of Bone/genetics , Giant Cell Tumor of Bone/pathology , Bone Neoplasms/diagnosis , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Jaw/pathologyABSTRACT
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.
Subject(s)
Cherubism , Tankyrases , Humans , Tankyrases/genetics , Tankyrases/chemistry , Tankyrases/metabolism , Cherubism/genetics , Cherubism/metabolism , Ubiquitination , Signal Transduction , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolismABSTRACT
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.
Subject(s)
Bone Diseases, Metabolic , Cherubism , Mice , Animals , Cherubism/drug therapy , Cherubism/genetics , Tumor Necrosis Factor-alpha/metabolism , Imatinib Mesylate/pharmacology , Imatinib Mesylate/therapeutic use , Adaptor Proteins, Signal Transducing/genetics , Inflammation/pathology , PhenotypeABSTRACT
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.
Subject(s)
Cherubism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Cherubism/diagnosis , Cherubism/genetics , Cherubism/pathology , Humans , Mutation , SiblingsABSTRACT
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.
Subject(s)
Cherubism , Granuloma, Giant Cell , Noonan Syndrome , Cherubism/genetics , Cherubism/pathology , Child , Giant Cells/pathology , Granuloma, Giant Cell/pathology , Humans , Jaw/pathology , Noonan Syndrome/complications , Noonan Syndrome/genetics , Noonan Syndrome/pathologyABSTRACT
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.
Subject(s)
Anesthesiology , Cherubism , Anesthesia, General , Cherubism/diagnostic imaging , Cherubism/genetics , Child , Child, Preschool , Female , Humans , Intubation, Intratracheal , LaryngoscopyABSTRACT
The purpose of this review was to integrate the clinical, radiological, microscopic, and molecular data of published cherubism cases, in addition to therapeutic approaches, to provide more concise information about the disease. An electronic search was undertaken in September 2019. Eligibility criteria included publications having enough clinical, radiological, and histological information to confirm the diagnosis. A total of 260 publications reporting 513 cherubism cases were included. Familial history was observed in 310/458 cases (67.7%). SH3BP2 mutations were reported in 101/108 cases (93.5%) and mainly occurred at protein residues 415, 418, 419, and 420. Retrospective clinical grading was possible in 175 cases. Advanced clinical grading was associated with tooth agenesis, but not with other clinical, radiological, and genetic features. Specific amino acid substitutions of SH3BP2 mutations were not associated with the clinical grading of the disease. 'Wait and see' was the most common therapeutic approach. In a small number of cases, drugs were used in the treatment, with variable response. In conclusion, there is no clear correlation between the genotype and the phenotype of the disease, but additional genomic and gene expression regulation information is necessary for a better understanding of cherubism.
Subject(s)
Cherubism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Cherubism/diagnostic imaging , Cherubism/genetics , Humans , Mutation , Phenotype , Retrospective StudiesABSTRACT
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.
Subject(s)
Cherubism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Bone Density , Bone and Bones/metabolism , Cherubism/diagnostic imaging , Cherubism/genetics , Humans , Inflammation , MiceABSTRACT
Cherubism is a rare genetic disorder caused primarily by mutations in SH3BP2 resulting in excessive bone resorption and fibrous tissue overgrowth in the lower portions of the face. Bone marrow derived cell cultures derived from a murine model of cherubism display poor osteogenesis and spontaneous osteoclast formation. To develop a deeper understanding for the potential underlying mechanisms contributing to these phenotypes in mice, we compared global gene expression changes in hematopoietic and mesenchymal cell populations between cherubism and wild type mice. In the hematopoietic population, not surprisingly, upregulated genes were significantly enriched for functions related to osteoclastogenesis. However, these upregulated genes were also significantly enriched for functions associated with inflammation including arachidonic acid/prostaglandin signaling, regulators of coagulation and autoinflammation, extracellular matrix remodeling, and chemokine expression. In the mesenchymal population, we observed down regulation of osteoblast and adventitial reticular cell marker genes. Regulators of BMP and Wnt pathway associated genes showed numerous changes in gene expression, likely implicating the down regulation of BMP signaling and possibly the activation of certain Wnt pathways. Analyses of the cherubism derived mesenchymal population also revealed interesting changes in gene expression related to inflammation including the expression of distinct granzymes, chemokines, and sulfotransferases. These studies reveal complex changes in gene expression elicited from a cherubic mutation in Sh3bp2 that are informative to the mechanisms responding to inflammatory stimuli and repressing osteogenesis. The outcomes of this work are likely to have relevance not only to cherubism, but other inflammatory conditions impacting the skeleton.
Subject(s)
Cherubism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cherubism/genetics , Disease Models, Animal , Gene Expression , Mice , Osteoclasts/metabolismABSTRACT
The adaptor protein 3BP2 (SH3-domain binding protein 2), which is encoded by the SH3BP2 locus, nucleates a signaling complex comprising ABL, SRC, VAV, and SYK, and facilitates an open active configuration of these proteins, leading to their kinase activation. Gain-of-function missense mutations in the SH3BP2 gene cause cherubism, an autosomal dominant disorder associated with severe craniofacial developmental defects in children. Previous studies have demonstrated that 3BP2 and its degradation pathway regulate bone metabolism, energy metabolism, and inflammation and that dysregulation of the 3BP2 degradation pathway is associated with human disorders. Herein, we discussed lessons from cherubism indicating that 3BP2 studies could elucidate the pathogenesis of bone loss caused by inflammation and identify suitable therapeutic targets.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Bone and Bones/metabolism , RNA-Binding Proteins/genetics , Rare Diseases , Cherubism/genetics , Energy Metabolism/genetics , Humans , Inflammation/genetics , Osteoblasts , Osteoporosis/genetics , Proteolysis , RNA-Binding Proteins/metabolism , Signal Transduction/genetics , Signal Transduction/physiologyABSTRACT
In literature there are few reports about multiple CGCG. But this is the first report of bilateral CGCG of the mandibular angles in three females from the same family.This report describes three cases of females from the same family - a mother and two young daughters - with bilateral CGCG in their jaw angles. All the lesions were surgically removed and the histopathologic diagnosis was always identical: giant cell central granulomas, with patterns that were absolutely superimposable between them and with that of the mother.The hypothesis is that this presentation of CGCG may be defined as hereditary bilateral CGCG of the mandibular angles (or also, cherubism-like lesions).
Subject(s)
Cherubism/genetics , Genetic Predisposition to Disease , Granuloma, Giant Cell/genetics , Mandibular Diseases/genetics , Monitoring, Physiologic/methods , Biopsy, Needle , Child , Female , Granuloma, Giant Cell/diagnostic imaging , Granuloma, Giant Cell/pathology , Granuloma, Giant Cell/surgery , Humans , Immunohistochemistry , Mandibular Diseases/diagnostic imaging , Mandibular Diseases/pathology , Mandibular Diseases/surgery , Middle Aged , Oral Surgical Procedures/methods , Pedigree , Prognosis , Radiography, Panoramic/methods , Rare Diseases , Risk AssessmentABSTRACT
BACKGROUND: Cherubism is a rare genetic disorder that causes prominence in the lower portion in the face. The authors present the case of an 11-year old boy showing bilateral enlargement of the mandible. CASE REPORT: Computer tomography evidenced the presence of characteristic cherubism changes. The genetic test confirmed heterozygote mutation c.1244G>A (p.R415Q) in second exon coding sequence of SH3BP2 gene. Radiographic examinations performed on some close relatives of the patient revealed typical changes. The patient did not require any surgical treatment and the "wait and see" protocol was applied.
Subject(s)
Cherubism/diagnostic imaging , Mandible/abnormalities , Mandible/diagnostic imaging , Cherubism/genetics , Child , Humans , Male , Radiography, Panoramic , Tomography, X-Ray ComputedABSTRACT
Cherubism is a rare autosomal dominant condition affecting the jaws and caused by mutations in the gene encoding for the adapter protein SH3BP2 that maps to chromosome 4p16.3. Cherubism is characterized by symmetrically developing bone lesions in the maxilla and mandible. The lesions have been radiographically and histopathologically well-described. Here, we present a family with cherubism with two of its members featuring odontogenic tumorous proliferations in association with persistent central giant cell lesions (CGCL). Specifically, the proband, a 25-year-old male, developed a radiolucent lesion characterized histologically by central odontogenic fibroma-like proliferation in association with a CGCL component, while his mother, at age 57, was diagnosed with primary intraosseous odontogenic carcinoma with areas of benign fibro-osseous lesions. In both patients the lesions occurred in the anterior mandible and presented with clinical enlargement. The son underwent incisional biopsy and did not have additional treatment. His mother underwent extensive mandibulectomy due to widespread tumor. The son has two affected children with classic cherubism while a third child at age 5, had not shown any features of the disease. Mutation analysis of three affected members resulted in the identification of a heterozygous mutation in SH3BP2 (c.1244G>C; p.Arg415Pro). To the best of our knowledge, association of cherubism with odontogenic neoplastic lesions has hitherto not been reported in the literature, thus suggesting a relationship between cherubism with disturbed odontogenesis.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Cherubism/complications , Mandibular Neoplasms/pathology , Odontogenic Tumors/pathology , Adult , Cell Proliferation , Cherubism/genetics , Female , Humans , Male , Mandibular Neoplasms/genetics , Middle Aged , Mutation , Odontogenic Tumors/genetics , PedigreeABSTRACT
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.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Cherubism/diagnosis , Cherubism/genetics , Cytoskeletal Proteins/genetics , Epilepsy/diagnosis , Epilepsy/genetics , Fibromatosis, Gingival/diagnosis , Fibromatosis, Gingival/genetics , Growth Disorders/diagnosis , Growth Disorders/genetics , Homozygote , Hypertrichosis/diagnosis , Hypertrichosis/genetics , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Mutation , Child, Preschool , Consanguinity , Echocardiography , Female , Genetic Association Studies , Genetic Testing , Genomics/methods , Humans , Phenotype , RadiographyABSTRACT
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.
Subject(s)
Cherubism/complications , Denture, Partial, Removable , Ectodermal Dysplasia/complications , Failure to Thrive/complications , Heart Defects, Congenital/complications , Jaw, Edentulous, Partially/complications , Prosthodontics/instrumentation , Cherubism/diagnosis , Cherubism/genetics , Child , Child, Preschool , Dental Prosthesis Design , Ectodermal Dysplasia/diagnosis , Ectodermal Dysplasia/genetics , Facies , Failure to Thrive/diagnosis , Failure to Thrive/genetics , Female , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/genetics , Humans , Jaw, Edentulous, Partially/diagnostic imaging , Jaw, Edentulous, Partially/etiology , Male , Patient Care Team , Prosthodontics/methods , Radiography, Panoramic , Treatment OutcomeABSTRACT
OBJECTIVE: To describe the clinical and genetic features of patients with cherubism. MATERIAL AND METHODS: A descriptive analysis of 14 cases from nine different families was carried out. Clinicopathological, imaging, and follow-up data were retrieved from patients' medical files and correlated with the genetic profile of each patient. Genomic DNA isolated from buccal mucosa cells was subjected to direct sequencing analysis of the SH3BP2 gene. RESULTS: Females were more affected than males (8:6), and the mean age at diagnosis was 8.6 years (range 3-30 years). Eleven patients exhibited simultaneous bilateral involvement of the maxilla and mandible. Two patients did not have a familial history of cherubism. Progressive growth pattern was found in six patients and stable lesions were observed in other seven patients, whereas in one patient, complete spontaneous remission was documented during the follow-up (31 years). Mutations were found in 13 cases and included the typical heterozygous missense mutations R415Q, P418T, and P418H at exon 9 of SH3BP2. No correlation between the mutations and the clinical manifestations was observed. CONCLUSION: Three different point mutations in the SH3BP2 gene were detected with variable clinical involvement. Genotype-phenotype association studies in larger population with cherubism are necessary to provide important knowledge about molecular mechanisms related to the disease.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Cherubism/diagnostic imaging , Cherubism/genetics , Adolescent , Adult , Child , Child, Preschool , Disease Progression , Female , Genotype , Humans , Male , Mandible/diagnostic imaging , Maxilla/diagnostic imaging , Mutation, Missense , Phenotype , Radiography , Remission, Spontaneous , Sequence Analysis, DNA , Young AdultABSTRACT
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.
Subject(s)
Cherubism , Adaptor Proteins, Signal Transducing/genetics , Cherubism/diagnosis , Cherubism/genetics , Cherubism/therapy , Child , Conservative Treatment , Diagnosis, Differential , Disease Management , Genes, Dominant , Humans , Jaw Cysts/diagnostic imaging , Jaw Cysts/genetics , Jaw Cysts/pathology , Male , Osteoblasts/pathology , Osteoclasts/pathologyABSTRACT
Cellular identity in metazoan organisms is frequently established through lineage-specifying transcription factors, which control their own expression through transcriptional positive feedback, while antagonizing the developmental networks of competing lineages. Here, we have uncovered a distinct positive feedback loop that arises from the reciprocal stabilization of the tyrosine kinase ABL and the transcriptional coactivator TAZ. Moreover, we determined that this loop is required for osteoblast differentiation and embryonic skeletal formation. ABL potentiated the assembly and activation of the RUNX2-TAZ master transcription factor complex that is required for osteoblastogenesis, while antagonizing PPARγ-mediated adipogenesis. ABL also enhanced TAZ nuclear localization and the formation of the TAZ-TEAD complex that is required for osteoblast expansion. Last, we have provided genetic data showing that regulation of the ABL-TAZ amplification loop lies downstream of the adaptor protein 3BP2, which is mutated in the craniofacial dysmorphia syndrome cherubism. Our study demonstrates an interplay between ABL and TAZ that controls the mesenchymal maturation program toward the osteoblast lineage and is mechanistically distinct from the established model of lineage-specific maturation.