RESUMEN
Background: Geniospasm is a rare genetic disorder characterized by paroxysmal rhythmic or irregular movements of the chin and lower lip due to repetitive contractions of the mentalis muscle. Pathophysiology is poorly understood, and optimal treatment has not been established. Methods: Geniospasm was characterized in a series of patients after evaluation in our clinics, and a comprehensive review of all cases in the medical literature was performed. Results: We evaluated four patients (1 female) in four families with geniospasm, aged 4 months to 9 years. Bothersome symptoms were present in one patient, who was treated with regular injections of onabotulinumtoxinA, with complete resolution of symptoms and no adverse effects. 9 patients in the literature have had similar outcomes. Conclusions: Limited data exist with regard to the effective treatment of geniospasm. Several treatments have been used historically, with variable outcomes. Our results, together with those of prior reported cases, demonstrate benefit of the use of botulinum toxin injections for management of this condition.
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Toxinas Botulínicas Tipo A/farmacología , Enfermedades Maxilomandibulares/tratamiento farmacológico , Fármacos Neuromusculares/farmacología , Temblor/tratamiento farmacológico , Toxinas Botulínicas Tipo A/administración & dosificación , Niño , Preescolar , Femenino , Humanos , Lactante , Enfermedades Maxilomandibulares/diagnóstico , Enfermedades Maxilomandibulares/genética , Enfermedades Maxilomandibulares/fisiopatología , Masculino , Fármacos Neuromusculares/administración & dosificación , Linaje , Temblor/diagnóstico , Temblor/genética , Temblor/fisiopatologíaRESUMEN
The association of the high blood pressure D variant of the angiotensin-converting enzyme (ACE) gene with medication-related jaw osteonecrosis (MRONJ) is described in two Greek patients. The first patient, a 73-year-old man, took zolendronate, 4 mg/100 ml IV once per month for two years for prostate cancer and bone metastases. Three months after drug discontinuation, extraction of the first premolar was performed. After the intervention, he suffered from osteonecrosis of the mandible. He presented with hypertension and genetic testing revealed that he was homozygous for the high blood pressure D variant of the ACE gene. The second patient, a 65 years old woman, took denosumab, 120 mg subcutaneously once per month for 6 months for possible bone metastases from breast cancer. Three months after extraction of the first molar, she suffered from MRONJ. He also presented with hypertension and genetic testing revealed that she had the high blood pressure D variant of the ACE gene in a heterozygous state, which moderately predisposes to hypertension. To our knowledge, this is the first report indicating that genetic predisposition to hypertension may increase risk for MRONJ.
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Hipertensión/genética , Enfermedades Maxilomandibulares/genética , Osteonecrosis/genética , Peptidil-Dipeptidasa A/genética , Anciano , Denosumab/efectos adversos , Pruebas Genéticas , Heterocigoto , Humanos , Hipertensión/etiología , Hipertensión/patología , Enfermedades Maxilomandibulares/inducido químicamente , Enfermedades Maxilomandibulares/complicaciones , Enfermedades Maxilomandibulares/patología , Masculino , Metástasis de la Neoplasia , Osteonecrosis/inducido químicamente , Osteonecrosis/complicaciones , Osteonecrosis/patología , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Ácido Zoledrónico/efectos adversosRESUMEN
Fibrous dysplasia is a non-neoplastic developmental process that affects the craniofacial bones, characterized by painless enlargement as a result of bone substitution by abnormal fibrous tissue. Postzygotic somatic activating mutations in the GNAS1 gene cause fibrous dysplasia and have been extensively investigated, as well as being helpful in the differential diagnosis of the disease. Fibrous dysplasia may involve one (monostotic) or multiple bones (polyostotic), sporadically or in association with McCune-Albright syndrome, Jeffe-Lichenstein syndrome, or Mazabreud syndrome. This review summarizes the current knowledge on fibrous dysplasia, emphasizing the value of integrating the understanding of its molecular pathogenesis with the clinical, radiological, and histopathological features. In addition, we address important aspects related to the differential diagnosis and patient management.
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Displasia Fibrosa Craneofacial/genética , Enfermedades Maxilomandibulares/genética , Cromograninas/genética , Displasia Fibrosa Craneofacial/diagnóstico por imagen , Displasia Fibrosa Craneofacial/patología , Diagnóstico Diferencial , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Humanos , Enfermedades Maxilomandibulares/diagnóstico por imagen , Enfermedades Maxilomandibulares/patología , MutaciónRESUMEN
BACKGROUND: Glandular odontogenic cyst (GOC) demonstrates a significant predilection toward localized biologic aggressiveness and recurrence. GOC shares certain histopathologic features with intraosseous mucoepidermoid carcinoma (IMEC). The current investigation evaluates a group of recurrent, biologically aggressive GOCs to determine whether any cases demonstrated unique histologic features or mastermind-like2 (MAML2) rearrangements common to IMEC. METHODS: Microscopic slides from 11 previously diagnosed GOCs were stained with hematoxylin and eosin and assessed by 2 study participants for 10 classic histopathologic features required to establish a diagnosis of GOC. Cases were evaluated utilizing break-apart fluorescent in situ hybridization (FISH) analysis for the presence of MAML2 gene rearrangements. Clinical and demographic data on all patients were recorded. RESULTS: The mean age for patients included in the study was 55.27 years with a range of 36 to 72 years. The most common presenting symptom was a jaw expansion, and all cysts presented initially as a unilocular or multilocular radiolucency. Cysts displayed a minimum of 6 of 10 histologic parameters necessary for a diagnosis of GOC. One case demonstrated MAML2 rearrangements by FISH. That case also showed marked ciliation of cyst-lining epithelial cells and extensive mucous-secreting goblet cell proliferation. CONCLUSION: Findings in the current study are in concert with previous investigations, and although this study finds only limited molecular evidence to support the premise that recurrent biologically aggressive GOCs are a precursor to IMEC, detection of MAML2 rearrangements in 1 case suggests that such a theoretic transition, while rare, is possible.
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Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Reordenamiento Génico , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Quistes Odontogénicos/genética , Quistes Odontogénicos/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/genética , Células Epiteliales/patología , Femenino , Humanos , Hibridación Fluorescente in Situ , Enfermedades Maxilomandibulares/genética , Neoplasias Maxilomandibulares/diagnóstico por imagen , Neoplasias Maxilomandibulares/genética , Queratinas/metabolismo , Masculino , Mandíbula/diagnóstico por imagen , Mandíbula/patología , Maxilar/diagnóstico por imagen , Maxilar/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Quistes Odontogénicos/diagnóstico por imagen , Radiografía , TransactivadoresRESUMEN
Stem cells isolated from the amniotic fluid have been shown as a promising candidate for cell therapy and tissue engineering. However, the experimental and preclinical applications of amniotic fluid-derived stem cells (AFSCs) in the very field of maxillofacial bone tissue engineering are still limited. In this study, rat AFSCs were successfully harvested and characterized in vitro. The rat AFSCs showed typical fibroblastoid morphology, stable proliferation activity and multi-differentiation potential. Flow-cytometry analysis demonstrated that these cells were positive for CD29, CD44, and CD90, while negative for hematopoietic markers such as CD34 and CD45. The regenerative performance of AFSCs-premixed with platelet rich plasma (PRP) gel in restoration of alveolar bone defect was further investigated using a modified rat maxillary alveolar defect model. Micro-computer tomography and histological examination showed a superior regenerative capacity of AFSCs-premixed with PRP gel at both 4 and 8 weeks after operation comparing with control groups. Moreover, the implanted AFSCs can survive in the defect site and directly participate in the bone tissue regeneration. Taken together, these results indicated the feasibility of an AFSCs-based alveolar bone tissue engineering strategy for alveolar defect restoration.
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Pérdida de Hueso Alveolar/terapia , Líquido Amniótico/citología , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Enfermedades Maxilomandibulares/terapia , Plasma Rico en Plaquetas , Células Madre/citología , Pérdida de Hueso Alveolar/genética , Pérdida de Hueso Alveolar/metabolismo , Animales , Regeneración Ósea/genética , Diferenciación Celular/genética , Células Cultivadas , Femenino , Citometría de Flujo , Expresión Génica , Receptores de Hialuranos/metabolismo , Integrina beta1/metabolismo , Enfermedades Maxilomandibulares/genética , Enfermedades Maxilomandibulares/metabolismo , Masculino , Microscopía Fluorescente , Embarazo , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Madre/metabolismo , Antígenos Thy-1/metabolismo , Ingeniería de Tejidos/métodosRESUMEN
INTRODUCTION: Osteoporosis is a highly prevalent skeletal disorder characterized by compromised bone strength, usually related to decreased bone mass and microstructural alterations of bone tissue, predisposing a person to an increased risk of fracture. As other prevalent disorders, osteoporosis is the result of a complex interplay of genetic and acquired factors. AREAS COVERED: We provide an update of recent studies aimed at identifying the clinical and genetic factors that influence the response to drugs used to treat osteoporosis, as well as those determining the risk of two intriguing adverse effects of antiresorptives: osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF). EXPERT OPINION: Several clinical factors have been suggested to increase the risk of a poor drug response, such as advanced age and frailty. Candidate gene studies suggest that some common polymorphisms of the Wnt pathway and farnesyl diphosphate synthase (FDPS), the target enzyme for bisphosphonates, also influence the response to antiresorptives. However, they await for replication in large independent cohorts of patients. Similarly, some genetic and acquired factors may influence the risk of ONJ and AFF. Preliminary data suggest that the risk of suffering these adverse effects may have a polygenic basis.
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Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/toxicidad , Osteoporosis/tratamiento farmacológico , Osteoporosis/genética , Remodelación Ósea/efectos de los fármacos , Difosfonatos/farmacología , Relación Dosis-Respuesta a Droga , Fracturas del Fémur/tratamiento farmacológico , Fracturas del Fémur/genética , Geraniltranstransferasa/genética , Geraniltranstransferasa/metabolismo , Humanos , Enfermedades Maxilomandibulares/tratamiento farmacológico , Enfermedades Maxilomandibulares/genética , Osteonecrosis/tratamiento farmacológico , Osteonecrosis/genética , Vía de Señalización WntRESUMEN
Molecular and cellular mechanisms that control jaw length are becoming better understood. This is significant since the jaws are not only critical for species-specific adaptation and survival, but they are often affected by a variety of size-related anomalies including mandibular hypoplasia, retrognathia, asymmetry, and clefting. This chapter overviews how jaw length is established during the allocation, proliferation, differentiation, and growth of jaw precursor cells, which originate from neural crest mesenchyme (NCM). The focus is mainly on results from experiments transplanting NCM between quail and duck embryos. Quail have short jaws whereas those of duck are relatively long. Quail-duck chimeras reveal that the determinants of jaw length are NCM mediated throughout development and include species-specific differences in jaw progenitor number, differential regulation of various signaling pathways, and the autonomous activation of programs for skeletal matrix deposition and resorption. Such insights help make the goal of devising new therapies for birth defects, diseases, and injuries to the jaw skeleton seem ever more likely.
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Tipificación del Cuerpo , Maxilares/embriología , Mesodermo/embriología , Cresta Neural/embriología , Animales , Patos , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Evolución Molecular , Regulación del Desarrollo de la Expresión Génica , Maxilares/anatomía & histología , Maxilares/metabolismo , Enfermedades Maxilomandibulares/embriología , Enfermedades Maxilomandibulares/genética , Mesodermo/citología , Mesodermo/metabolismo , Cresta Neural/citología , Cresta Neural/metabolismo , Codorniz , Especificidad de la EspecieAsunto(s)
Familia , Enfermedades Maxilomandibulares/diagnóstico , Enfermedades Maxilomandibulares/genética , Espasticidad Muscular/genética , Temblor/diagnóstico , Temblor/genética , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Enfermedades Maxilomandibulares/fisiopatología , Masculino , Linaje , República de Corea , Temblor/fisiopatologíaRESUMEN
Glandular odontogenic cyst (GOC) is a cyst of the gnathic bones that is characterized by squamous and glandular differentiation. The histopathologic features of GOC overlap considerably with central mucoepidermoid carcinoma (MEC), suggesting that GOC could be a precursor lesion to, or even a low-grade form of, central MEC. Differentiating the two lesions may be difficult or impossible on a limited biopsy. MAML2 rearrangements have been recently found to be specific for MEC, even those arising in the jaws. An analysis of MAML2 in GOCs could help clarify its relationship with central MEC. Tissue blocks from 21 GOCs and 5 central MECs were retrieved from the surgical pathology archives of The Johns Hopkins Hospital. Each MEC exhibited solid areas and clear-cut stromal invasion. In addition, 4 of the MECs demonstrated cystic areas that were histologically similar to GOC. Break-apart fluorescence in situ hybridization for MAML2 was performed. For the MECs, analysis was performed on both the solid components and the cystic areas that resembled GOC. MAML2 rearrangements were identified in all 5 of the MECs, but in none of the 21 GOCs (100 vs. 0 %; p < 0.0001, Fisher's Exact). In the MECs, the rearrangement was present in both the solid and GOC-like cystic areas. While central MECs consistently harbor the MAML2 rearrangement, even in low-grade cystic areas that resemble a pre-existing GOC, true GOCs do not. Accordingly, GOC does not appear to represent an early or low-grade form of central MEC, but rather an unrelated lesion. The high sensitivity and specificity of MAML2 rearrangement for MECs points to its utility as a diagnostic adjunct in separating mucinous cystic lesions of the gnathic bones.
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Carcinoma Mucoepidermoide/genética , Proteínas de Unión al ADN/genética , Enfermedades Maxilomandibulares/genética , Neoplasias Maxilomandibulares/genética , Proteínas Nucleares/genética , Quistes Odontogénicos/genética , Factores de Transcripción/genética , Biomarcadores de Tumor/genética , Reordenamiento Génico , Humanos , Hibridación Fluorescente in Situ , Sensibilidad y Especificidad , TransactivadoresRESUMEN
OBJECTIVE: An analysis of the genes involved in both osteoporosis and modifications of the jawbone, through text mining, using a web search tool, of information regarding gene/protein interaction. DESIGN: The final set of genes involved in the present phenomenon was obtained by expansion-filtering loop. Using a web-available software (STRING), interactions among all genes were searched for, and a clustering procedure was performed in which only high-confidence predicted associations were considered. RESULTS: Two hundred forty-two genes potentially involved in osteoporosis and in modifications of the jawbone were recorded. Seven "leader genes" were identified (CTNNB1, IL1B, IL6, JUN, RUNX2, SPP1, TGFB1), while another 10 genes formed the cluster B group (BMP2, BMP7, COL1A1, ICAM1, IGF1, IL10, MMP9, NFKB1, TNFSF11, VEGFA). Ninety-eight genes had no interactions, and were defined as "orphan genes". CONCLUSIONS: The expansion of knowledge regarding the molecular basis causing osteoporotic traits has been brought about with the help of a de novo identification, based on the data mining of genes involved in osteoporosis and in modification of the jawbone. A comparison of the present data, in which no role was verified for 98 genes that had been previously supposed to have a role, with that of the literature, in which another 81 genes, as obtained from GWAS reviews and meta-analyses, appeared to be strongly associated with osteoporosis, probably attests to a lack of information on osteoporotic disease.
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Enfermedades Maxilomandibulares/genética , Familia de Multigenes/genética , Osteoporosis/genética , Proteína Morfogenética Ósea 2/genética , Proteína Morfogenética Ósea 7/genética , Regeneración Ósea/genética , Remodelación Ósea/genética , Resorción Ósea/genética , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Biología Computacional , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Minería de Datos , Genes jun/genética , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Molécula 1 de Adhesión Intercelular/genética , Interleucina-10/genética , Interleucina-1beta/genética , Interleucina-6/genética , Metaloproteinasa 9 de la Matriz/genética , Subunidad p50 de NF-kappa B/genética , Osteopontina/genética , Ligando RANK/genética , Factor de Crecimiento Transformador beta1/genética , Factor A de Crecimiento Endotelial Vascular/genética , beta Catenina/genéticaRESUMEN
OBJECTIVE: To investigate HRPT2 in jaw ossifying fibroma (OF), fibrous dysplasia (FD), and osteosarcoma (OS). STUDY DESIGN: We combined microsatellite loss of heterozygosity (LOH), HRPT2 sequence alterations at the mRNA level by reverse-transcription polymerase chain reaction (PCR), cDNA sequencing, and quantitative PCR (qPCR) and immunohistochemistry (IHC) in a total of 19 OF, 15 FD, and 9 OS. Because HRPT2 (parafibromin) interacts with cyclin D1, we investigated cyclin D1 expression with the use of qPCR and IHC. RESULTS: LOH was detected in 3/5 FD, 6/9 OF, and 2/2 OS heterozygous samples. LOH was not associated with decreased mRNA levels or HRPT2 protein expression except for 1 OF which harbored an inactivating mutation. However, this tumor did not display altered transcription or protein levels of HRPT2 nor cyclin compared with the other OF. CONCLUSIONS: The contribution of HRPT2 inactivation to the pathogenesis of OF, FD, and OS is marginal at best and may be limited to progression rather than tumor initiation.
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Fibroma Osificante/genética , Displasia Fibrosa Ósea/genética , Hiperparatiroidismo/genética , Enfermedades Maxilomandibulares/genética , Neoplasias Maxilomandibulares/genética , Osteosarcoma/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Anciano , Mapeo Cromosómico , Cromosomas Humanos Par 1/genética , Ciclina D1/genética , Progresión de la Enfermedad , Exones/genética , Femenino , Silenciador del Gen , Humanos , Pérdida de Heterocigocidad/genética , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Mutación/genética , ARN Mensajero/genética , Eliminación de Secuencia/genética , Transcripción Genética/genética , Adulto JovenRESUMEN
UNLABELLED: Tumoral calcinosis (TC) is a rare familial disease characterized by abnormal peri-articular calcification in affected joints, without any associated renal, metabolic or collagen vascular disease. It is characterized by usual hyperphosphataemia with normal serum calcium and alkaline phosphatase values. There are only a few reported cases ofTC patients with dental findings. This article reviews the dental literature and describes progressive gingival, alveolar and mandibular tori enlargement in a 41-year-old female from Zimbabwe with tumoral calcinosis. CLINICAL RELEVANCE: Tumoral calcinosis is a rare disorder of mineral metabolism with oral manifestations.
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Calcinosis/genética , Alargamiento de Corona , Sobrecrecimiento Gingival/genética , Enfermedades Maxilomandibulares/genética , Adulto , Calcinosis/cirugía , Resultado Fatal , Femenino , Genes Recesivos , Sobrecrecimiento Gingival/cirugía , Humanos , Hiperostosis/genética , Hiperostosis/cirugía , Enfermedades Maxilomandibulares/cirugía , Artropatías/genética , Artropatías/cirugía , Mutación , N-Acetilgalactosaminiltransferasas/genética , Zimbabwe , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
BACKGROUND: Bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) is an unpredictable, debilitating adverse effect. Recently, genetic polymorphisms have arisen as promising tools to identify patients with a higher risk of drug-related adverse events. AIM: We aimed to examine the association between the aromatase polymorphism g.132810C>T, and the estrogen receptor polymorphisms g.156705T>C and g.156751A>G, and the risk of BP-related ONJ. METHODS: Eighty-three subjects were included in the study. A clinical and radiological examination was conducted on oncologic subjects treated with zoledronic acid. Subjects with histologically confirmed ONJ were included in the test group (n = 30) whereas subjects with good oral health were included in control group (n = 53). Aromatase and estrogen receptor polymorphisms from blood samples were analyzed. RESULTS: The aromatase g.132810C>T polymorphism displayed an over-representation of the TT genotype in the test group (36.67 vs 16.98%; p < 0.05). There was no significant difference in either estrogen receptor polymorphism genotype frequency between the test and control groups. CONCLUSION: Our data suggest a role for the g.132810C>T polymorphism in predicting ONJ risk. These results can pave the way to the personalization of BP therapy, based on individual genotype.
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Aromatasa/genética , Difosfonatos/efectos adversos , Enfermedades Maxilomandibulares/enzimología , Enfermedades Maxilomandibulares/genética , Osteonecrosis/enzimología , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Aromatasa/metabolismo , Estudios de Casos y Controles , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Genotipo , Humanos , Maxilares/efectos de los fármacos , Maxilares/enzimología , Enfermedades Maxilomandibulares/inducido químicamente , Masculino , Persona de Mediana Edad , Osteonecrosis/inducido químicamente , Osteonecrosis/genética , Factores de RiesgoRESUMEN
Osteonecrosis of the jaw (ONJ), a side-effect of bisphosphonate therapy, is characterized by exposed bone that fails to heal within eight weeks. Healing time of oral epithelial wounds is decreased in the presence of amino-bisphosphonates; however, the mechanism remains unknown. We examined human tissue from individuals with ONJ and non-bisphosphonate-treated control individuals to identify changes in oral epithelium and connective tissue. Oral and intravenous bisphosphonate-treated ONJ sites had reduced numbers of basal epithelial progenitor cells, as demonstrated by a 13.8±1.1% and 31.9±5.8% reduction of p63 expression, respectively. No significant differences in proliferation rates, vessel density, or macrophage number were noted. In vitro treatment of clonal and primary oral keratinocytes with zoledronic acid (ZA) inhibited p63, and expression was rescued by the addition of mevalonate pathway intermediates. In addition, both ZA treatment and p63 shRNA knock-down impaired formation of 3D Ex Vivo Produced Oral Mucosa Equivalents (EVPOME) and closure of an in vitro scratch assay. Analysis of our data suggests that bisphosphonate treatment may delay oral epithelial healing by interfering with p63-positive progenitor cells in the basal layer of the oral epithelium in a mevalonate-pathway-dependent manner. This delay in healing may increase the likelihood of osteonecrosis developing in already-compromised bone.
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Células Madre Adultas/efectos de los fármacos , Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/efectos adversos , Imidazoles/efectos adversos , Enfermedades Maxilomandibulares/genética , Queratinocitos/efectos de los fármacos , Proteínas de la Membrana/genética , Osteonecrosis/genética , Análisis de Varianza , Estudios de Casos y Controles , Línea Celular Transformada , Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Enfermedades Maxilomandibulares/inducido químicamente , Queratinocitos/metabolismo , Proteínas de la Membrana/biosíntesis , Ácido Mevalónico/metabolismo , Osteonecrosis/inducido químicamente , ARN Interferente Pequeño , Técnicas de Cultivo de Tejidos , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/genética , Ácido ZoledrónicoAsunto(s)
Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/efectos adversos , Imidazoles/efectos adversos , Mieloma Múltiple/genética , Osteonecrosis/genética , PPAR gamma/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Enfermedades Maxilomandibulares/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Ácido ZoledrónicoRESUMEN
Bisphosphonate induced osteonecrosis of the jaw (BONJ) is a complication in patients taking bisphosphonate (BP) that affects their quality of life and compliance. In this cohort study, patients with multiple myeloma (MM) on intravenous BP therapy were enrolled over 1 year. Demographic and clinical data and genotyping of 10 single nucleotide polymorphisms (SNPs) from seven candidate genes associated with drug or bone metabolism were determined. Of the 78 patients enrolled, 12 had BONJ. The median time to developing BONJ was 28 months. Univariate and multivariate analysis revealed a significant association between BONJ and smoking (p=0.048) and type of BP treatment (p=0.03). A trend for higher odds for BONJ was found for SNPs in five genes: COL1A1 (rs1800012), RANK (rs12458117), MMP2 (rs243865), OPG (rs2073618) and OPN (rs11730582). Considering all five SNPs together, patients with genotype scores ≥ 5 had a BONJ event rate of 57%; those with scores < 5 had a rate of 10%. The adjusted odds ratio was 11.2 (95% confidence interval of 1.8-69.9; p value 0.0097). Smoking, type of BP and combined genotype score of COL1A1, RANK, MMP2, OPG and OPN were significantly associated with BONJ in MM patients undergoing BP therapy.
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Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/efectos adversos , Enfermedades Maxilomandibulares/inducido químicamente , Osteonecrosis/inducido químicamente , Polimorfismo Genético/genética , Adulto , Anciano , Hidrocarburo de Aril Hidroxilasas/genética , Conservadores de la Densidad Ósea/administración & dosificación , Estudios de Cohortes , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Citocromo P-450 CYP2C8 , Difosfonatos/administración & dosificación , Femenino , Frecuencia de los Genes/genética , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Inyecciones Intravenosas , Enfermedades Maxilomandibulares/genética , Masculino , Metaloproteinasa 2 de la Matriz/genética , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Osteonecrosis/genética , Osteopontina/genética , Osteoprotegerina/genética , Pamidronato , Polimorfismo de Nucleótido Simple/genética , Receptor Activador del Factor Nuclear kappa-B/genética , Factores de Riesgo , Fumar , Factores de Tiempo , Factor de Necrosis Tumoral alfa/genética , Ácido ZoledrónicoRESUMEN
OBJECTIVE: To investigate the polymorphisms of the vascular endothelial growth factor (VEGF) gene in relation to female patients who developed bisphosphonate-related osteonecrosis of the jaws (BRONJ). METHODS: Test subjects were 30 Italian female patients with BRONJ (Group A). Control subjects were 30 female patients with a history of intravenous bisphosphonate use without any evidence of osteonecrosis (Group B) and 125 unrelated healthy volunteers (Group C). Three single-nucleotide polymorphisms were investigated: -634 G>C, occurring in 5' untranslated region (UTR); +936 C>T, occurring in 3' UTR; and -2578 C>A of the promoter region. RESULTS: The frequency of the VEGF CAC (+936/-2578/-634) haplotype was increased in patients with BRONJ, compared with female disease-negative controls [odds ratio (OR) = 2.76, 95% CI = 1.09-4.94, P = 0.039; corrected P value: P(c) = 0.117], and was also increased compared with female healthy controls (OR = 2.11, 95% CI = 1.14-3.89, P = 0.024; corrected P value: P(c) = 0.072). The CC homozygotes of -634G>C of VEGF gene and AA homozygotes of -2578C>A have also been significantly correlated in female patients who developed BRONJ compared with healthy controls (OR = 2.04, 95% CI = 1.12-3.70, P = 0.008; corrected P value: P(c) = 0.024). CONCLUSIONS: These results suggest a possible haplotype effect of VEGF polymorphisms expression in BRONJ Italian female patients. Studies with different and larger populations possibly using TagSNP to represent all haplotypes within the VEGF gene are needed to further delineate the genetic contribution of this gene to BRONJ.