RESUMEN
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.
Asunto(s)
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
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.
Asunto(s)
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
BACKGROUND: Activation mutations of SH3BP2 gene have been demonstrated in cherubism and central giant cell lesion (CGCL). In the present study we first attempted to investigate the SH3BP2 gene in peripheral giant cell lesion (PGCL). The effect of SH3BP2 gene mutations on the transcription of the downstream genes nuclear factor of activated T cells (NFATc1) and the cytokine tumor necrosis factor-alpha (TNF-alpha) was also investigated together with the immunolocalization of NFATc1 protein in a set of cases of PGCL, CGCL and cherubism with and without SH3BP2 mutation. METHOD: Fresh samples of five PGCL, five CGCL and one cherubism cases were included in this study. One of the samples of CGCL presented a somatic heterozygous mutation c.1442A>T in exon 11. The cherubism case showed a heterozygotic substitution c.320C>T in both blood and lesion. These mutations were previously published. All coding and flanking regions of the SH3BP2 gene were sequenced in the cases of PGCL. The real-time polymerase chain reaction (RT-PCR) was performed to analyze the transcription of NFATc1 and TNF-alpha genes. The immunohistochemical analysis of the NFATc1 protein was also performed. RESULTS: No SH3BP2 gene mutation was found in PGCL. The RT-PCR showed increased expression of NFATc1 and decreased transcription of TNF-alpha in all the samples. The immunohistochemical analysis of the NFATc1 protein showed a predominant nuclear staining in the multinucleated giant cells. CONCLUSION: The development of giant cells lesions of the jaws and cherubism are possibly mediated by overexpression of NFAT in the nucleus of the multinucleated cells.
Asunto(s)
Querubismo/genética , Granuloma de Células Gigantes/genética , Enfermedades Maxilomandibulares/genética , Mutación/genética , Factores de Transcripción NFATC/genética , Factor de Necrosis Tumoral alfa/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina , Núcleo Celular/ultraestructura , Querubismo/sangre , Querubismo/patología , Citosina , Exones/genética , Regulación de la Expresión Génica/genética , Células Gigantes/patología , Glutamina/genética , Granuloma de Células Gigantes/patología , Heterocigoto , Humanos , Enfermedades Maxilomandibulares/patología , Leucina/genética , Metionina/genética , Factores de Transcripción NFATC/análisis , Polimorfismo Genético/genética , Treonina/genética , Timina , Transcripción Genética/genética , Factor de Necrosis Tumoral alfa/análisis , Dominios Homologos src/genéticaRESUMEN
Central giant cell lesion (CGCL) is a reactive bone lesion that occurs mainly in the mandible, characterized by the multinucleated osteoclast-like giant cells in a background of oval to spindle-shaped mononuclear cells. The etiology is unknown and occurs more commonly in young adults. Cherubism, a rare disease found predominantly in females has histologic characteristics indistinguishable from those of CGCL and is caused by mutations mostly present in exon 9 of the SH3BP2 gene. In this study, we investigated four cases of CGCL and one case of cherubism. DNA was extracted from peripheral blood and tumor tissue and all coding and flanking regions of the SH3BP2 amplified by PCR and directly sequenced to identify underlying mutations. Two novel mutations were found; a heterozygous missense mutation c.1442A>T (Q481L) in exon 11 in one sporadic case of CGCL and a heterozygous germline and tumor tissue missense mutation c.320C>T (T107M) in exon 4 in one patient with cherubism. These findings open a new window to investigate the possible relationship between the pathogenesis of the cherubism and CGCL.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Querubismo/genética , Granuloma de Células Gigantes/genética , Enfermedades Maxilomandibulares/genética , Mutación/genética , Dominios Homologos src/genética , Adenina , Adulto , Niño , Citosina , Exones/genética , Femenino , Mutación de Línea Germinal/genética , Glutamina/genética , Heterocigoto , Humanos , Leucina/genética , Masculino , Metionina/genética , Persona de Mediana Edad , Mutación Missense/genética , Treonina/genética , Timina , Adulto JovenRESUMEN
Older paternal age has previously been documented as a factor in sporadic fresh mutational cases of several autosomal dominant disorders. In this collaborative study, an older mean paternal age has been documented in sporadic cases of at least five additional dominantly inheritable disorders; the basal cell nevus syndrome, the Waardenburg syndrome, the Crouzon syndrome, the oculo-dental-digital sysdrome, and the Treacher-Collins syndrome. It was also found to be a factor in acrodysostosis and progeria, suggesting a fresh mutant gene etiology for these two conditions in which virtually all cases have been sporadic and the mode of genetic etiology has been unknown.