RESUMEN
Heritable disorders that feature high bone mass (HBM) are rare. The etiology is typically a mutation(s) within a gene that regulates the differentiation and function of osteoblasts (OBs) or osteoclasts (OCs). Nevertheless, the molecular basis is unknown for approximately one-fifth of such entities. NF-κB signaling is a key regulator of bone remodeling and acts by enhancing OC survival while impairing OB maturation and function. The NF-κB transcription complex comprises five subunits. In mice, deletion of the p50 and p52 subunits together causes osteopetrosis (OPT). In humans, however, mutations within the genes that encode the NF-κB complex, including the Rela/p65 subunit, have not been reported. We describe a neonate who died suddenly and unexpectedly and was found at postmortem to have HBM documented radiographically and by skeletal histopathology. Serum was not available for study. Radiographic changes resembled malignant OPT, but histopathological investigation showed morphologically normal OCs and evidence of intact bone resorption excluding OPT. Furthermore, mutation analysis was negative for eight genes associated with OPT or HBM. Instead, accelerated bone formation appeared to account for the HBM. Subsequently, trio-based whole exome sequencing revealed a heterozygous de novo missense mutation (c.1534_1535delinsAG, p.Asp512Ser) in exon 11 of RELA encoding Rela/p65. The mutation was then verified using bidirectional Sanger sequencing. Lipopolysaccharide stimulation of patient fibroblasts elicited impaired NF-κB responses compared with healthy control fibroblasts. Five unrelated patients with unexplained HBM did not show a RELA defect. Ours is apparently the first report of a mutation within the NF-κB complex in humans. The missense change is associated with neonatal osteosclerosis from in utero increased OB function rather than failed OC action. These findings demonstrate the importance of the Rela/p65 subunit within the NF-κB pathway for human skeletal homeostasis and represent a new genetic cause of HBM.
Asunto(s)
Enfermedades Genéticas Congénitas/genética , Mutación Missense , Osteopetrosis/genética , Transducción de Señal/genética , Factor de Transcripción ReIA/genética , Adulto , Sustitución de Aminoácidos , Femenino , Enfermedades Genéticas Congénitas/diagnóstico por imagen , Enfermedades Genéticas Congénitas/metabolismo , Humanos , Recién Nacido , Masculino , Osteopetrosis/diagnóstico por imagen , Osteopetrosis/metabolismo , Radiografía , Factor de Transcripción ReIA/metabolismoRESUMEN
The forensic pathologist has always had a central role in the identification of the dead in every day practice, in accidents, and in disasters involving hundreds or thousands of victims. This role has changed in recent years, as advances in forensic odontology, genetics and anthropology have improved the chances of identifying victims beyond recognition. According to the Interpol DVI Guide, fingerprints, dental examination and DNA are the primary identifiers, and this has given new emphasis to the role of the forensic pathologist as the leader of a multidisciplinary team of experts in a disaster situation, based on his or her qualifications and the experience gained from doing the same work in the everyday situation of an institute of forensic medicine.
Asunto(s)
Desastres , Patologia Forense , Rol Profesional , Conducta Cooperativa , Dermatoglifia del ADN , Desastres/historia , Odontología Forense , Patologia Forense/historia , Patologia Forense/organización & administración , Patologia Forense/normas , Adhesión a Directriz , Guías como Asunto , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Comunicación Interdisciplinaria , Liderazgo , Incidentes con Víctimas en Masa , Objetivos Organizacionales , Rol Profesional/historia , Control de CalidadRESUMEN
Following the December 2004 tsunami in Thailand experts from many countries, including Denmark, went to Thailand to help with identification work. The Interpol system for Disaster Victim Identification (DVI) was employed for the identification of the many casualties. This paper describes the work of the Danish teams in Thailand from the 30th December 2004 until the 6th June 2005. The investigation covers all Danes reported missing directly after the tsunami in Thailand on the 26th December 2004 and who were later found deceased, or, in one case, never recovered. The AM and PM forms were reviewed retrospectively and the relevant information compared. Forensic odontology alone was responsible for 70.3% of identifications, and in two more cases (5.4%) the identification was established using a combination of odontology and fingerprint information. Fingerprints were used to establish identity in 8 cases (21.6%). DNA-typing was only used in one identification, in combination with fingerprinting data. Only one Danish victim was not identified. This review of the 37 Danish cases confirms that odontological examination yielded the most identifications, fingerprint data much fewer, and DNA was only used to a small extent, due to organisational problems with the examination and because the initial samples were of inferior quality.