Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling. The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity. Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18S64 and D18S51 on chromosome 18q21.2-21.3 in a large Northern Irish family. The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RANK is essential in osteoclast formation. We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB). One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.

Paget's disease of bone is a common bone disease characterized by increased and disorganized bone remodeling at focal sites throughout the skeleton. The etiology of the disease is unresolved. A persistent viral infection has long been suggested to cause the disease. Antigen and/or nucleic acid sequences of paramyxoviruses (in particular measles virus [MV], canine distemper virus [CDV], and respiratory syncytial virus [RSV]) have been reported in pagetic bone by a number of groups; however, others have been unable to confirm this and so far no virus has been isolated from patients. Here, we reexamined the question of viral involvement in Paget's disease in a study involving 53 patients with established disease recruited from seven centers throughout the United Kingdom. Thirty-seven patients showed clear signs of active disease by bone scan and/or histological assessment of the bone biopsy specimens and 12 of these had not received any therapy before samples were taken. Presence of paramyxovirus nucleic acid sequences was sought in bone biopsy specimens, bone marrow, or peripheral blood mononuclear cells using reverse-transcription polymerase chain reaction (RT-PCR) with a total of 18 primer sets (7 of which were nested), including 10 primer sets (including 3 nested sets) specifically for MV or CDV. For each patient at least one sample was tested with all primer sets by RT-PCR and no evidence for the presence of paramyxovirus RNA was found in any patient. In 6 patients, bone biopsy specimens with clear histological evidence of active disease tested negative for presence of measles and CDV using immunocytochemistry (ICC) and in situ hybridization (ISH). Intranuclear inclusion bodies, similar to those described by others previously, were seen in pagetic osteoclasts. The pagetic inclusions were straight, smooth tubular structures packed tightly in parallel bundles and differed from nuclear inclusions, known to represent MV nucleocapsids, in a patient with subacute sclerosing panencephalitis (SSPE) in which undulating, diffuse structures were found, arranged loosely in a nonparallel fashion. In the absence of amplification of viral sequences from tissues that contain frequent nuclear inclusions and given that identical inclusions are found in other bone diseases with a proven genetic, rather than environmental, etiology, it is doubtful whether the inclusions in pagetic osteoclasts indeed represent viral nucleocapsids. Our findings in this large group of patients recruited from throughout the United Kingdom do not support a role for paramyxovirus in the etiology of Paget's disease. (J Bone Miner Res 2000;15:2315-2329)

We report 40 cases in one family of an autosomal dominant bone dysplasia, which, though similar in some aspects to Paget's disease, seems unique in some features and in its natural history. The disease shows both general and focal skeletal changes, the latter being mainly in the limbs with an onset from the second decade. Progressive osteoclastic resorption is accompanied by medullary expansion which leads to pain, severe deformity and a tendency to pathological fracture. The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal. Most patients had an associated deafness of early onset and loss of dentition. No previous description of this disease has been found in the literature.

Familial expansile osteolysis is a rare bone dysplasia which is transmitted as an autosomal dominant trait in a large kindred in Northern Ireland. The gene which causes the disease shows tight linkage with several polymorphic markers on chromosome 18q with a maximum lod score of 11.53 at a recombination fraction of 0.00 with D18S64. The gene is flanked by D18S35 and D18S61 and is located at chromosome 18q21.1-q22. Mapping a new locus for a gene involved in regulation of bone metabolism may also have implications in the study of Paget's disease of bone which is a common related bone dysplasia.

Background: There has been considerable debate about the best treatment for acute rupture of the Achilles tendon. At our institution, a well-documented and structured program of nonoperative management of Achilles tendon rupture with use of casts and a removable orthosis was developed. Methods: We assessed the results in 140 consecutive patients with a complete rupture of the Achilles tendon who had been treated with our nonoperative regimen at our center between 1992 and 1998. Patients were evaluated on the basis of the subjective results and clinically with physiological testing. Results: Overall, 56% of our patients had an excellent result; 30%, good; 12%, fair; and 2%, poor. The overall complication rate was 8%, with three complete and five partial tendon reruptures, two deep vein thromboses, and one temporary dropfoot. Conclusions: The results of our nonoperative orthotic treatment were better overall than published results of operative repair of acute Achilles tendon rupture. Our patients were quite satisfied with their treatment. Level of Evidence: Therapeutic study, Level IV (case series [no, or historical, control group]). See Instructions to Authors for a complete description of levels of evidence.

No abstract

Controversy surrounds the most appropriate treatment method for patients with a rupture of the tendo Achillis. The aim of this study was to assess the long term rate of re-rupture following management with a non-operative functional protocol. We report the outcome of 945 consecutive patients (949 tendons) diagnosed with a rupture of the tendo Achillis managed between 1996 and 2008. There were 255 female and 690 male patients with a mean age of 48.97 years (12 to 86). Delayed presentation was defined as establishing the diagnosis and commencing treatment more than two weeks after injury. The overall rate of re-rupture was 2.8% (27 re-ruptures), with a rate of 2.9% (25 re-ruptures) for those with an acute presentation and 2.7% (two re-ruptures) for those with delayed presentation. This study of non-operative functional management of rupture of the tendo Achillis is the largest of its kind in the literature. Our rates of re-rupture are similar to, or better than, those published for operative treatment. We recommend our regime for patients of all ages and sporting demands, but it is essential that they adhere to the protocol.

The radiographic features of a unique autosomal dominant bone dysplasia are presented. The features are classified as generalised and/or focal. Generalised features are either altered trabecular pattern or modelling abnormalities. Focal features comprise lytic areas which progressively enlarge, producing expansion of the bone and eventual disintegration due to fibrous and finally fatty replacement of the normal medulla. Almost 90% of these lesions occur in the appendicular skeleton. Clinically, hearing loss is the earliest manifestation of the disease, presenting sometimes as early as 4 years of age. Apical and cervical resorption of teeth is extremely common, resulting in premature loss of teeth. Radiologically, the differential diagnosis refers to Paget's disease, polyostotic fibrous dysplasia, and osteofibrous dysplasia. The progressive destruction of the bone is similar to massive osteolysis (Gorham's disease). The radiographic features in combination with the histopathology render the condition unique.