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A familial case of Paget’s disease of bone with mutation at exon 8 of the sequestosome gene: Results
17 Dec2011
Mutational screening of the exons 7 and 8 of the SQSTM1/p62 gene revealed the presence of a C/T transversion at position 1215 in exon 8 (Fig. 2) in the affected individuals (VB and VG). This mutation causes the substitution proline/leucine at codon 392 (P392L), and it has been described by other reports in different populations. No mutation was found in the not affected subject VS.
Figure 2 – SQSTM1 gene mutation (bottom) detected in two Italian PDB patients from the same family. Specific forward and reverse sequences have been reported. Arrows indicate the presence of mutation, a C>T transition at exon 8.
Discussion
The aminoacidic residue 392 was conserved in the mouse and rat homologues. The P392 residue is located in the C-terminal end of the p62 protein flanking the ubiquitin associated domain (UBA) and could thus be important for the conformation and/or function of this region. The UBA domain of SQSTM1/p62 consists of three anti-parallel a-helices; P392 is the first residue of helix 1. P392L mutation modifies the secondary structure of the UBA domain by extending the N-terminus of helix 1, and this could result in an altered conformation and/or function of p62 protein.
A familial case of Paget’s disease of bone with mutation at exon 8 of the sequestosome gene: Treatment
16 Dec2011
In all patients pharmacological treatment was prescribed when serum AP and BAP levels firstly increased at least 25% above the upper limit of the normal range. During the whole observation period we used in these PDB patients synthetic sCT at the dosage of 100 UI i.m/day for 6 months and bisphosphonates (clodronate, 300 mg i.v./day for 5 days, and neridronate, 100 mg/day i.v. for 2 days). As regards sCT, another course of treatment was prescribed after the sixth month of follow-up when total serum AP activity newly increased above the upper limit of the normal range by at least 25%. Overall, regarding bisphosphonates therapy, we have treated about 50 PDB outpatients. The nadir of our patients’ serum AP and BAP levels were observed between the third and the fifth month after therapy and the zenith usually after the ninth month (data not published). Disease activity was evaluated by the means of serum total AP and BAP determined at three, five, and nine months after therapy. Another course of drugs was prescribed when, after the ninth month, total serum AP and BAP had an increase of at least 25% above the upper limit of the normal range. After 5 months of treatment with clodronate, the patients showing serum AP and BAP above the upper limit of the normal range, although exhibiting a reduction of their values to 50% or more of the pre-treatment value, were classified as not responders to the therapy and switched to neridronate.
Patients
We monitored for a long period 3 members of a family affected by polyostotic PDB at the Bone Metabolic Unit of the IRCCS Ospedale Maggiore di Milano. The members of this family were a woman (proband), her brother, their father and the brother’s daughter (Fig. 1).
Brother, sister and their father were visited since 1987. Diagnosis of PBD was confirmed by X-rays, bone scintigraphy and bone markers measurements. Total alkaline phosphatase (AP) and its bone isoenzyme (BAP) were used to assess disease activity. The woman (VB), born in 1928, is affected by polyostotic PBD, diagnosed in 1987, involving dorsal spine (D9, D11, D12) and left hemipelvis. She also presented a colloid goitre since 1989, developed in hypothyroidism in 2003 and treated with L-thyroxin (100 mg/day). A benign M-component hypergammaglobulinemia was diagnosed in 2002. VB underwent several courses of salmon calcitonin (sCT) till 1992 and thereafter nine courses of bisphosphonates treatment (clodronate till 2001 and neridronate in 2002).
A familial case of Paget’s disease of bone with mutation at exon 8 of the sequestosome gene
25 Nov2011
Introduction
Paget’s disease of bone (PDB) is a disorder of bone metabolism reported to affect up to 3% of Caucasian over 55 years of age. PDB is a genetically heterogeneous disorder characterized by abnormal osteoclastic activity leading to bone destruction and macroscopic deformities, which cause bone pain and pathological fractures. There is evidence of genetic abnormalities in its pathogenesis, and at least 8 different human chromosomal loci have been correlated to PDB. The PDB 3 locus in chromosome 5q35-qter hosts the SQ STM1/p62 gene, whose mutations account for most of the sporadic and familial forms of PDB reported in the literature. SQSTM1/p62 gene encodes the SQSTM1/p62 protein, that is component of the NF-kB signaling pathway crucial for osteoclastic differentiation and activation. The exon 8 DNA sequence accounts for the ubiquitin protein-binding domain (UBA) and represents a mutational hot spot area. An abnormal UBA region is reported to account the inability to bind to ubiquitin with consequential accumulation of sesquestosome protein. Different mutations of SQSTM1/p62 have been reported in French Canadian PDB families, and a recent observation seems to confirm the causal relationship between this gene and Paget’s disease of bone also in sporadic Italian patients.
A clinical case of familial Paget’s disease of bone complicated by early osteogenic sarcoma: Discussion
14 Nov2011
Familial Paget’s disease accounts for about 20% of PDB cases, and it is often found to segregate in an autosomal dominant pattern. Mutations of p62/sequestosome 1 gene (SQSTM1/p62) account for familial forms of PDB.
It is well known that the presentation of familial PDB is most frequently poliostotic than in sporadic cases, and that levels of alkaline phosphatase are frequently higher.
From PDB diagnosis, patient was treated with antireabsorptive therapy. There are four general indications for treatment of Paget’s disease: symptoms due to metabolically active Paget’s disease such as bone pain or neurological syndromes; patient planning to undergo elective surgery on a pagetic site; the management of hypercalcemia, a rare occurrence following prolonged immobilization; finally, some investigators believe that treatment is indicated as an attempt to decrease local progression and reduce the risk of future complications. Nowadays pharmacological treatment is based upon the use of bisphosphonates.
Bisphosphonates approved by the US Food and Drug Administration for the treatment of Paget’s disease include pamidronate, which is given intravenously, and etidronate, tilu- dronate, alendronate and risedronate, all of which are taken orally. Clodronate, though not approved for treatment of Paget’s disease in many countries, has been successfully used. Daily infusions of clodronate 300 mg for 5 days have showed the ability to significantly reduce disease activity. Our patient was repeatedly treated with clodronate infusions with a satisfying clinical and biochemical response during the past years.
Investigators have recognized that secondary resistance to individual bisphosphonates can occur. Therefore, it may be necessary for a patient to use more than one bisphosphonate in long-term management of the disease. In this patient, after the diagnosis of osteosarcoma was made, we used pamidronate to obtain both an antiresorptive effect and a reduction of pain.
A clinical case of familial Paget’s disease of bone complicated by early osteogenic sarcoma
9 Nov2011
Case presentation
A 65 years-old Italian woman came to our attention at the Me- dicina-Malattie Metaboliche dell’Osso Department. She came as an outpatient and the reason of the visit was persistent bone pain.
Through family history of the patient, it was possible to ascertain a familial form of Paget’s disease of bone (PDB), because the father, two uncles and 4 cousins (2 males and 2 females) were affected by the disease, suggesting that the disease segregates in an autosomal dominant pattern (Figure 1). She was diagnosed with Paget’s disease of bone when she was 62 years-old because of the occasional finding of an elevated alkaline phosphatase and subsequent bone scintigraphy. Bone scintigraphy showed signs of disease at right pelvis, right proximal femur and IV and VIII left ribs.
After the diagnosis of PDB she was followed-up at our Department with clinical evaluation and dosage of alkaline phos- phatase every 4 months, and she was treated with clodronate infusion whenever bone pain was reported or alkaline phosphatase level was more than twice the laboratory upper limit.
During the period from the diagnosis of Paget s disease when she was 62 years old until the age of 65, a total of 3 clodronate infusion (each consisting in five days courses with clodronate 300 mg daily) were employed, without significant side effects and with a good response in term of clinical and biochemical parameters.
Three years after the diagnosis of PDB, bone pain at right pelvis markedly increased.
Paget’s disease of the hip: Treatment
1 Nov2011
Management of patients with Paget’s disease can be challenging. The mainstay of treatment is to relieve pain and improve function. This often necessitates administration of nonsteroidal anti-inflammatory medications and other analgesics. In order to retard excessive osteoclastic activity bisphosphonate drugs may be administered. Joint arthroplasty for Paget’s patients with end-stage symptomatic arthritis may be indicated. Due to gross deformities osteotomy of the affected bone either as an isolated procedure or at the time of arthroplasty may be indicated. When a subcapital or intracapsular hip fracture occurs in a pre-existing pagetoid bone, total hip arthroplasty may be indicated if acetabular bone is also affected.
Outcomes
Although few patients with Paget’s disease ever require surgical therapy, successful surgical management of severe orthopedic complications has improved the quality of life for these patients. Total hip arthroplasty (THA) has consistently been reported to improve function for these patients. The optimal method of fixation of hip components against pagetoid bone has been debated in the past. Cemented total hip arthroplasty is reported to be a viable and accepted treatment modality for symptomatic coxarthritis of the hip in patients with Paget’s disease. However, a higher incidence of symptomatic and asymptomatic radiolucencies around the bone-cement interface of components placed against pagetoid bone has been documented with the possibility of increased rates of implant failure over an intermediate time frame postoperatively discussed. Radiolucencies occurred in twenty of thirty-two acetabular components implanted against pagetoid bone in one series. Merkow et al. reported on twenty-one cemented hips that showed the need for two revisions (9.5%) at 5.2 years follow-up.