To define the clinical, pathological and molecular genetic characteristics of a family with mild spondyloepiphyseal dysplasia (SED) and precocious osteoarthritis.The proband was a 46-year-old man with precocious generalized OA, tall stature, mild chondrodysplasia and moderate deafness. His daughter, aged 21, showed similar clinical features. Electron microscopic (EM) analysis of collagen from an affected joint of the proband was performed. DNA was extracted from whole blood on the proband, his affected daughter, unaffected wife and second daughter, to look for a mutation in exons 31 or 11, sites where point mutations have been previously described in mild forms of SED. After finding no mutation in exon 31, exon 11 of COL2A1 was further analyzed. Exon 11 was amplified using polymerase chain reaction (PCR), and screening for the mutation was undertaken using a restriction enzyme digestion, the recognition sequence of which is altered by this point mutation. Sequence analysis was then performed.Electron microscopic (EM) analysis of cartilage from the proband showed thin appearing collagen fibrils organized into parallel lamellar structures. DNA studies revealed a single base change in one allele of exon 11 which produced an arginine to cysteine mutation at position 75 of the triple helix of type II collagen in the proband and his affected daughter.This is the 2nd example of an Arginine75-Cysteine mutation associated with SED; in our case, however, contrasting clinical features were present. Recurrent mutations at a few specific sites of COL2A1 suggest the possibility of susceptibility "hot spots" for mutational events.
Abstract Background: The objective of this study was to determine the neurophysiological effects of leflunomide on peripheral nerves in rheumatoid arthritis. Methods: We conducted a prospective cohort trial of 32 patients with rheumatoid arthritis with 16 patients receiving leflunomide treatment and 16 receiving other disease‐modifying anti‐rheumatic drug therapies. Clinical, laboratory and neurophysiological measurements were used to determine the presence of a peripheral neuropathy in these patients at study entry and then after a further 3 and 6 months. Results: Fifty‐four per cent of the leflunomide group and 8% of the control group had an increase in their neuropathy symptom score 6 months into the study ( P = 0.01). No correlation was found between the electrophysiological findings and the clinical symptoms. There was no significant difference between the two groups in upper and lower limb sensory and motor amplitudes and conduction velocities recorded at 3 and 6 months. One patient developed both clinical and neurophysiological evidence of a peripheral neuropathy 5 months into the study that improved after cessation of leflunomide therapy and cholestyramine washout. Conclusion: After 6 months of exposure we found that leflunomide was associated with an apparent increase in the clinical symptoms of peripheral neuropathy in patients with rheumatoid arthritis. These symptoms did not correlate with neurophysiological studies.
BK virus nephropathy (BKVN) is well described in renal allografts with the most consistent risk factor being overall degree of immunosuppression.1 BKVN in native kidneys is far less common and hitherto described most frequently in heart and hematopoietic cell transplant recipients.2 Native BKVN in a liver transplant recipient has been documented only once before in the literature3; here, we report a second case. A 59-year-old Vietnamese-born man received an ABO-incompatible orthotopic liver transplant for acute liver failure secondary to hepatitis B virus reactivation. Due to blood group incompatibility, his induction therapy was according to our standard protocol of pretransplant rituximab and posttransplant methylprednisolone, basiliximab, tacrolimus, and plasmapheresis. His maintenance immunosuppression was more intense than standard at our center consisting of prednisone 5 mg daily, mycophenolate mofetil 1000 mg BID, and tacrolimus with trough levels between 7 and 10 ng/mL, as he had a rebound in anti-B titer from 1:4 to 1:16 posttransplant. He had excellent graft function with no rejection, and his posttransplant serum creatinine had been 60 and 80 μmol/L and estimated glomerular filtration rate >90 mL/min/1.73 m2. He received hepatitis B prophylaxis with long-term entecavir. Twenty-two months posttransplant, he presented with diarrhea due to biopsy-proven cytomegalovirus colitis and acute kidney injury. Despite clinical improvement after intravenous ganciclovir and fluid resuscitation, his renal function remained significantly impaired with a creatinine level of 280 µmol/L (estimated glomerular filtration rate, 20 mL/min/1.73 m2). He had no proteinuria or hematuria, and his renal ultrasound did not demonstrate any evidence of obstruction. A serum quantitative polymerase chain reaction test for BK virus was strongly positive with 754 976 copies/mL. A renal biopsy later confirmed severe BK nephropathy with considerable interstitial inflammation (Figure 1). His immunosuppression was reduced, and he was commenced on fortnightly cidofovir infusions.FIGURE 1.: A, Light microscopy of native renal biopsy (hematoxylin and eosin stain, magnification ×400) demonstrated abnormally enlarged tubular nuclei containing viral inclusions (arrows). B, These large, abnormal tubular epithelial cells nuclei were strongly positive on immunostaining for SV-40 (polyomavirus) (magnification ×400). C, Electron microscopy showed round-shaped particles within the tubule lumena consistent with BK virions with a mean diameter of 41.5 nm.Recent studies have suggested a high prevalence of BK viremia and viruria among liver transplant recipients; however, there are conflicting data on their relationship with renal function.2,4,5 To date, there was only one other reported case of BKVN in a liver transplant recipient 7 years posttransplant who had received heavy immunosuppression to treat multiple rejection episodes.3 Little is known about the risk factors for the development of BKVN after liver transplant; however, both our patient and that previously reported are male, are older than 55 years, and have a history of greater than standard exposure to immunosuppression. In this case, the additional complication of cytomegalovirus colitis was also probably reflective of heavy immunosuppression used. As renal biopsy is not routinely performed in liver transplant patients with acute kidney injury, and with the perceived rarity of BKVN in this patient group, we suspect that BKVN is underrecognized. The optimal treatment of BKVN in native kidneys of recipients of organs other than kidneys is not known. The best available evidence supports a reduction in immunosuppression; however, other strategies, such as cidofovir and intravenous immunoglobulin, have also been used.1 Further studies are required to determine those liver recipients most at risk of developing BKVN and to investigate the role of renal biopsy in this group to assist in the timely detection and prompt management of this increasingly recognized complication.
There are increasing numbers of mutations described in the gene for type II collagen (COL2A1). Recently, COL2A1 mutations were shown to be associated with milder forms of chondrodysplasia, which may present with precocious generalized osteoarthritis (OA). The arginine519-cysteine and the arginine75-cysteine mutations are 2 such sites on COL2A1 where multiple unrelated families have been reported presenting with early onset, generalized OA and chondrodysplasia. The observation of multiple sites where recurrent mutations occur suggests that certain areas of COL2A1 are more prone to mutational events.
Abstract Background : Hip disease is a major cause of immobility and pain in children and young adults with inflammatory arthritides. Total hip arthroplasty (THA) has previously been avoided in young patients because of the concern about durability of the prosthesis and the need for multiple revisions. There are now, however, growing reports of the success of such procedures in improving mobility and relieving pain in the young patient with severe hip disease. In this study we aimed to determine the clinical and radiological results in patients with inflammatory arthritides who had undergone THA before the age of 35 years. Methods : Twenty‐one patients who had undergone a total of 38 hip arthroplasties were identified. Patients' hips were scored both pre‐operatively and at follow‐up using the scoring system of the Hospital for Special Surgery, which allots a score for pain, walking, motion and muscle power, and function. Complications were noted and follow‐up X‐rays were compared to postoperative films to assess radiological loosening. Results : The mean age at operation was 24 years, and the mean follow‐up was 8.6 years. The results in terms of pain relief, mobility, movement and functional capacity were good. Revision was required in 13 hips (34%). This was mostly due to the failure of resurfacing prostheses. Radiological loosening was evident in a further six hips, five of which were asymptomatic. Conclusions : THA can dramatically improve the quality of life of the young patient with arthritis. The main concern is the likely need for multiple revisions, with progressive loss of bone stock.
To define the genetic basis of a family with an autosomal, dominantly inherited form of spondyloepiphyseal dysplasia (SED) associated with tall stature.A 6 generation family with early onset osteoarthritis (OA) associated with mild SED was studied. 14 individuals were examined clinically and radiologically, and DNA analysis was performed on 5. As the clinical pattern of joint involvement and tall stature of affected individuals resembled a family recently reported with an exon 11 mutation in COL2A1, this same mutation was specifically sought. In 2 clinically affected and 3 unaffected family members, exon 11 was amplified by polymerase chain reaction (PCR) followed by restriction enzyme digestion with Asp H1, the enzyme recognition sequence of which is altered by the mutation. The PCR product containing exon 11 was then directly sequenced.OA with widespread involvement of peripheral joints, in addition to spondylodysplasia, was seen in 14 members of the kindred. Affected family members had brachydactyly and were of average to above average height. Asp H1 digestion of the PCR product containing exon 11 in those with clinical disease was consistent with the presence of a mutation. Direct sequencing of this PCR product conclusively showed that a single base substitution was present in those with clinical disease, resulting in an arginine 75-cysteine (Arg75-Cys) mutation.We describe a 3rd family with an Arg75-Cys mutation with precocious generalized OA and mild SED. This finding supports the concept of mutational hot spots on COL2A1 related to the hypermutability of the cytosine-guanine doublet.
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