Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively - coincidence within one family

<p>Abstract</p> <p>Background</p> <p>Osteopoikilosis is a rare autosomal dominant genetic disorder, characterised by the occurrence of the hyperostotic spots preferentially localized in the epiphyses and metaphyses of the long bones, and in the carpal and tarsal bones <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. Heterozygous <it>LEMD3 </it>gene mutations were shown to be the primary cause of the disease <abbrgrp><abbr bid="B2">2</abbr></abbrgrp>. Association of the primarily asymptomatic osteopokilosis with connective tissue nevi of the skin is categorized as Buschke-Ollendorff syndrome (BOS) <abbrgrp><abbr bid="B3">3</abbr></abbrgrp>. Additionally, osteopoikilosis can coincide with melorheostosis (MRO), a more severe bone disease characterised by the ectopic bone formation on the periosteal and endosteal surface of the long bones <abbrgrp><abbr bid="B4">4</abbr><abbr bid="B5">5</abbr><abbr bid="B6">6</abbr></abbrgrp>. However, not all MRO affected individuals carry germ-line <it>LEMD3 </it>mutations <abbrgrp><abbr bid="B7">7</abbr></abbrgrp>. Thus, the genetic cause of MRO remains unknown. Here we describe a familial case of osteopoikilosis in which a novel heterozygous <it>LEMD3 </it>mutation coincides with a novel mutation in <it>EXT1</it>, a gene involved in aetiology of multiple exostosis syndrome. The patients affected with both <it>LEMD3 </it>and <it>EXT1 </it>gene mutations displayed typical features of the osteopoikilosis. There were no additional skeletal manifestations detected however, various non-skeletal pathologies coincided in this group.</p> <p>Methods</p> <p>We investigated <it>LEMD3 </it>and <it>EXT1 </it>in the three-generation family from Poland, with 5 patients affected with osteopoikilosis and one child affected with multiple exostoses.</p> <p>Results</p> <p>We found a novel c.2203C > T (p.R735X) mutation in exon 9 of <it>LEMD3</it>, resulting in a premature stop codon at amino acid position 735. The mutation co-segregates with the osteopoikilosis phenotype and was not found in 200 ethnically matched controls. Another new substitution G > A was found in <it>EXT1 </it>gene at position 1732 (cDNA) in Exon 9 (p.A578T) in three out of five osteopoikilosis affected family members. Evolutionary conservation of the affected amino acid suggested possible functional relevance, however no additional skeletal manifestations were observed other then those specific for osteopoikilosis. Finally in one member of the family we found a splice site mutation in the <it>EXT1 </it>gene intron 5 (IVS5-2 A > G) resulting in the deletion of 9 bp of cDNA encoding three evolutionarily conserved amino acid residues. This child patient suffered from a severe form of exostoses, thus a causal relationship can be postulated.</p> <p>Conclusions</p> <p>We identified a new mutation in <it>LEMD3 </it>gene, accounting for the familial case of osteopoikilosis. In the same family we identified two novel <it>EXT1 </it>gene mutations. One of them A598T co-incided with the <it>LEMD3 </it>mutation. Co-incidence of <it>LEMD3 </it>and <it>EXT1 </it>gene mutations was not associated with a more severe skeletal phenotype in those patients.</p

The predictive value of anti-cyclic citrullinated peptide antibodies in early arthritis.

OBJECTIVE: To assess the additional predictive value of anti-cyclic citrullinated peptide (anti-CCP) antibodies above conventional variables for progressive erosive or disabling disease in a cohort of patients with early inflammatory oligo- and polyarthritis. Methods. Consecutive new patients with peripheral arthritis of > 2 joints and < 2 years of symptom duration, referred between 1995 and 1999 were studied. Excluded were patients with bacterial, psoriatic, crystal-induced arthritis or spondyloarthropathy. Optimal cut-off values for serum IgM-rheumatoid factor (RF) and anti-CCP were deduced from receiver operating characteristics curves. At 2 year followup, progressive erosive disease was defined as: radiographic progression > 5 (Sharp-van der Heijde units) and low functional capacity as a Health Assessment Questionnaire score > 1. For the statistical analysis, a logistic regression model was used. RESULTS: A total of 282 patients [68% female, median age 56 yrs (18-83)] were included. Thirty-two percent of the patients were positive for anti-CCP at baseline. Anti-CCP correlated significantly (p < 0.001) with a progressive erosive disease after 2 years, but not with a low functional capacity. The combination of a positive anti-CCP status and radiographic damage at baseline could predict the radiographic progression with a sensitivity, specificity, and accuracy of 78%, 82%, and 81%, respectively. The positive predictive value (PPV) for radiographic progressive disease was 63%, while the negative predictive value (NPV) was 90%. The accuracy of the model decreased from 81 to 76% after leaving out anti-CCP from the model. In a subgroup of 178 IgM-RF negative patients, the PPV for radiographic progressive disease was 40%, while the NPV was 95%. CONCLUSION: Anti-CCP positivity has a small additional value above the conventional prognostic variables for progressive erosive disease in a cohort of patients with early inflammatory oligo- and polyarthritis. The prognostic value of anti-CCP lies mainly in its ability to predict mild disease. This effect is accentuated in the subgroup of IgM-RF negative patients

CARD15 gene mutations are not associated with ankylosing spondylitis.

An insertion mutation at nucleotide 3020 (3020insC) and a missense mutation G2722C in the CARD15 gene on chromosome 16p have been reported to be associated with Crohn's disease (CD). The protein encoded by the CARD15 gene is expressed in peripheral monocytes and regulates apoptosis and NF-κB activation, factors which play an important role in inflammation. Since CD and ankylosing spondylitis (AS) are interrelated disorders, we have investigated whether these mutations in the CARD 15 gene are also associated with AS. We studied 113 unrelated AS patients and 152 unrelated healthy controls. No significant differences were found between patients and controls in the prevalence of the insertion 3020insC mutation and the G2722C missense mutation, OR = 1.36, 95% CI: 0.27-6.84, P = 0.70 and OR = 0. 58; 95% CI: 0. 18-1.94; P = 0.38, respectively. We conclude that the insertion 3020insC mutation and the G2722C missense mutation in the CARD15 gene are not involved in the susceptibility to AS. © 2003 Nature Publishing Group All rights reserved

Preventing progression from arthralgia to arthritis: targeting the right patients

Pathophysiology and treatment of rheumatic disease

IgG4 Characteristics and Functions in Cancer Immunity

IgG4 is the least abundant subclass of IgG in normal human serum, but elevated IgG4 levels are triggered in response to a chronic antigenic stimulus and inflammation. Since the immune system is exposed to tumor-associated antigens over a relatively long period of time, and tumors notoriously promote inflammation, it is unsurprising that IgG4 has been implicated in certain tumor types. Despite differing from other IgG subclasses by only a few amino acids, IgG4 possesses unique structural characteristics that may be responsible for its poor effector function potency and immunomodulatory properties. We describe the unique attributes of IgG4 that may be responsible for these regulatory functions, particularly in the cancer context. We discuss the inflammatory conditions in tumors that support IgG4, the emerging and proposed mechanisms by which IgG4 may contribute to tumor-associated escape from immune surveillance and implications for cancer immunotherapy