Consideration concerning similarities and differences between ANCA-associated vasculitis and IgG-4-related diseases: case series and review of literature.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and immunoglobulin G4-related diseases (IgG4-RD) are regarded as entirely different disease types with different etiological mechanisms. However, we experienced two cases that had clinical features of both AAV and IgG4-RD. The first case is an 81-year-old woman who showed periaortitis and retroperitoneal fibrosis and periarteritis with elevation of myeloperoxidase-anti-neutrophil cytoplasmic antibody and IgG4 levels. The second case is a 63-year-old woman who had dura mater, ear, nose, lung, and kidney involvement with serum negative for ANCA and elevated IgG4. Renal biopsy revealed tubulointerstitial nephritis involving IgG4+ plasma cells (IgG4+/IgG+ cell ratio of ≥ 40%). On the other hand, lung biopsy showed features of granulomatosis with polyangiitis (GPA). These two cases suggested that AAV and IgG4-RD might overlap. To investigate the similarities and differences between AAV and IgG4-RD, we retrospectively analyzed 13 cases of typical GPA, a subtype of AAV, and 13 cases of typical IgG4-RD at our hospital for comparison of clinical features and found some differences that can be useful in the differential diagnosis between the two diseases. Although AAV and IgG4-RD are distinguishable based on characteristic findings in many cases, the diagnosis can be unclear in rare cases, in which clinicians should consider possible coexistence of AAV and IgG4-RD when performing further workup. Here, we discuss the similarities and differences between AAV and IgG4-RD on the basis of our results and past literature.

Identification of biallelic LRRK1 mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity.

BACKGROUND: Osteosclerotic metaphyseal dysplasia (OSMD) is a unique form of osteopetrosis characterised by severe osteosclerosis localised to the bone ends. The mode of inheritance is autosomal recessive. Its genetic basis is not known. OBJECTIVE: To identify the disease gene for OSMD. METHODS AND RESULTS: By whole exome sequencing in a boy with OSMD, we identified a homozygous 7 bp deletion (c.5938_5944delGAGTGGT) in the LRRK1 gene. His skeletal phenotype recapitulated that seen in the Lrrk1-deficient mouse. The shared skeletal hallmarks included severe sclerosis in the undermodelled metaphyses and epiphyseal margins of the tubular bones, costal ends, vertebral endplates and margins of the flat bones. The deletion is predicted to result in an elongated LRRK1 protein (p.E1980Afs*66) that lacks a part of its WD40 domains. In vitro functional studies using osteoclasts from Lrrk1-deficient mice showed that the deletion was a loss of function mutation. Genetic analysis of LRRK1 in two unrelated patients with OSMD suggested that OSMD is a genetically heterogeneous condition. CONCLUSIONS: This is the first study to identify the causative gene of OSMD. Our study provides evidence that LRRK1 plays a critical role in the regulation of bone mass in humans.

Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.

Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.

GPC3 mutations in seven patients with Simpson-Golabi-Behmel syndrome.

We analyzed mutations of the GPC3gene in seven males with typical manifestations of Simpson-Golabi-Behmel syndrome (SGBS). Genomic DNA was PCR amplified for its all eight exons and exon-intron boundaries using designed set of primers, and PCR products were directly sequenced. All seven males studied had mutations: One patient had a large deletion spanning introns 6 and 7, four each had a C --> T base substitution resulting in a stop codon formation in exons 2, 3, and 4, one had a single-base insertion in exon 2, and the other had a six-base deletion and a three-base insertion in exon 3; all resulting in loss-of-function of the glypican-3 protein. These results, together with previous studies of GPC3 mutations, indicate that there is no hot spot for GPC3 mutations or deletions in the patients with the syndrome. Also, no correlation has been noted between the location and nature of mutations and the phenotype of the patients studied, as is the case of the present study.

A woman with 46,XX,dup(16)(p13.11 p13.3) and the ATR-X phenotype.

We report a Japanese woman with 46,XX,dup(16)(p13.11p13.3), who closely resembled the phenotype of X-linked alpha-thalassemia/mental retardation syndrome (ATR-X, MIM # 301040). Although she never had alpha-thalassemia, she showed characteristic clinical features including severe mental retardation, characteristic facies and behavior. ATR-X is caused by mutations of the ATRX gene. Although the function of ATRX protein has remained unclarified, it is thought to be involved in the regulation of several genes. The only target gene identified so far is the alpha-globin gene at 16p13.3. Clinical similarity among patients with ATR-X and dup(16)(p13.11p13) may indicate that some target genes regulated by ATRX reside in the duplicated region between 16p13.11 and 16p13.3, and that these genes are abnormally upregulated in ATR-X differently from the alpha-globin gene.

Effect of surface treatment on the bonding of an autopolymerizing soft denture liner to a denture base resin.

PURPOSE: This in vitro study evaluated the effects of surface treatments and thermocycling on the bonding of autopolymerizing silicone soft denture liner (Sofreliner) to denture base resin. MATERIALS AND METHODS: The bonding surfaces of denture base cylinders were polished with 600-grit silicon carbide paper and pretreated with applications of Sofreliner Primer, Sofreliner Primer after air abrasion, Reline Primer, or Reline Primer after air abrasion. Failure loads and elongation at failure were measured after subjecting specimens to 0, 10,000, 20,000, and 30,000 thermocycles. Failure modes were assessed for all specimens. Seven specimens were fabricated for each of 16 groups, including four pretreatments and four thermocycle groups. RESULTS: Failure loads of the Sofreliner Primer group were significantly higher than those of the air-abrasion group up to 20,000 thermocycles; both groups showed cohesive failures of the soft denture liner. Failure loads of the Reline Primer group were significantly higher than with Reline Primer after air abrasion up to 10,000 thermocycles. Failure mode after 10,000 thermocycles was cohesive for the Reline Primer group and mixed cohesive/adhesive for Reline Primer after air abrasion. Failure loads of the Sofreliner Primer group were significantly higher than those of the Reline Primer group at each thermocycling interval. Elongation values decreased after 10,000 thermocycles for all groups. CONCLUSION: Air abrasion on the denture base resin surface was not effective in enhancing failure load. Cyclic thermal stress is one factor degrading the bond between soft denture liner and acrylic resin denture base.