Exploratory Study of MYD88 L265P, Rare NLRP3 Variants, and Clonal Hematopoiesis Prevalence in Patients With Schnitzler Syndrome.

Objective: To assess the prevalence of the MYD88 L265P mutation and variants within NLRP3 and evaluate the status of oligoclonal hematopoiesis in 30 patients with Schnitzler syndrome (SchS).

Methods: Thirty patients with SchS were recruited from 3 clinical centers. Six patients with known acquired cryopyrin-associated periodic syndromes (aCAPS) were included as controls.

How to prescribe a genetic test for the diagnosis of autoinflammatory diseases?

The systemic autoinflammatory disorders (SAIDs) are associated with dysregulation of the innate immune system, affecting pro-inflammatory cytokines and apoptosis pathways. The spectrum of SAIDs continues to grow with over 30 different disorders identified to date. The main indication for genetic referral is when a patient presents with clinical symptoms consistent with one or more of the SAIDs.

Molecular genetic investigation, clinical features, and response to treatment in 21 patients with Schnitzler syndrome.

To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1β (IL-1β) production, although interest in the contribution of genetic factors has been fueled by detection of somatic mosaicism in 2 patients with the variant-type Schnitzler syndrome. At 2 specialist UK centers, we have identified 21 patients who fulfilled diagnostic criteria for Schnitzler syndrome with urticarial rash, fever, arthralgia, and bone pain; 47% reported weight loss, 40% fatigue, and 21% lymphadenopathy. An immunoglobulin M (IgM) κ paraprotein was detected in 86%; the remainder had IgM λ or IgG κ.

Late-Onset Cryopyrin-Associated Periodic Syndromes Caused by Somatic NLRP3 Mosaicism-UK Single Center Experience.

Cryopyrin-associated periodic syndrome (CAPS) is caused by mutations. Recently, somatic mosaicism has been reported in some CAPS patients who were previously classified as "mutation-negative." We describe here the clinical and laboratory findings in eight British adult patients who presented with symptoms typical of CAPS other than an onset in mid-late adulthood.

International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors.

Objective: To provide outcome data concerning pregnancies exposed to the Interleukin-1 (IL-1) inhibitors prior to conception in both men and women, during pregnancy and breast feeding.

Methods: Retrospective data were collected from members of the International Society for Systemic Autoinflammatory diseases and collated in a single centre. A uniform data collection sheet was used to obtain standardized data including maternal age and diagnosis, type, duration of and response to IL-1 blockade, pregnancy duration, delivery, mode of feeding and neonatal development.

Changing epidemiology of AA amyloidosis: clinical observations over 25 years at a single national referral centre.

Objective: Systemic AA amyloidosis is a serious complication of chronic inflammation; however, there are relatively few published data on its incidence. We investigated the changing epidemiology of AA amyloidosis over a 25-year period at a single national referral centre.

Methods: We conducted a retrospective study of all patients diagnosed with AA amyloidosis who had attended the centre between 1990 and 2014 inclusive.

Occult Transthyretin Cardiac Amyloid in Severe Calcific Aortic Stenosis: Prevalence and Prognosis in Patients Undergoing Surgical Aortic Valve Replacement.

Background: Calcific aortic stenosis (cAS) affects 3% of individuals aged >75 years, leading to heart failure and death unless the valve is replaced. Wild-type transthyretin cardiac amyloid is also a disorder of ageing individuals. Prevalence and clinical significance of dual pathology are unknown.

Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue-a case series and genetic exploration.

Objective: This study was undertaken to characterize the phenotype and response to treatment in patients with autosomal dominant FMF caused by MEFV p.M694del mutation and to use haplotype reconstruction to investigate the possibility of common ancestry.

Methods: MEFV gene was analysed in 3500 subjects with suspected FMF referred to a single UK centre between 2002 and 2014.

Brief Report: Association of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome With Gonosomal Mosaicism of a Novel 24-Nucleotide TNFRSF1A Deletion.

Objective: To investigate the molecular cause of persistent fevers in a patient returning from working overseas, in whom investigations for tropical diseases yielded negative results.

Methods: DNA was extracted from the patient's whole blood, leukocyte subpopulations, saliva, hair root, and sperm. The TNFRSF1A gene was analyzed by polymerase chain reaction (PCR), allele-specific PCR, Sanger sequencing, and next-generation sequencing.

A novel transthyretin variant p.H110D (H90D) as a cause of familial amyloid polyneuropathy in a large Irish kindred.

Hereditary transthyretin (ATTR) amyloidosis is caused by inheritance of an abnormal TTR gene in an autosomal dominant fashion. In its native state, TTR is a homotetramer consisting of four identical polypeptides. Mutations in the TTR gene contribute to destabilization and dissociation of the TTR tetramer, enabling abnormally folded monomers to self-assemble as amyloid fibrils.

Online registry for mutations in hereditary amyloidosis including nomenclature recommendations.

Hereditary systemic amyloidosis comprises a group of rare monogenic diseases inherited in an autosomal dominant fashion. It is associated with mutations in genes encoding eight different proteins, including transthyretin, apolipoprotein AI, apolipoprotein AII, lysozyme, fibrinogen A α-chain, cystatin C, gelsolin and beta-2-microglobulin. With support from the EU FP6 EURAMY project we have designed an online registry of genes and mutations in hereditary amyloidosis including their associated clinical phenotypes, with a view to having a single free online portal for the collection and distribution of this information.

Brief Report: whole-exome sequencing revealing somatic NLRP3 mosaicism in a patient with chronic infantile neurologic, cutaneous, articular syndrome.

Objective: To identify the genetic cause of chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) using whole-exome sequencing in a child who had typical clinical features but who was NLRP3 mutation negative based on conventional Sanger sequencing.

Methods: We performed whole-exome sequencing on DNA from peripheral blood, using Illumina TruSeq Exome capture and the HiSeq sequencing platform. Exome data were analyzed in the Galaxy Web-based suite.

Retinal microangiopathy as an initial manifestation of familial amyloid cardiomyopathy associated with transthyretin e89k mutation.

Purpose: To report a rare case of transthyretin (TTR) familial amyloid cardiomyopathy with retinal microangiopathy and vitreous amyloid as the initial manifestation.

Methods: A 54-year-old woman presented with bilateral retinal microangiopathy, presumed idiopathic retinal vasculitis. She subsequently developed retinal ischemia associated vitreous hemorrhage and was treated with panretinal laser photocoagulation.

Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature.

Introduction: Mutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). The significance of the V198M variant is unclear; it has been reported in association with various CAPS phenotypes and as a variant of uncertain consequence. The aim of this study was to characterize the clinical phenotypes and treatments in individuals with V198M assessed in a single UK center.

AA amyloidosis complicating the hereditary periodic fever syndromes.

Objective: AA amyloidosis is a life-threatening complication of the hereditary periodic fever syndromes (HPFS), which are otherwise often compatible with normal life expectancy. This study was undertaken to determine the characteristics, presentation, natural history, and response to treatment in 46 patients who had been referred for evaluation at the UK National Amyloidosis Centre.

Methods: Disease activity was monitored by serial measurement of serum amyloid A.

A prospective study of nutritional status in immunoglobulin light chain amyloidosis.

Weight loss is common in systemic immunoglobulin light chain amyloidosis but there are limited data on the impact of nutritional status on outcome. Using the Patient-Generated Subjective Global Assessment (PG-SGA) score, we prospectively examined nutritional status in 110 consecutive newly-diagnosed, treatment-naïve patients with immunoglobulin light chain amyloidosis attending the UK National Amyloidosis Centre. At study entry, 72 of 110 (66%) patients had a PG-SGA score of 4 or over, indicating malnutrition requiring specialist nutritional intervention.

AA amyloidosis complicating hyperimmunoglobulinemia D with periodic fever syndrome: a report of two cases.

AA amyloidosis is the most serious potential complication of the inherited autoinflammatory syndromes and frequently results in end-stage renal failure. Although this complication is well recognized in familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and Muckle-Wells syndrome, there is only 1 previous published report of its occurrence in hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). We report 2 further cases of patients with AA amyloidosis in HIDS, both of whom developed dialysis-dependent renal failure, and we describe the outcome of the first renal transplant in this setting.