A new corneal disease with recurrent erosive episodes and autosomal-dominant inheritance

Purpose: The aim of this study was to characterize the phenotype in a large family with autosomal-dominant recurrent corneal erosions, and also to exclude genetic linkage to known autosomal-dominant inherited corneal dystrophies with clinical resemblance. Methods: We describe the medical history and clinical findings in patients from a six-generation family with recurrent corneal erosions. A total of 28 individuals were evaluated by ophthalmological examination. Genomic DNA was prepared from peripheral blood and analysed with polymorphic microsatellite markers close to known genes causing autosomal-dominant corneal dystrophies. Results: The patients had erosive symptoms that usually lasted from 1 to 7 days. The symptoms were described as early as at 8 months of age, and by the age of 5 the majority of the affected individuals suffered from recurrent corneal erosions. The attacks generally declined in frequency and intensity with age, and 52% of the patients developed central keloid-like corneal opacities. Nine patients received corneal grafts, and recurrences were seen in all grafts. The affected patients did not share haplotypes for genetic microsatellite markers surrounding known genes causing autosomal-dominant corneal dystrophies. Conclusion: We describe a new hereditary disease with recurrent corneal erosions. Attacks of symptoms similar to recurrent erosions dominate the phenotype, but half of those affected also developed corneal, keloid-like, central opacities. This disorder was not genetically linked to any clinically resembling corneal dystrophies with autosomal-dominant inheritance

Dystrophia Helsinglandica: a new type of hereditary corneal recurrent erosions with late subepithelial fibrosis

Purpose: To describe the phenotype of an autosomal-dominant corneal dystrophy with an early onset of recurrent corneal erosions and development of subepithelial fibrosis in the cornea, and also to exclude genetic linkage to known corneal dystrophies with autosomal-dominant inheritance and clinical resemblance. Methods: We describe the medical history and clinical findings in individuals from a seven-generation family with recurrent corneal erosions. A total of 43 individuals were evaluated by ophthalmological examination. Genomic DNA was prepared from peripheral blood and polymorphic microsatellite markers were analysed to study haplotypes surrounding genes causing corneal dystrophies with similar phenotypes. Results: Erosive symptoms usually lasted for between 1 and 10 days. By the age of 7 almost all of the affected individuals suffered from recurrent corneal erosions. The attacks generally declined in frequency and intensity from the late 20s, but all examined individuals had developed subepithelial fibrosis by the age of 37. The fibrosis generally started in the mid periphery and was followed in some family members by central fibrosis and the development of gelatinous superficial elevations. Only a marginal reduction of visual acuity was seen in a few individuals. The affected individuals did not share haplotypes for genetic microsatellite markers surrounding genes that are known to cause autosomal-dominant corneal dystrophies. Conclusion: We describe a new type of autosomal-dominant corneal disorder with recurrent corneal erosions and subepithelial fibrosis not significantly affecting visual acuity

Prevalence of colonic neoplasia and advanced lesions in the normal population: a prospective population-based colonoscopy study

Objective: There are few prospective studies of the prevalence of colonic neoplasia in the normal population. In order to properly evaluate screening-protocols for colorectal cancer in risk groups (e.g., older subjects or those with a family history), it is essential to know the prevalence of adenomas and cancer in the normal population. Methods: A prospective population-based colonoscopy study on 745 individuals born in Sweden aged 19–70 years was conducted (mean age 51.1 years). All polyps seen were retrieved and examined. Results: Out of the 745 individuals 27% had polyps, regardless of kind. Adenomas were found in 10% of the individuals and finding of adenomas was positively correlated to higher age. Men had adenomas in 15% and women in 6% of the cases. Women had a right-sided dominance of adenomas. Hyperplastic polyps were seen in 21% of the individuals. The presence of hyperplastic polyps was significantly positively correlated to the presence of adenomas. Advanced adenomas were seen in 2.8% of the study participants, but no cancers were detected. Conclusion: One in 10 healthy subjects had an adenoma but advanced adenomas were uncommon. Men and women have a different adenoma prevalence and localization. The results provide baseline European data for evaluating colonoscopy screening-protocols for colorectal cancer risk groups, and the findings may have implications for colon cancer screening in the normal, otherwise-healthy population

A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families

BackgroundLynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families.MethodsData were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population.ResultsA total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations.ConclusionLynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2-carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types

A retrospective two centre study of Birt-Hogg-Dube syndrome reveals a pathogenic founder mutation in FLCN in the Swedish population

Birt-Hogg-Dube syndrome (BHDS) (MIM: 135150) is a rare autosomal dominant disorder with variable penetrance, caused by pathogenic variants in the FLCN gene. Only a few hundreds of families have so far been described in the literature. Patients with BHDS present with three distinct symptoms: fibrofolliculomas, pneumothorax due to lung cyst formation, and increased lifetime risk of kidney tumours. The aim of the current study was to estimate the incidence of BHDS in the Swedish population and further describe the clinical manifestations and their frequency. Splice variant c.779+1G>T was the most common pathogenic variant, found in 57% of the families, suggesting this may be a founder mutation in the Swedish population. This was further investigated using haplotype analysis in 50 families that shared a common haplotype. Moreover, according to gnomAD the carrier frequency of the c.779+1G>T variant has been estimated to be 1/3265 in the Swedish population, however our data suggest that the carrier frequency in the Swedish population may be significantly higher. These findings should raise awareness among physicians of different specialties to patients presenting with fibrofolliculomas, pneumothorax and/or kidney tumours. We also stress the importance of consensus recommendations regarding diagnosis and clinical management of this, not that uncommon, syndrome

Summary of a workshop on extreme weather events in a warming world organized by the Royal Swedish Academy of Sciences

Climate change is not only about changes in means of climatic variables such as temperature, precipitation and wind, but also their extreme values which are of critical importance to human society and ecosystems. To inspire the Swedish climate research community and to promote assessments of international research on past and future changes in extreme weather events against the global climate change background, the Earth Science Class of the Royal Swedish Academy of Sciences organized a workshop entitled ‘Extreme weather events in a warming world’ in 2019. This article summarizes and synthesizes the key points from the presentations and discussions of the workshop on changes in floods, droughts, heat waves, as well as on tropical cyclones and extratropical storms. In addition to reviewing past achievements in these research fields and identifying research gaps with a focus on Sweden, future challenges and opportunities for the Swedish climate research community are highlighted

Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation

Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.Peer reviewe

Hereditary spastic paraplegia 3A associated with axonal neuropathy

OBJECTIVE: To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia. DESIGN: We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4. RESULTS: In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy. CONCLUSIONS: We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A.status: publishe