Brain Abnormalities in Patients with Germline Variants in H3F3: Novel Imaging Findings and Neurologic Symptoms Beyond Somatic Variants and Brain Tumors.

BACKGROUND AND PURPOSE: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B (H3F3) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants. MATERIALS AND METHODS: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range. RESULTS: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation. CONCLUSIONS: Imaging phenotypes in germline H3F3-affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles.

Genome-wide association analysis suggests novel loci for Hashimoto's thyroiditis.

PURPOSE: Hashimoto's thyroiditis (HT) is the most common form of autoimmune thyroid diseases. Current knowledge of HT genetics is limited, and not a single genome-wide association study (GWAS) focusing exclusively on HT has been performed to date. In order to decipher genetic determinants of HT, we performed the first GWAS followed by replication in a total of 1443 individuals from Croatia. METHODS: We performed association analysis in a discovery cohort comprising 405 cases and 433 controls. We followed up 13 independent signals (P < 10-5) in 303 cases and 302 controls from two replication cohorts and then meta-analyzed results across discovery and replication datasets. RESULTS: We identified three variants suggestively associated with HT: rs12944194 located 206 kb from SDK2 (P = 1.8 × 10-6), rs75201096 inside GNA14 (P = 2.41 × 10-5) and rs791903 inside IP6K3 (P = 3.16 × 10-5). Genetic risk score (GRS), calculated using risk alleles of these loci, accounted for 4.82% of the total HT variance, and individuals from the top GRS quartile had 2.76 times higher odds for HT than individuals from the lowest GRS quartile. CONCLUSIONS: Although discovered loci are implicated with susceptibility to HT for the first time, genomic regions harboring these loci exhibit good biological candidacy due to involvement in the regulation of the thyroid function and autoimmunity. Additionally, we observe genetic overlap between HT and several related traits, such as hypothyroidism, Graves' disease and TPOAb. Our study adds a new knowledge of underlying HT genetics and sets a firm basis for further research.

[Onset of a fulminant malignant hyperthermia crisis. Case report of a 74-year-old patient with previously subclinical central core disease]. / Erstmanifestation einer fulminanten malignen-hyperthermie-krise. Fall eines 74-jährigen patienten mit bislang subklinischer "central core disease".

Malignant hyperthermia (MH) is a latent, autosomal dominant inherited syndrome of skeletal musculature which results in excessive hypermetabolism induced by halogenated anesthetic agents and depolarizing muscle relaxants and is caused by an uncontrolled intramuscular calcium release. This case report focuses on the description of symptoms of a fulminant MH crisis. A possible link between central core disease (CCD) and the clinical severity of MH crisis is postulated in this paper.

[Werner syndrome. A prototypical form of segmental progeria.] / Werner-Syndrom.

Werner syndrome is a segmental progeroid disorder with onset in adolescence or early adulthood. Typical symptoms contributing to patients' prematurely aged appearance include postpubertal development of short stature, cataracts, premature greying/thinning of scalp hair, scleroderma-like skin changes and regional atrophy of subcutaneous fat tissue. In addition, an increased rate and early onset of typical age-related diseases such as type 2 diabetes mellitus, osteoporosis, atherosclerosis, and various malignancies is observed. Werner syndrome is autosomal recessively inherited and caused by mutations in the Werner gene (WRN). To date, more than 70 WRN mutations have been identified. These are spread over the entire gene and typically represent loss of function mutations. WRN encodes a RecQ type helicase involved in DNA repair and the maintenance of DNA integrity, which is reflected by an increased genetic instability in patient cells. Despite the relative rarity of Werner syndrome, its analysis provides important general insights into the roles of DNA stability and integrity for the ageing process and the development of age-associated diseases.

A Novel LMNA Mutation Causes Altered Nuclear Morphology and Symptoms of Familial Partial Lipodystrophy (Dunnigan Variety) with Progeroid Features.

Dunnigan-type partial lipodystrophy (familial partial lipodystrophy, Dunnigan variety, FPLD2) can be caused by LMNA mutations. We identified a novel heterozygous LMNA mutation, P485R, in a patient referred to the International Registry of Werner Syndrome because of features consistent with that of progeroid disorder but who was wild type at the WRN locus. The novel mutation is located 2 amino acids away from the canonical FPLD mutations in exon 8 of the LMNA gene. Immunocytochemical analysis revealed abnormal nuclear morphology characteristic of laminopathies within primary fibroblast cultures, but not in a lymphoblastoid cell line, in keeping with previous observations. Our findings indicate that FPLD2 should be considered in the differential diagnosis of the Werner syndrome.