ABSTRACT
Neurosarcoidosis represents a significant diagnostic challenge, as clinical features overlap with other neuroinflammatory conditions, and biopsy of affected neuronal tissue is often high risk or not feasible. Here we highlight application of the modified Zajicek criteria to diagnose probable spinal neurosarcoidosis in the absence of histology from affected neuronal tissue.
ABSTRACT
Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur-Chung neurodevelopmental syndrome. More recently, through trio-based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome.
Subject(s)
Mutation , Neurodevelopmental Disorders/diagnosis , Neurodevelopmental Disorders/genetics , Phenotype , Alleles , Amino Acid Motifs , Amino Acid Sequence , Amino Acid Substitution , Casein Kinase II/chemistry , Casein Kinase II/genetics , Child , Exons , Facies , Female , Humans , Male , Protein Binding , Protein Interaction Domains and MotifsSubject(s)
Asthma/complications , Churg-Strauss Syndrome/diagnosis , Cyclophosphamide/administration & dosage , Glomerulonephritis/diagnosis , Glucocorticoids/administration & dosage , Immunosuppressive Agents/administration & dosage , Methylprednisolone/administration & dosage , Aged , Asthma/immunology , Asthma/physiopathology , Churg-Strauss Syndrome/drug therapy , Churg-Strauss Syndrome/immunology , Dyspnea , Glomerulonephritis/drug therapy , Glomerulonephritis/immunology , Humans , Male , Myalgia , Renal Dialysis/methods , Treatment OutcomeABSTRACT
Wilms' tumour (WT) is a pediatric tumor of the kidney that arises via failure of the fetal developmental program. The absence of identifiable mutations in the majority of WTs suggests the frequent involvement of epigenetic aberrations in WT. We therefore conducted a genome-wide analysis of promoter hypermethylation in WTs and identified hypermethylation at chromosome 5q31 spanning 800 kilobases (kb) and more than 50 genes. The methylated genes all belong to alpha-, beta-, and gamma-protocadherin (PCDH) gene clusters (Human Genome Organization nomenclature PCDHA@, PCDHB@, and PCDHG@, respectively). This demonstrates that long-range epigenetic silencing (LRES) occurs in developmental tumors as well as in adult tumors. Bisulfite polymerase chain reaction analysis showed that PCDH hypermethylation is a frequent event found in all Wilms' tumor subtypes. Hypermethylation is concordant with reduced PCDH expression in tumors. WT precursor lesions showed no PCDH hypermethylation, suggesting that de novo PCDH hypermethylation occurs during malignant progression. Discrete boundaries of the PCDH domain are delimited by abrupt changes in histone modifications; unmethylated genes flanking the LRES are associated with permissive marks which are absent from methylated genes within the domain. Silenced genes are marked with non-permissive histone 3 lysine 9 dimethylation. Expression analysis of embryonic murine kidney and differentiating rat metanephric mesenchymal cells demonstrates that Pcdh expression is developmentally regulated and that Pcdhg@ genes are expressed in blastemal cells. Importantly, we show that PCDHs negatively regulate canonical Wnt signalling, as short-interfering RNA-induced reduction of PCDHG@ encoded proteins leads to elevated beta-catenin protein, increased beta-catenin/T-cell factor (TCF) reporter activity, and induction of Wnt target genes. Conversely, over-expression of PCDHs suppresses beta-catenin/TCF-reporter activity and also inhibits colony formation and growth of cancer cells in soft agar. Thus PCDHs are candidate tumor suppressors that modulate regulatory pathways critical in development and disease, such as canonical Wnt signaling.
