Fetal hydrops caused by a novel pathogenic MECOM variant.

We report a fetus with hydrops, congenital heart disease and bilateral radioulnar synostosis caused by a novel pathogenic MECOM variant. The female fetus was referred for post-mortem examination after fetal hydrops and intrauterine death was diagnosed at 20 weeks gestation. Post-mortem examination confirmed fetal hydrops, pallor, truncus arteriosus and bilateral radioulnar synostosis. Trio whole genome sequencing analysis detected a novel de novo heterozygous pathogenic loss-of-function variant in MECOM (NM_004991), associated with a diagnosis of Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2 (RUSAT-2). RUSAT-2 is a variable condition associated postnatally with bone marrow failure, radioulnar synostosis and congenital anomalies. RUSAT-2 is not currently associated with a prenatal phenotype or fetal demise, and was not present on diagnostic NHS prenatal gene panels at time of diagnosis. This case highlights the diagnostic value of detailed phenotyping with post-mortem examination, and of using a broad sequencing approach.

VHL mutation analysis in patients with isolated central nervous system haemangioblastoma.

Haemangioblastomas of the CNS are a cardinal feature of von Hippel-Lindau (VHL) disease, a dominantly inherited multisystem familial cancer syndrome caused by germline mutation of the VHL tumour suppressor gene. We investigated the frequency of VHL mutations in 188 patients presenting with a single haemangioblastoma, no family history of VHL disease and no evidence of retinal or abdominal manifestations of the disease at the time of diagnosis. We found that approximately 4% of patients had a detectable VHL mutation and all of these cases presented age 40 years or less. Although the identification of a germline VHL mutation has important consequences for the patient (e.g. risk of further CNS and extra-CNS tumours) and their relatives, four patients had germline VHL missense mutations [C162Y, D179N and R200W (two patients)] that may represent haemangioblastoma-only and/or low penetrance mutations. Approximately 5% of patients without a detectable VHL mutation subsequently developed a further 'VHL type tumour' (in most cases a further CNS haemangioblastoma). These findings suggest that a subset of patients with apparently sporadic CNS haemangioblastoma will have a germline VHL mutation but may not be at risk for developing classical VHL disease and a further group may be mosaic for a germline VHL mutation that cannot be detected in blood cells.

Bilateral epiretinal membranes in Gorlin syndrome associated with a novel PTCH mutation.

PURPOSE: To present the detailed ocular phenotype of a subject with Gorlin syndrome (GS) (basal cell nevus syndrome; OMIM 109400) and to undertake mutation screening of the gene Patched (PTCH). DESIGN: Interventional case report. METHODS: Clinical examination, color fundus photography, fundus autofluorescence imaging, optical coherence tomography (OCT), detailed electrophysiological assessment, and mutation screening of PTCH. The protocol of the study was approved by the local Ethics Committee and informed consent was obtained. RESULTS: A 34-year-old man with findings consistent with GS was identified. Ophthalmoscopy and OCT identified bilateral epiretinal membranes (ERMs). Fundus autofluorescence (AF) imaging and electrophysiological testing [full-field electroretinogram (ERG), pattern ERG, and electrooculogram] were normal. Mutation screening identified a novel nonsense mutation in PTCH (c.1136C > G; p.Ser383X), the gene associated with GS. CONCLUSIONS: We present a case of bilateral ERM in GS with a molecular genetic diagnosis. We also document data supporting the lack of focal or generalized retinal dysfunction.

Neuroblastoma - a developmental perspective.

Genetic investigation of neuroblastoma has provided few clues to account for the variability in clinical phenotype which is such a characteristic feature of this tumour. Indeed, efforts to identify the primary genetic event(s) responsible for tumour development have been overwhelmed by the number and range of different genetic abnormalities observed, particularly in the more aggressive neuroblastoma subtypes. Since neuroblastoma is a consequence of aberrant development of the sympathetic nervous system (SNS), investigation of the genetic components known to be involved in the control of SNS developmental, may provide the key to understanding tumour behaviour. The neurotrophins and the glial family ligands both play very significant roles in different stages of SNS development and merit more detailed investigation as to how they might influence neuroblastoma tumorigenesis.