Congenital anaemia associated with loss-of-function variants in DNA polymerase epsilon 1.

DNA polymerase epsilon (Pol ε), a component of the core replisome, is involved in DNA replication. Although genetic defects of Pol ε have been reported to cause immunodeficiency syndromes, its role in haematopoiesis remains unknown. Here, we identified compound heterozygous variants (p.[Asp1131fs];[Thr1891del]) in POLE, encoding Pol ε catalytic subunit A (POLE1), in siblings with a syndromic form of severe congenital transfusion-dependent anaemia. In contrast to Diamond-Blackfan anaemia, marked reticulocytopenia or marked erythroid hypoplasia was not found. Their bone marrow aspirates during infancy revealed erythroid dysplasia with strongly positive TP53 in immunostaining. Repetitive examinations demonstrated trilineage myelodysplasia within 2 years from birth. They had short stature and facial dysmorphism. HEK293 cell-based expression experiments and analyses of patient-derived induced pluripotent stem cells (iPSCs) disclosed a reduced mRNA level of Asp1131fs-POLE1 and defective nuclear translocation of Thr1891del-POLE1. Analysis of iPSCs showed compensatory mRNA upregulation of the other replisome components and increase of the TP53 protein, both suggesting dysfunction of the replisome. We created Pole-knockout medaka fish and found that heterozygous fishes were viable, but with decreased RBCs. Our observations expand the phenotypic spectrum of the Pol ε defect in humans, additionally providing unique evidence linking Pol ε to haematopoiesis.

Use of Cervical Ultrasonography in Globus Sensation Investigation: A Retrospective Cohort Study.

BACKGROUND: A globus sensation is one of the most common complaints in otolaryngological practice. Patients with no associated abnormalities detected during the usual examinations performed in ENT clinics, are being diagnosed with globus sensation. Cervical ultrasonography is usually not performed in ENT clinics; however, it is useful in screening diseases of the subcutaneous tissue/organs, whose detection is not possible with the routine ENT examinations. The purpose of our study was to elucidate whether cervical ultrasound examination identifies abnormalities in patients with globus sensation. METHODS: A single-centre retrospective cohort study. Cervical ultrasonographic examinations were performed on patients with globus sensation at the Department of Otolaryngology, Head and Neck Surgery of Tottori university hospital, a tertiary care centre, from January 2013 to September 2017. The subjects were 74 patients who complained of globus sensation with no abnormality in general otolaryngological examination including laryngoscopy. RESULTS: Ultrasonography detected structural abnormalities in 60.8% of the patients with globus sensation: thyroid disorders in 41 patients, including: 35 patients with thyroid nodules, 4 patients with Hashimoto's disease, 1 patient with Grave's disease, and 1 patient with subacute thyroiditis; Sjögren syndrome in 2 patients; and cervical lipoma in 1 patient. Furthermore, 2 patients with thyroid disorders had concomitant esophageal cancer. CONCLUSION: Cervical ultrasonography identified thyroid disorders in patients with globus sensation, despite the normal ENT status. Therefore, it would be appropriate to adopt cervical ultrasonography as a routine examination at ENT clinics for patients with globus sensation.

Natural History of Exophytic Type Gastrointestinal Stromal Tumor: A Case Report.

Gastrointestinal stromal tumor (GIST) is the most common submucosal tumor of the stomach. GISTs are often detected by esophagogastroduodenal endoscopy. We have previously reported on endoscopically invisible medium-sized exophytic type GISTs. We present here a case of small exophytic GIST detected by transabdominal ultrasonography (TUS) in which the natural history of the tumor could be traced retrospectively through incidental findings obtained during follow-up for intraductal papillary mucinous neoplasm by magnetic resonance of imaging or computed tomography over about 10 years. The tumor appeared 7 years before its detection, and the doubling time was calculated as 6.9 years. In conclusion, low-risk exophytic GIST was estimated to have taken at least about 7 years to reach a size detectable by TUS.