Background During the investigation of causative variants of Mendelian disorders using next-generation sequencing, the enormous number of possible candidates makes the detection process complex, and the use of multidimensional methods is required. Although the utility of several variant prioritization tools has been reported, their effectiveness in Japanese patients remains largely unknown.

Methods We selected 5 free variant prioritization tools (PhenIX, hiPHIVE, Phen-Gen, eXtasy-order statistics, and eXtasy-combined max) and assessed their effectiveness in Japanese patient populations. To compare these tools, we conducted 2 studies: one based on simulated data of 100 diseases and another based on the exome data of 20 in-house patients with Mendelian disorders. To this end we selected 100 pathogenic variants from the “Database of Pathogenic Variants (DPV)” and created 100 variant call format (VCF) files that each had pathogenic variants based on reference human genome data from the 1000 Genomes Project. The later “in-house” study used exome data from 20 Japanese patients with Mendelian disorders. In both studies, we utilized 1-5 terms of “Human Phenotype Ontology” as clinical information.

Results In our analysis based on simulated disease data, the detection rate of the top 10 causative variants was 91% for hiPHIVE, and 88% for PhenIX, based on 100 sets of simulated disease VCF data. Also, both software packages detected 82% of the top 1 causative variants. When we used data from our in-house patients instead, we found that these two programs (PhenIX and hiPHIVE) produced higher detection rates than the other three systems in our study. The detection rate of the top 1 causative variant was 71.4% for PhenIX, 65.0% for hiPHIVE.

Conclusion The rates of detecting causative variants in two Exomizer software packages, hiPHIVE and PhenIX, were higher than for the other three software systems we analyzed, with respect to Japanese patients.

Descending necrotizing mediastinitis (DNM) is a life-threatening disease with a high fatality rate that occurs as a complication of deep neck abscess. DNM complicated by severe dysphagia during the postoperative period has been previously reported, but there have been no published cases of surgical treatment for severe dysphagia secondary to DNM. A 63-year-old man was diagnosed with a deep neck abscess followed by DNM. The patient had dysphagia after incision and drainage of the abscess and drainage for DNM with video-assisted thoracic surgery (VATS). A comprehensive long-term physiotherapy program with a speech and language therapist did not reduce his dysphagia. Thus, the patient underwent laryngeal elevation and cricopharyngeal myotomy, which enabled oral intake. Surgery should be considered for prolonged severe restriction of laryngeal elevation and esophageal introitus opening that is unresponsive to physiotherapy with a speech and language therapist.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer. To diagnose nodal MCC with an unknown primary disease is challenging, and it has to be separated from other nodal metastatic neoplasms. We report a unique case of nodal MCC in head and neck lesions with an unknown primary. A 70-year-old woman was admitted to our department with a right submandibular mass. Fine needle aspiration biopsy was performed and indicated malignancy. F-18-fluorodeoxyglucose positron emission tomography (PET) demonstrated abnormal accumulation in the right submandibular lymph node, right palatine tonsil, and right thyroid gland. For diagnostics and treatment, bilateral selective neck lymph node dissection, right tonsillectomy, and right thyroidectomy were performed. Histopathological examination revealed that most parts of the submandibular lymph node were occupied by diffuse sheets of tumor cells. Contrary to our expectation, malignant cells were not detected in the right palatine tonsil and right thyroid. Immunohistochemistry demonstrated a marked positive reaction for AE1/AE3, chromogranin A, synaptophysin, cytokeratin 20 (CK20) and CD56 and a negative reaction for vimentin, leucocyte common antigen (LCA), thyroid transcription factor-1 (TTF1) and cytokeratin 7 (CK7) in the tumor cells. Immunostaining of Merkel cell polyomavirus-large T antigen (MCPyV-LT) showed a positive reaction and MCPyV-positive MCCs were assessed by PCR analysis, demonstrating that viral copy number was 12.8 copies per cell. These histological findings confirmed the diagnosis of Merkel cell carcinoma of the lymph node. In cases of tumors in the lymph node with a neuroendocrine appearance in head and neck lesions, it is necessary to eliminate the possibility of metastasis from MCC.

Juvenile granulosa cell tumor (JGCT), classified as a sex cord-stromal tumor, is a rare neoplasm. This is an instructive case report of JGCT accompanied by augmented interleukin (IL)-6 secretion. A 13-year-old girl with prolonged fever and delayed puberty was diagnosed with JGCT of the left ovary based on an imaging study and pathological investigation. Although it was not clear whether IL-6 was secreted from the tumor cells, her serum level of IL-6 was very high. After tumorectomy, the patient’s symptoms immediately disappeared, her IL-6 level decreased, and she entered puberty. Therefore, augmented IL-6 secretion production induced by tumors should be considered a potential cause of prolonged fever and/or delayed puberty.