三谷 忠宏

INTRODUCTION: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare disorder caused by antibodies against platelet factor 4 (PF4) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines using non-replicable adenoviral vectors. It emerged during the pandemic, with patients typically presenting with thrombosis at uncommon sites, thrombocytopenia, and elevated D-dimer levels. VITT antibodies and heparin-dependent antibodies bind to distinct PF4 epitopes. Recently, VITT-like clinical, laboratory, and anti-PF4 antibody features have also been observed in patients with adenoviral infections. Only four pediatric cases of cerebral venous sinus thrombosis (CVST) have been reported. CASE REPORT: The patient was a previously healthy 2-year-old girl with no history of heparin exposure or SARS-CoV-2 vaccination. She presented with fever and was diagnosed with adenovirus infection. The fever resolved by day 4, but by day 6 she became increasingly lethargic and experienced vomiting. On day 12, Laboratory data showed severe thrombocytopenia and elevated D-dimer levels. Computed tomography revealed CVST along with a secondary hemorrhage in the right temporal lobe. She underwent hematoma removal with external/internal decompression and was started on continuous intravenous unfractionated heparin, and she was switched to warfarin. The thrombus decreased, platelet count spontaneously increased. Platelet activation assays using acute-phase serum identified a PF4-dependent platelet-activating antibody. CONCLUSION: We report a case of CVST in a 2-year-old girl following adenovirus infection. Unlike heparin-induced thrombocytopenia, where heparin exacerbates the condition, it is effective here by competitively inhibiting anti-PF4 antibody binding. In patients with prior adenovirus infection presenting with CVST and thrombocytopenia, anti-PF4 disorders should be considered.

Rare diseases are collectively common, affecting approximately 1 in 20 individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in next-generation sequencing, development of new computational and functional genomics approaches to prioritize genes and variants and increased global sharing of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Furthermore, all data generated, currently representing over 7,500 individuals from over 3,000 families, are rapidly made available to researchers worldwide through the Analysis, Visualization and Informatics Lab-space (AnVIL) to catalyse global efforts to develop approaches for genetic diagnoses in rare diseases. Most of these families have undergone previous clinical genetic testing but remained unsolved, with most being exome-negative. Here we describe the collaborative research framework, datasets and discoveries comprising GREGoR that will provide foundational resources and substrates for the future of rare disease genomics.

We report a rare case of pediatric supraclavicular pyogenic lymphadenitis presenting with an "asymmetrical shoulder" in a five-year-old boy. The boy developed right neck and shoulder pain following the resolution of cellulitis at the site of insect bites on his right forearm. Despite the absence of visible inflammation in the shoulder or proximal lymph nodes, short tau inversion recovery magnetic resonance imaging (STIR-MRI) revealed an enlarged supraclavicular lymph node with surrounding edema. He fully recovered following intravenous antibiotic treatment. This case highlights that lymphadenitis in remote drainage sites, such as the supraclavicular nodes, may develop even after the resolution of distal cellulitis at the primary site. Notably, in the present case, inflammation was absent in the anatomically proximal lymph nodes (such as those at the elbow or subclavicular lymph nodes) and appeared only in the supraclavicular region. Lastly, the asymmetrical shoulder appearance may serve as a valuable clinical sign of the underlying lymphadenitis. We also discuss key considerations when encountering supraclavicular lymphadenitis, which carries a high risk of malignancy at all ages.

OBJECTIVE: This study aimed to evaluate the dynamics of the neutrophil-to-lymphocyte ratio (NLR) during the initial hospitalization of patients with eating disorders (EDs) and to assess its potential as a biomarker for monitoring disease severity and treatment response. METHODS: A retrospective chart review was conducted with 55 patients aged ≤ 16 years diagnosed with anorexia nervosa or avoidant/restrictive food intake disorder and admitted to Jichi Medical University Hospital between 2015 and 2021. Sociodemographic and clinical characteristics including sex, age, rate of weight gain, percentage of ideal body weight (%IBW), tube feeding treatment, and NLR were obtained. Statistical analyses used a mixed model for repeated measures to assess NLR changes regarding %IBW and other clinical factors. RESULTS: The NLR at admission was lower in the malnourished state but increased with weight recovery. MMRM revealed that tube feeding treatment (β = 0.538) and restoration of %IBW (β = 0.029) significantly predicted an increase in the NLR. The interaction between tube feeding and the quadratic term of %IBW was also significant, indicating distinct patterns of NLR changes: without tube feeding, NLR increased linearly with weight recovery, whereas with tube feeding, NLR exhibited a non-linear, upward-convex parabolic trend. DISCUSSION: These findings suggest that NLR may offer an objective recovery marker less influenced by patient self-report. Monitoring NLR before and after tube feeding may help distinguish true physiological recovery from transient stress responses, providing complementary information to conventional assessments. Further research is warranted to establish its clinical relevance.

The 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) is a mitochondria-localized protein involved in the biosynthesis of coenzyme Q10 in the electron transfer system, and its variants have been reported to cause progressive neurodegenerative diseases such as neonatal leukoencephalopathy and hereditary spastic paraplegia. In this case report, we present a case of a nine-year-old girl with exotropia with a novel HPDL variant who underwent strabismus surgery. She was referred to the ophthalmology department with exotropia and a history of progressive spastic paraplegia with gait disturbance. Brain MRI showed no remarkable findings. Whole-exome sequencing revealed a homozygous variant c.1040delC (p.Thr347Metfs*66) in the HPDL gene. Ophthalmic examination revealed a best-corrected visual acuity of 20/12 in both eyes. Fundoscopy showed retinal discoloration at the level of the retinal pigment epithelium in the right eye. As the patient had intermittent exotropia with good convergence, she was followed up conservatively. One year after the initial examination, the patient could not keep her eyes in a central position by convergence. The alternate prism cover test revealed exotropia of 80 prism diopters. We diagnosed that intermittent exotropia had deteriorated into constant exotropia. The patient's family requested a strabismus surgery, which was conducted under general anesthesia. Standard left lateral rectus recession, left medial rectus resection, and right lateral rectus recession were also performed. Postoperatively, her exotropia was reduced, and she achieved good convergence. The patient and her family were satisfied with the surgical outcome, and no recurrence was noted one year postoperatively. Our results provide important information for the associations of variant in HPDL with progressive spastic paraplegia, strabismus and retinal changes and broaden the genetic spectrum of HPDL-related disease. This is the first report to present a novel HPDL variant and document the performance of strabismus surgery for constant exotropia.