Background: Head and neck paragangliomas (HNPGLs) are typically slow-growing, hormonally inactive tumors of parasympathetic paraganglia. Inactivation of prolyl-hydroxylase domain-containing 2 protein causing indirect gain-of-function of hypoxia-inducible factor-2α (HIF-2α), encoded by EPAS1, was recently shown to cause carotid body hyperplasia. We previously described a syndrome with multiple sympathetic paragangliomas caused by direct gain-of-function variants in EPAS1 (Pacak-Zhuang syndrome, PZS) and developed a corresponding mouse model. Methods: We evaluated a cohort of patients with PZS (n = 9) for HNPGL by positron emission tomography, magnetic resonance imaging, and computed tomography and measured carotid body size compared to literature reference values. Resected tumors were evaluated by histologic sectioning and staining. We evaluated the corresponding mouse model at multiple developmental stages (P8 and adult) for lesions of the head and neck by high resolution ex vivo imaging and performed immunohistochemical staining on histologic sections of the identified lesions. Results: Three patients had imaging consistent with HNPGL, one of which warranted resection and was confirmed on histology. Three additional patients had carotid body enlargement (Z-score > 2.0), and 3 had carotid artery malformations. We found that 9 of 10 adult variant mice had carotid body tumors and 6 of 8 had a paraganglioma on the cranio-caval vein, the murine homologue of the superior vena cava; these were also found in 4 of 5 variant mice at post-natal day 8. These tumors and the one resected from a patient were positive for tyrosine hydroxylase, synaptophysin, and chromogranin A. Brown fat in a resected patient tumor carried the EPAS1 pathogenic variant. Conclusions: These findings (1) suggest HNPGL as a feature of PZS and (2) show that these pathogenic variants are sufficient to cause the development of these tumors, which we believe represents a continuous spectrum of disease starting from hyperplasia.

Schizophrenia is a multifaceted mental illness characterized by cognitive and neurobehavioral abnormalities. Carnitine palmitoyltransferase II (CPT II) deficiency is a metabolic disorder resulting in impaired transport of long-chain fatty acids from the cytosol to the mitochondrial inner membrane, where fatty acid β-oxidation takes place. Here, we present an interesting clinical case of an adolescent male that presented with psychosis and a history of mild-to-moderate CPT II deficiency. To identify germline genetic variation that may contribute to the phenotypes observed, we performed whole-exome sequencing on DNA from the proband, unaffected fraternal twin, and biological parents. The proband was identified to be homozygous for the p.Val368Ile and heterozygous for the p.Met647Val variant in CPT2. Each of these variants are benign on their own; however, their combined effect is unclear. Further, variation was identified in the dopamine β-hydroxylase (DBH) gene (c.339+2T>C), which may contribute to decreased activity of DBH; however, based on the patient’s presentation, severe DBH deficiency is unlikely. In conclusion, the variants identified in this study do not clearly explain the observed patient phenotypes, indicating that the complex phenotypes are likely caused by an interplay of genetic and environmental factors that warrant further investigation.

We recently described a transtentorial venous system (TTVS), which to our knowledge was previously unknown, connecting venous drainage throughout the brain in humans. Prior to this finding, it was believed that the embryologic tentorial plexus regresses, resulting in a largely avascular tentorium. Our finding contradicted this understanding and necessitated further investigation into the development of the TTVS. Herein, we sought to investigate mice as a model to study the development of this system. First, using vascular casting and ex vivo micro-CT, we demonstrated that this TTVS is conserved in adult mice. Next, using high-resolution MRI, we identified the primitive tentorial venous plexus in the murine embryo at day 14.5. We also found that, at this embryologic stage, the tentorial plexus drains the choroid plexus. Finally, using vascular casting and micro-CT, we found that the TTVS is the dominant venous drainage in the early postnatal period (P8). Herein, we demonstrated that the TTVS is conserved between mice and humans, and we present a longitudinal study of its development. In addition, our findings establish mice as a translational model for further study of this system and its relationship to intracranial physiology.