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BACKGROUND: Parathyroid adenomas are the main cause of primary hyperparathyroidism (PHPT). PHPT most often affects adults between ages 50-60 and is considered rare in children and adolescents, representing less than 5% of cases1. It is more common among females than among males in the proportion 3 to 1. During embryogenesis, both the superior and inferior parathyroid glands detach from their pharyngeal origin and migrate towards their final location, posteriorly to the thyroid gland. Migration can be faulty and ectopic glands can appear along the path of embryologic descent2. We present a case of an adolescent male who presented with symptomatic PHPT in the setting of an intrathymic parathyroid adenoma. CASE PRESENTATION: 17-year-old male with no significant past medical history developed symptoms of anxiety, nausea and fatigue. Laboratory values revealed calcium 14.3 mg/dL (8.6-10.3), PTH 227 pg/mL (15-65), 25-dihydroxyvitamin D (vit-D) 8.31 ng/mL (30-100), and phosphorus 1.5 mg/dL (2.5-5. 0). He denied any personal history of bone fractures or nephrolithiasis. CT parathyroid scan showed an enhancing oblong 1.7×0.6 cm lesion in the left upper mediastinal space suggestive of a parathyroid adenoma. Focal sestamibi uptake confirmed a 1.7×0.6 cm enhancing nodule in the left upper anterior mediastinum within the thymus. He was instructed to take 2,000 IU of vit-D daily. Repeat blood work one month later showed that his serum calcium decreased to 13.4 mg/dL and PTH decreased to 122 pg/mL. Additional labs revealed vit-D 16.81 ng/mL, 1,25-dihydroxyvitamin D (calcitriol) 160 pg/mL (19.9-79.3) and 24-hour urine calcium excretion of 409 mg (0-320). Patient underwent successful excision of an intrathymic hyperplastic parathyroid gland adenoma with a >50% drop in peak PTH levels intraoperatively at 10 minutes post excision, later confirmed by pathology. CONCLUSION: This case highlights an adolescent with symptomatic primary hyperparathyroidism due to an intrathymic parathyroid adenoma. Ectopic adenomas have been reported in approximately 4 to 16% of patients with hyperparathyroidism2. When embryological development of the parathyroid glands is defective, it can predispose to the formation of ectopic glands, which is an important cause of failed parathyroid exploration. Unfortunately, PHPT has greater morbidity in the younger age group since most of these patients develop complications from the hypercalcemia, such as kidney stones, hypercalciuria, bone disease and symptoms of abdominal pain/vomiting. This case emphasizes the importance for clinicians to be aware of ectopic parathyroid adenoma in adolescents who present with symptoms and labs consistent with primary hyperparathyroidism. References 1. Roizen J, Levine MA. Primary hyperparathyroidism in children and adolescents. J Chin Med Assoc. 2012;75(9): 425-434. doi: 10.1016/j. jcma.2012. 06. 0122. Chang, B. A., Sharma, A. & Anderson, D. W. Ectopic parathyroid adenoma in the soft palate: a case report. J of Otolaryngol - Head & Neck Surg 45, 53 (2016). doi.org/10.1186/s40463-016-0165-z Presentation: No date and time listed

Introduction/Background Paragangliomas are rare tumors arising from extra-adrenal chromaffin tissue (1,2). The majority of paragangliomas occur in the head and neck, with the heart representing an uncommon site (3). We present a rare case of a patient who was incidentally found to have a hypersecretory retro-cardiac paraganglioma. Clinical Case A 72-year-old woman with a history of hypertension, hyperlipidemia, migraines, and prior cerebrovascular accident presented to the Emergency Department with sudden, substernal, pleuritic chest pain. She described weeks of a "fluttering sensation" in the chest with one episode of syncope. She denied shortness of breath or diaphoresis. Vitals were normal and EKG did not demonstrate ischemia. Troponin uptrended and the patient was admitted due to concern for non-ST-elevation myocardial infarction (NSTEMI). She promptly underwent cardiac catheterization which revealed non-obstructive coronaries and a left atrial mass with blood supply from the right coronary artery and the left circumflex artery. Cardiac MRI demonstrated an extracardiac, interpericardial 42×24×37 mm mass below the left atrium without aggressive features, and delayed homogenous enhancement with dynamic perfusion, suggestive of a paraganglioma. Biochemical evaluation demonstrated elevated free plasma normetanephrines of 5.5 nmol/L (normal: < 0.90 nmol/L) and normal free plasma metanephrines. Chromogranin-A was elevated at 454 ng/ml (normal: She was seen in follow-up with Cardiac Surgery, who felt the resection would be technically difficult, but that there were no other alternatives. The patient's procedure was postponed due to a COVID-19 surge and patient was begun on alpha- and beta-blockade, instead of pure alpha-blockade with phenoxybenzamine, in view of her recent history of NSTEMI. Conclusion We present a rare case of an incidentally-found cardiac mass, discovered during cardiac catheterization, with biochemical and radiographic evaluations concerning for a retro-atrial paraganglioma. Cardiac paragangliomas can present with a range of symptoms, from hypertension to different obstructive symptoms, including ischemia, depending on the tumor's location. The secretory activity of cardiac paragangliomas can also vary; the literature reports that about 31% are biochemically active (2). Though rare, our case highlights the importance of understanding the atypical presentation and evaluation of cardiac paragangliomas. References 1. Lenders J, et al. Pheochromocytoma. Lancet 2005; 366(9486): 65-675. 2. Chen H, Sippel RS. North American Neuroendocrine Tumors Society consensus guidelines for diagnosis and management of neuroendocrine tumors. Pancreas 2010; 39 (6): 775 3. Erickson D, et al. Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab 2001;86(11): 5210-5216. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Although many lysosomal disorders are corrected by a small amount of the missing enzyme, it has been generally accepted that 20-30% of normal acid alpha-glucosidase (GAA) activity, provided by gene or enzyme replacement therapy, would be required to reverse the myopathy and cardiomyopathy in Pompe disease. We have addressed the issue of reversibility of the disease in the Gaa(-/-) mouse model. We have made transgenic lines expressing human GAA in skeletal and cardiac muscle of Gaa(-/-) mice, and we turned the transgene on at different stages of disease progression by using a tetracycline-controllable system. We have demonstrated that levels of 20-30% of normal activity are indeed sufficient to clear glycogen in the heart of young Gaa(-/-) mice, but not in older mice with a considerably higher glycogen load. However, in skeletal muscle-a major organ affected in infantile and in milder, late-onset variants in humans-induction of GAA expression in young Gaa(-/-) mice to levels greatly exceeding wildtype values did not result in full phenotypic correction, and some muscle fibers showed little or no glycogen clearance. The results demonstrate that complete reversal of pathology in skeletal muscle or long-affected heart muscle will require much more enzyme than previously expected or a different approach.

Objective— The site-specificity of endothelial phenotype is attributable to the local hemodynamic forces. The flow regulation of microRNAs in endothelial cells (ECs) plays a significant role in vascular homeostasis and diseases. The objective of this study was to elucidate the molecular mechanism by which the pulsatile shear flow–induced microRNA-23b (miR-23b) exerts antiproliferative effects on ECs. Approach and Results— We used a combination of a cell perfusion system and experimental animals to examine the flow regulation of miR-23b in modulating EC proliferation. Our results demonstrated that pulsatile shear flow induces the transcription factor Krüppel-like factor 2 to promote miR-23b biosynthesis; the increase in miR-23b then represses cyclin H to impair the activity and integrity of cyclin-dependent kinase–activating kinase (CAK) complex. The inhibitory effect of miR-23b on CAK exerts dual actions to suppress cell cycle progression, and reduce basal transcription by deactivating RNA polymerase II. Whereas pulsatile shear flow regulates the miR-23b/CAK pathway to exert antiproliferative effects on ECs, oscillatory shear flow has little effect on the miR-23b/CAK pathway and hence does not cause EC growth arrest. Such flow pattern–dependent phenomena are validated with an in vivo model on rat carotid artery: the flow disturbance induced by partial carotid ligation led to a lower expression of miR-23b and a higher EC proliferation in comparison with the pulsatile flow regions of the unligated vessels. Local delivery of miR-23b mitigated the proliferative EC phenotype in partially ligated vessels. Conclusions— Our findings unveil a novel mechanism by which hemodynamic forces modulate EC proliferative phenotype through the miR-23b/CAK pathway.

Both enzyme replacement and gene therapy of lysosomal storage disorders rely on the receptor-mediated uptake of lysosomal enzymes secreted by cells, and for each lysosomal disorder it is necessary to select the correct cell type for recombinant enzyme production or for targeting gene therapy. For example, for the therapy of Pompe disease, a severe metabolic myopathy and cardiomyopathy caused by deficiency of acid alpha-glucosidase (GAA), skeletal muscle seems an obvious choice as a depot organ for local therapy and for the delivery of the recombinant enzyme into the systemic circulation. Using knockout mice with this disease and transgenes containing cDNA for the human enzyme under muscle or liver specific promoters controlled by tetracycline, we have demonstrated that the liver provided enzyme far more efficiently. The achievement of therapeutic levels with skeletal muscle transduction required the entire muscle mass to produce high levels of enzyme of which little found its way to the plasma, whereas liver, comprising5% of body weight, secreted 100-fold more enzyme, all of which was in the active 110 kDa precursor form. Furthermore, using tetracycline regulation, we somatically induced human GAA in the knockout mice, and demonstrated that the skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early.

The authors would like to thank Dr. Steve Jackson's Laboratory at the University of Cambridge for the MRE11 antibody and Dr. Sandra Costa from ICVS, University of Minho, for the disease-free controls DNA, High grade gliomas (HGG) are one of the leading causes of cancer-related deaths in children, and there is increasing evidence that pediatric HGG may harbor distinct molecular characteristics compared to adult tumors. We have sought to clarify the role of microsatellite instability (MSI) in pediatric versus adult HGG. MSI status was determined in 144 patients (71 pediatric and 73 adults) using a well established panel of five quasimonomorphic mononucleotide repeat markers. Expression of MLH1, MSH2, MSH6 and PMS2 was determined by immunohistochemistry, MLH1 was assessed for mutations by direct sequencing and promoter methylation using MS-PCR. DNA copy number profiles were derived using array CGH, and mutations in eighteen MSI target genes studied by multiplex PCR and genotyping. MSI was found in 14/71 (19.7%) pediatric cases, significantly more than observed in adults (5/73, 6.8%; p=0.02, Chi-square test). MLH1 expression was downregulated in 10/13 cases, however no mutations or promoter methylation were found. MSH6 was absent in one pediatric MSI-High tumor, consistent with an inherited mismatch repair deficiency associated with germline MSH6 mutation. MSI was classed as Type A, and associated with a remarkably stable genomic profile. Of the eighteen classic MSI target genes, we identified mutations only in MSH6 and DNAPKcs and described a polymorphism in MRE11 without apparent functional consequences in DNA double strand break detection and repair. This study thus provides evidence for a potential novel molecular pathway in a proportion of gliomas associated with the presence of MSI., British Council and the Portuguese Council of Rectors, Treaty of Windsor Anglo-Portuguese Joint Research Programme (R.M. Reis, C. Jones). M. Viana-Pereira is funded by a PhD fellowship ‘[SFRH/BD/29145/2006]’ of Fundação para a Ciência e Tecnologia, Portugal. (FCT).

At close hand to one's genomic material are the histones that make up the nucleosome. Standing guard, one variant stays hidden doubling as one of the core histones. But, thanks to its prime positioning, a variation in the tail of H2AX enables rapid modification of the histone code in response to DNA damage. A role for H2AX phosphorylation has been demonstrated in DNA repair, cell cycle checkpoints, regulated gene recombination events, and tumor suppression. In this review, we summarize what we have learned about this marker of DNA breaks, and highlight some of the questions that remain to be elucidated about the physiological role of H2AX. We also suggest a model in which chromatin restructuring mediated by H2AX phosphorylation serves to concentrate DNA repair/signaling factors and/or tether DNA ends together, which could explain the pleotropic phenotypes observed in its absence.

Although many lysosomal disorders are corrected by a small amount of the missing enzyme, it has been generally accepted that 20-30% of normal acid alpha-glucosidase (GAA) activity, provided by gene or enzyme replacement therapy, would be required to reverse the myopathy and cardiomyopathy in Pompe disease. We have addressed the issue of reversibility of the disease in the Gaa(-/-) mouse model. We have made transgenic lines expressing human GAA in skeletal and cardiac muscle of Gaa(-/-) mice, and we turned the transgene on at different stages of disease progression by using a tetracycline-controllable system. We have demonstrated that levels of 20-30% of normal activity are indeed sufficient to clear glycogen in the heart of young Gaa(-/-) mice, but not in older mice with a considerably higher glycogen load. However, in skeletal muscle-a major organ affected in infantile and in milder, late-onset variants in humans-induction of GAA expression in young Gaa(-/-) mice to levels greatly exceeding wildtype values did not result in full phenotypic correction, and some muscle fibers showed little or no glycogen clearance. The results demonstrate that complete reversal of pathology in skeletal muscle or long-affected heart muscle will require much more enzyme than previously expected or a different approach.