Pheochromocytomas (PCCs) and paragangliomas (PGLs; together PPGLs) are uncommon neuroendocrine tumors arising from adrenal medullary chromaffin cells and sympathetic/parasympathetic paraganglia. Though PPGLs predominate in adult populations, pediatric cases of PPGLs represent more aggressive disease outcomes with 12% being diagnosed as metastatic. Metastatic disease (spread to bone, lung, lymph nodes, or liver) occurs in a subset of PPGLs, ranging from 15% to 17% depending on the underlying pathogenic variant. Historically, pulmonary metastases present clinically as multiple small lesions; however, cases of PPGLs with innumerable small metastases (a miliary pattern) overwhelming lung parenchyma define a novel yet exceptionally challenging disease presentation. This pattern of pulmonary lesions upon treatment and/or cellular lysis may lead to both respiratory decompensation as well as prolific catecholamine release, incurring significant morbidity and mortality if not appropriately managed. Of the 2,649 PPGL patients enrolled in our protocol from January 1, 2000, to April 30, 2023, 500 had metastatic disease, 122 were children/adolescents, and 3 of the 122 children/adolescents had extensive pulmonary metastatic disease. All three adolescent patients with extensive pulmonary metastases had cluster 1 PPGLs and suffered hypoxemia (due to pulmonary metastases) leading to overactive hypoxia signaling and catecholamine-induced signs and symptoms [among them hypertension and/or tachyarrhythmia(s)]. Interventions including surgery, chemotherapy, and radiotherapy were pursued. Two patients achieved disease stability, while one patient succumbed to disease. Ultimately these divergent outcomes emphasize the importance of recognizing poor prognostic factors and aggressive disease early, to select appropriate treatments. Thus, optimal management of these patients must consider complications of catecholamine excess and the profound influence of hypoxia. Herein, we describe three adolescent cases of extensive pulmonary metastatic PPGL and the unique clinical challenges faced in treating these tumors alongside relevant literature to provide guidance on appropriate interventions (ClinicalTrials.gov identifier: NCT00004847).

A 74-year-old male patient with beta thalassemia minor presented in 2022 for a follow-up of osteoporosis diagnosed prior to 2004. At the time of presentation, his medical history included: radiation exposure to his head and neck, goiter, prostate cancer status post resection in 2019 without a history of anti-androgen therapy, and atrial fibrillation, for which he had been prescribed apixaban since 2021. Treatment with risedronate occurred from approximately 2004 to about 2011, with improvement in bone density to osteopenia. He had also taken vitamin D and calcium supplementation and engaged in regular weight-bearing exercise. The patient had no other known risk factors for decreased bone mineral density preceding the onset of his osteoporosis, and a previous workup for secondary causes of his osteoporosis etiology proved negative. We propose that beta thalassemia minor is potentially a risk factor for osteopenia and osteoporosis, and that bisphosphonates can be considered for management when therapeutic intervention is indicated. Even in the absence of other known risk factors, clinicians should consider periodically screening beta thalassemia minor patients with DXA for evaluation of bone health.

Stress hormones, namely glucocorticoids, have diverse actions throughout the body in regulating development, tissue metabolism, inflammation, circadian rhythms, and skeletal homeostasis. While endogenous glucocorticoid levels are important to support bodily homeostasis, chronically elevated levels can cause damage to tissues and drive diseases including bone loss (i.e., osteoporosis), myopathy (i.e., sarcopenia) and metabolic disturbances (i.e., glucose intolerance, diabetes, and abnormal fat accrual). There is substantial evidence that basal glucocorticoid levels increase during ageing while at the same time the amplitude of the diurnal variation in glucocorticoid secretion decreases. However, the significance of these changes for skeletal health is not well understood and has only recently been studied in more detail. Evidence from genetically modified mouse models indicates that changes in glucocorticoid signaling associated with ageing induce bone loss, sarcopenia and drive osteoarthritic joint disease. These studies provide important insights into the role of glucocorticoids in age-related skeletal diseases which will aid in the development of novel treatments especially needed for osteoarthritis which disproportionally affects the elderly.