Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumoral production of fibroblast growth factor 23 (FGF23). The hallmark biochemical features include hypophosphatemia due ...to renal phosphate wasting, inappropriately normal or frankly low 1,25-dihydroxy-vitamin D, and inappropriately normal or elevated FGF23. TIO is caused by typically small, slow growing, benign phosphaturic mesenchymal tumors (PMTs) that are located almost anywhere in the body from the skull to the feet, in soft tissue or bone. The recent identification of fusion genes in a significant subset of PMTs has provided important insights into PMT tumorigenesis. Although management of this disease may seem straightforward, considering that complete resection of the tumor leads to its cure, locating these often-tiny tumors is frequently a challenge. For this purpose, a stepwise, systematic approach is required. It starts with thorough medical history and physical examination, followed by functional imaging, and confirmation of identified lesions by anatomical imaging. If the tumor resection is not possible, medical therapy with phosphate and active vitamin D is indicated. Novel therapeutic approaches include image-guided tumor ablation and medical treatment with the anti-FGF23 antibody burosumab or the pan-FGFR tyrosine kinase inhibitor, BGJ398/infigratinib. Great progress has been made in the diagnosis and treatment of TIO, and more is likely to come, turning this challenging, debilitating disease into a gratifying cure for patients and their providers.
Abstract
Context
Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumors that can secrete norepinephrine (NE). Brown adipose tissue (BAT) activation is mediated through the action of NE on ...β-adrenoceptors (β-ARs). In some malignancies, BAT activation is associated with higher cancer activity.
Objective
To study the relationship between BAT activation and PPGL clinical outcomes.
Design
A retrospective case-control study that included 342 patients with PPGLs who underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) imaging at the National Institutes of Health (NIH). We excluded all patients with parasympathetic tumors and those who underwent 18F-FDG PET/CT after PPGL resection. Scans of 205 patients were reviewed by 2 blinded nuclear medicine physicians; 16 patients had BAT activation on 18F-FDG PET/CT 7.80%; age 27.50 (15.00–45.50) years; 10 female/6 male; body mass index BMI 24.90 19.60–25.35 kg/m2). From the remaining 189 patients, we selected 36 matched controls (age 34.4 25.4–45.5 years; 21 female/15 male; BMI 25.0 22.0–26.0 kg/m2).
Primary Outcome Measure
Overall survival.
Results
The presence of active BAT on 18F-FDG PET/CT was associated with decreased overall survival when compared with the control group (HRz 5.80; 95% CI, 1.05–32.05; P = 0.02). This association remained significant after adjusting for the SDHB mutation. Median plasma NE in the BAT group was higher than the control group 4.65 vs 0.55 times above the upper limit of normal; P < 0.01. There was a significant association between higher plasma NE levels and mortality in PPGLs in both groups.
Conclusions
Our findings suggest that the detection of BAT activity in PPGL patients is associated with higher mortality. We suggest that BAT activation could either be reflecting or contributing to a state of increased host stress that may predict poor outcome in metastatic PPGL.
Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of ...GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion.
We performed deep phenotyping of 20 GACI survivors.
Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies.
GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.
Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has ...emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals.
To develop this technique, 4 patients with hyperphosphatemic familial tumoral calcinosis, a monogenic disorder of FGF23 (fibroblast growth factor-23) deficiency with a high prevalence of vascular calcification, underwent radiolabeled sodium fluoride positron emission tomography/computed tomography imaging. One patient received serial imaging 1 year after treatment with an IL-1 (interleukin-1) antagonist. A radiolabeled sodium fluoride-based microcalcification score, as well as calcification volume, was computed at all perpendicular slices, which were then mapped onto a standardized vascular atlas. Segment-wise mCS
and mCS
were computed to compare microcalcification score levels at predefined vascular segments within subjects.
Patients with hyperphosphatemic familial tumoral calcinosis had notable peaks in microcalcification score near the aortic bifurcation and distal femoral arteries, compared with a control subject who had uniform distribution of vascular radiolabeled sodium fluoride uptake. This technique also identified microcalcification in a 17-year-old patient, who had no computed tomography-defined calcification. This technique could not only detect a decrease in microcalcification score throughout the patient treated with an IL-1 antagonist but it also identified anatomic areas that had increased responsiveness while there was no change in computed tomography-defined macrocalcification after treatment.
This technique affords the ability to visualize spatial patterns of the active microcalcification process in the peripheral vasculature. Further, this technique affords the ability to track microcalcifications at precise locations not only across time but also across subjects. This technique is readily adaptable to other diseases of vascular calcification and may represent a significant advance in the field of vascular biology.
Fracture Risk in Pediatric Patients With MEN2B Li, Iris; Hartley, Iris R; Klubo-Gwiedzdzinska, Joanna ...
The journal of clinical endocrinology and metabolism,
11/2022, Letnik:
107, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The skeletal phenotype of patients with MEN2B has been described but fracture risk in these patients has not yet been evaluated.
This work aims to better delineate fracture risk in patients with ...multiple endocrine neoplasia type 2B (MEN2B).
This case series with chart review was conducted at the National Institutes of Health, Pediatric Oncology Branch. A total of 48 patients with MEN2B were identified, with an age range of 5 to 36 years, median of 19; 24 of 48 (50%) patients were female. Medical records, demographic information, available imaging, and laboratory results were reviewed. History up to age 19 was included in the statistical analyses.
Of the 48 patients with MEN2B, 20 patients experienced at least one fracture. The majority (n = 18) experienced their first fracture at or before age 19. The observed frequency of fracture occurrence throughout childhood (0-19 years) was 38%, with very little difference between males and females. This frequency is higher than the 9.47 to 36.1 fractures per 1000 persons per year that has been reported in healthy pediatric cohorts in the United States. Less common sites of fracture including vertebral compression fracture and pelvic fractures were observed in patients with MEN2B.
In this group of patients with MEN2B, there was an increased overall risk of fracture compared to general pediatric cohorts in the United States. Less common sites of fracture were also observed. This suggests a possible effect of an activating RET mutation on bone physiology and warrants further investigation.
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