Publications by authors named "Iris R Hartley"

9 Publications

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A Cross-Sectional Cohort Study of the Effects of FGF23 Deficiency and Hyperphosphatemia on Dental Structures in Hyperphosphatemic Familial Tumoral Calcinosis.

JBMR Plus 2021 May 22;5(5):e10470. Epub 2021 Mar 22.

National Institute of Dental and Craniofacial Research, National Institutes of Health Bethesda MD USA.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder caused by mutations in , , , or FGF23 autoantibodies. Prominent features include high blood phosphate and calcific masses, usually adjacent to large joints. Dental defects have been reported, but not systematically described. Seventeen patients with HFTC followed at the National Institutes of Health underwent detailed clinical, biochemical, molecular, and dental analyses. Studies of teeth included intraoral photos and radiographs, high-resolution μCT, histology, and scanning electron microscopy (SEM). A scoring system was developed to assess the severity of tooth phenotype. Pulp calcification was found in 13 of 14 evaluable patients. Short roots and midroot bulges with apical thinning were present in 12 of 13 patients. Premolars were most severely affected. μCT analyses of five HFTC teeth revealed that pulp density increased sevenfold, whereas the pulp volume decreased sevenfold in permanent HFTC teeth compared with age- and tooth-matched control teeth. Histology revealed loss of the polarized odontoblast cell layer and an obliterated pulp cavity that was filled with calcified material. The SEM showed altered pulp and cementum structures, without differences in enamel or dentin structures, when compared with control teeth. This study defines the spectrum and confirms the high penetrance of dental features in HFTC. The phenotypes appear to be independent of genetic/molecular etiology, suggesting hyperphosphatemia or FGF23 deficiency may be the pathomechanistic driver, with prominent effects on root and pulp structures, consistent with a role of phosphate and/or FGF23 in tooth development. Given the early appearance and high penetrance, cognizance of HFTC-related features may allow for earlier diagnosis and treatment. © 2021 The Authors. published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101615PMC
May 2021

Burosumab for Tumor-Induced Osteomalacia: Not Enough of a Good Thing.

J Bone Miner Res 2021 May 5. Epub 2021 May 5.

National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1002/jbmr.4318DOI Listing
May 2021

Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).

Genet Med 2021 02 2;23(2):396-407. Epub 2020 Oct 2.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Purpose: 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.

Methods: We performed deep phenotyping of 20 GACI survivors.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1038/s41436-020-00983-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867608PMC
February 2021

Ocular Adverse Effects of Infigratinib, a New Fibroblast Growth Factor Receptor Tyrosine Kinase Inhibitor.

Ophthalmology 2021 Apr 1;128(4):624-626. Epub 2020 Sep 1.

National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.ophtha.2020.08.026DOI Listing
April 2021

Tumor-Induced Osteomalacia.

Calcif Tissue Int 2021 01 5;108(1):128-142. Epub 2020 Jun 5.

Skeletal Disorders and Mineral Homeostasis Section, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.

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.
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http://dx.doi.org/10.1007/s00223-020-00691-6DOI Listing
January 2021

Pheochromocytoma and Paraganglioma Patients With Poor Survival Often Show Brown Adipose Tissue Activation.

J Clin Endocrinol Metab 2020 04;105(4)

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

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.
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http://dx.doi.org/10.1210/clinem/dgz314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059996PMC
April 2020

Cushing disease in a patient with nonbullous congenital ichthyosiform erythroderma: lessons in avoiding glucocorticoids in ichthyosis.

J Pediatr Endocrinol Metab 2019 Aug;32(8):911-914

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH and Section on Endocrinology and Genetics (SEGEN), NICHD, NIH, Bethesda, MD, USA.

Nonbullous congenital ichthyosis erythroderma (CIE) is an autosomal recessive disorder of ineffective keratinization. We present a unique case of a 16-year-old female with CIE who developed Cushing disease (CD) at age 13 with concomitant worsening of her skin disease. After transsphenoidal resection of her pituitary adenoma, she had both resolution of her Cushing symptoms and significantly milder skin manifestations of her CIE. To the best of our knowledge, this is the first reported case of a patient with both CD and CIE, one that is important in demonstrating the role of glucocorticoids in this disorder.
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http://dx.doi.org/10.1515/jpem-2019-0055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427504PMC
August 2019

Consideration of ICD-9 code-derived disease-specific safety indicators in CKD.

Clin J Am Soc Nephrol 2013 Dec 19;8(12):2123-31. Epub 2013 Sep 19.

Departments of Medicine and, †Epidemiology and Public Health, School of Medicine and, ‡Department of Pharmaceutical Health Services Research, School of Pharmacy, University of Maryland, Baltimore, Maryland, §Fairleigh Dickinson University, Pharmacy Practice Division, School of Pharmacy, Florham Park, New Jersey.

Background And Objectives: The Agency for Healthcare and Research Quality patient safety indicators track adverse safety events in hospitalized patients but overlook safety incidents specific to CKD. This study considers candidate CKD-pertinent patient safety indicators and compares them with the Agency for Healthcare and Research Quality patient safety indicators.

Design, Setting, Participants, & Measurements: Using a national Veterans Health Administration database of hospitalized veterans from fiscal year 2005, 247,160 hospitalized veterans with prehospitalization measures of renal function were retrospectively examined for proposed CKD patient safety indicators versus Agency for Healthcare and Research Quality patient safety indicators using International Classification of Diseases, Ninth Revision diagnosis codes. Candidate CKD-pertinent patient safety indicators included in-hospital acute kidney failure; in-hospital congestive heart failure (and related diagnostic codes); electrolyte disturbances; and medication errors, poisoning, and intoxication. Patients with a prehospital estimated GFR<60 ml/min per 1.73 m(2) (CKD group) were compared with a non-CKD group. For CKD patient safety indicators, hospitalizations were excluded if the admitting condition was a potential cause of the secondary condition. Regression methods were used to present adjusted rates in study groups of interest.

Results: The CKD patient safety indicators were generally more common than the Agency for Healthcare and Research Quality patient safety indicators in all groups, tended to occur in different patients than those patients who experienced Agency for Healthcare and Research Quality patient safety indicators, and were more common in the CKD group than the non-CKD group, except for hypoglycemia, hypokalemia, and hyponatremia. The adjusted composite CKD patient safety indicators rate (per 1000 patient-hospitalizations) was 398.0 (95% confidence interval, 391.2 to 405.0) for patients in the CKD group and 250.0 (95% confidence interval, 247.4 to 252.7) for patients in the non-CKD group. The prevalence ratio of CKD patient safety indicators to Agency for Healthcare and Research Quality patient safety indicators was 23.4 (95% confidence interval, 21.9 to 25.0).

Conclusion: The candidate CKD patient safety indicators that occur in hospitalized patients are distinct from the Agency for Healthcare and Research Quality patient safety indicators and tend to be more common in CKD than non-CKD patients. These measures have the potential to serve as sentinel tools for identifying patients with CKD who warrant examination for disease-pertinent safety events.
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http://dx.doi.org/10.2215/CJN.12671212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848413PMC
December 2013