Publications by authors named "Kelly L Roszko"

10 Publications

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Ophthalmology 2021 Jun 18. Epub 2021 Jun 18.

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

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http://dx.doi.org/10.1016/j.ophtha.2021.05.015DOI Listing
June 2021

Genotype-Phenotype Correlation in Fibrous Dysplasia/McCune-Albright Syndrome.

J Clin Endocrinol Metab 2021 Apr;106(5):1482-1490

Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.

Context: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder resulting in fractures, pain, and disability. There are no targeted or effective therapies to alter the disease course. Disease arises from somatic gain-of-function variants at the R201 codon in GNAS, replacing arginine by either cysteine or histidine. The relative pathogenicity of these variants is not fully understood.

Objective: This work aimed 1) to determine whether the most common GNAS variants (R201C and R201H) are associated with a specific clinical phenotype, and 2) to determine the prevalence of the most common GNAS variants in a large patient cohort.

Methods: This retrospective cross-sectional analysis measured the correlation between genotype and phenotype characterized by clinical, biochemical, and radiographic data.

Results: Sixty-one individuals were genotyped using DNA extracted from tissue or circulating cell-free DNA. Twenty-two patients (36.1%) had the R201C variant, and 39 (63.9%) had the R201H variant. FD skeletal disease burden, hypophosphatemia prevalence, fracture incidence, and ambulation status were similar between the 2 groups. There was no difference in the prevalence of endocrinopathies, ultrasonographic gonadal or thyroid abnormalities, or pancreatic involvement. There was a nonsignificant association of cancer with the R201H variant.

Conclusion: There is no clear genotype-phenotype correlation in patients with the most common FD/MAS pathogenic variants. The predominance of the R201H variant observed in our cohort and reported in the literature indicates it is likely responsible for a larger burden of disease in the overall population of patients with FD/MAS, which may have important implications for the future development of targeted therapies.
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http://dx.doi.org/10.1210/clinem/dgab053DOI Listing
April 2021

Successful Intravascular Treatment of an Intraosseous Arteriovenous Fistula in Fibrous Dysplasia.

Calcif Tissue Int 2020 08 17;107(2):195-200. Epub 2020 Jun 17.

Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 207, Bethesda, MD, 20892-4320, USA.

Fibrous dysplasia (FD) is a benign bone disease characterized by expansile lesions that typically stabilize with age. Rarely, FD can undergo malignant transformation, presenting with atypical, rapid growth and destruction of adjacent bone. Other potential causes of rapid FD expansion include secondary lesions, such as aneurysmal bone cysts. We describe a case of an aggressive occipital lesion that presented with pain associated with diplopia and tinnitus, raising concern for malignant transformation. A massive intraosseous arteriovenous fistula was identified giving rise to an anomalous vein coursing to the cavernous sinus with compression of the abducens nerve. The vascular anomaly was mapped and after embolization symptoms resolved; a biopsy with extensive genetic analyses excluded malignancy. The differential diagnosis for expanding FD lesions includes aggressive FD, malignant transformation, and secondary vascular anomalies. In cases when traditional radiographic and histologic assessments are nondescript, use of additional radiographic modalities and genetic analyses are required to make an accurate diagnosis and guide treatment. When vascular anomalies are suspected, detailed angiography with embolization is necessary to define and treat the lesion. However, to rule out malignant transformation, genetic screening is recommended.
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http://dx.doi.org/10.1007/s00223-020-00712-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449234PMC
August 2020

Hyperphosphatemic Tumoral Calcinosis: Pathogenesis, Clinical Presentation, and Challenges in Management.

Front Endocrinol (Lausanne) 2020 8;11:293. Epub 2020 May 8.

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

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) , which encodes a protein responsible for FGF23 glycosylation; and (3) , the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling. An acquired autoimmune form of hyperphosphatemic tumoral calcinosis has also been reported. Periarticular tumoral calcinosis is the primary cause of disability in HFTC, leading to pain, reduced range-of-motion, and impaired physical function. Inflammatory disease is also prominent, including diaphysitis with cortical hyperostosis. Multiple treatment strategies have attempted to manage blood phosphate, reduce pain and inflammation, and address calcifications and their complications. Unfortunately, efficacy data are limited to case reports and small cohorts, and no clearly effective therapies have been identified. The purpose of this review is to provide a background on pathogenesis and clinical presentation in HFTC, discuss current approaches to clinical management, and outline critical areas of need for future research.
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http://dx.doi.org/10.3389/fendo.2020.00293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225339PMC
May 2021

Approach to patients with hypophosphataemia.

Lancet Diabetes Endocrinol 2020 02 7;8(2):163-174. Epub 2020 Jan 7.

Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, Rome, Italy.

Phosphate metabolism is an evolving area of basic and clinical research. In the past 15 years, knowledge on disturbances of phosphate homoeostasis has expanded, as has the discovery of new targeted therapies. Hypophosphataemia might be the biochemical finding in several diseases, and its clinical evaluation should initially focus on the assessment of pathophysiological mechanisms leading to low serum phosphate concentrations. Clinical consequences of hypophosphataemia can involve multiple organ systems and vary depending on several factors, the most important being the underlying disorder. This Review focuses on the approach to patients with hypophosphataemia and how underlying pathophysiological mechanisms should be understood in the evaluation of differential diagnosis. We define an algorithm for the assessment of hypophosphataemia and review the most up-to-date literature on specific therapies. Continuous research in this area will result in a better understanding and management of patients with hypophosphataemia.
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http://dx.doi.org/10.1016/S2213-8587(19)30426-7DOI Listing
February 2020

Mosaic Effects of Growth Hormone on Fibrous Dysplasia of Bone.

N Engl J Med 2018 11;379(20):1964-1965

National Institutes of Health, Bethesda, MD

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http://dx.doi.org/10.1056/NEJMc1808583DOI Listing
November 2018

Knockin mouse with mutant G mimics human inherited hypocalcemia and is rescued by pharmacologic inhibitors.

JCI Insight 2017 02 9;2(3):e91079. Epub 2017 Feb 9.

Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Heterotrimeric G proteins play critical roles in transducing extracellular signals generated by 7-transmembrane domain receptors. Somatic gain-of-function mutations in G protein α subunits are associated with a variety of diseases. Recently, we identified gain-of-function mutations in Gα in patients with autosomal-dominant hypocalcemia type 2 (ADH2), an inherited disorder of hypocalcemia, low parathyroid hormone (PTH), and hyperphosphatemia. We have generated knockin mice harboring the point mutation c.C178T (p.Arg60Cys) identified in ADH2 patients. The mutant mice faithfully replicated human ADH2. They also exhibited low bone mineral density and increased skin pigmentation. Treatment with NPS 2143, a negative allosteric modulator of the calcium-sensing receptor (CASR), increased PTH and calcium concentrations in WT and mutant mice, suggesting that the gain-of-function effect of GNA11 is partly dependent on coupling to the CASR. Treatment with the Gα-specific inhibitor YM-254890 increased blood calcium in heterozygous but not in homozygous mice, consistent with published crystal structure data showing that Arg60 forms a critical contact with YM-254890. This animal model of ADH2 provides insights into molecular mechanism of this G protein-related disease and potential paths toward new lines of therapy.
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http://dx.doi.org/10.1172/jci.insight.91079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291736PMC
February 2017

Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2.

Front Physiol 2016 18;7:458. Epub 2016 Oct 18.

Endocrine Unit, Massachusetts General Hospital and Harvard Medical School Boston, MA, USA.

Extracellular calcium is essential for life and its concentration in the blood is maintained within a narrow range. This is achieved by a feedback loop that receives input from the calcium-sensing receptor (CASR), expressed on the surface of parathyroid cells. In response to low ionized calcium, the parathyroids increase secretion of parathyroid hormone (PTH) which increases serum calcium. The CASR is also highly expressed in the kidneys, where it regulates the reabsorption of calcium from the primary filtrate. Autosomal dominant hypocalcemia (ADH) type 1 is caused by heterozygous activating mutations in the CASR which increase the sensitivity of the CASR to extracellular ionized calcium. Consequently, PTH synthesis and secretion are suppressed at normal ionized calcium concentrations. Patients present with hypocalcemia, hyperphosphatemia, low magnesium levels, and low or low-normal levels of PTH. Urinary calcium excretion is typically increased due to the decrease in circulating PTH concentrations and by the activation of the renal tubular CASR. Therapeutic attempts using CASR antagonists (calcilytics) to treat ADH are currently under investigation. Recently, heterozygous mutations in the alpha subunit of the G protein G11 (Gα11) have been identified in patients with ADH, and this has been classified as ADH type 2. ADH2 mutations lead to a gain-of-function of Gα11, a key mediator of CASR signaling. Therefore, the mechanism of hypocalcemia appears similar to that of activating mutations in the CASR, namely an increase in the sensitivity of parathyroid cells to extracellular ionized calcium. Studies of activating mutations in the CASR and gain-of-function mutations in Gα11 can help define new drug targets and improve medical management of patients with ADH types 1 and 2.
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http://dx.doi.org/10.3389/fphys.2016.00458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067375PMC
October 2016
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