Publications by authors named "Kristen S Pan"

11 Publications

  • Page 1 of 1

Denosumab Treatment for Giant Cell Tumors, Aneurysmal Bone Cysts, and Fibrous Dysplasia-Risks and Benefits.

Curr Osteoporos Rep 2021 Apr 22;19(2):141-150. Epub 2021 Feb 22.

Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30 Room 228 MSC 4320, Bethesda, MD, 20892, USA.

Purpose Of Review: This review summarizes current understanding of the role of denosumab, an inhibitor of receptor activator of nuclear kappa-B ligand (RANKL), in the management of 3 skeletal neoplasms: giant cell tumors, aneurysmal bone cysts, and fibrous dysplasia.

Recent Findings: A growing body of literature supports denosumab use in giant cell tumors, a neoplasm in which RANKL plays a clear pathogenic role. Comparatively less data is available in aneurysmal bone cysts and fibrous dysplasia; however, the pathogenic similarity of these disorders to giant cell tumors, as well as encouraging preliminary data, suggests denosumab may be useful. Denosumab's inhibitory effects on bone turnover are fully reversible after drug discontinuation. This raises important unanswered questions for clinical management, including potential risks of tumor recurrence and bone turnover rebound. Denosumab is a promising potential treatment for skeletal neoplasms. However, its clinical use is impacted by ongoing safety concerns related to postdiscontinuation rebound, particularly in children. There is a critical need to understand denosumab treatment and discontinuation effects on tumor recurrence and to develop strategies for long-term treatment in patients who cannot be managed surgically.
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http://dx.doi.org/10.1007/s11914-021-00657-zDOI Listing
April 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

Optic disc edema in fibrous dysplasia/McCune-Albright syndrome: Prevalence, etiologies, and clinical implications.

Bone 2021 02 24;143:115661. Epub 2020 Sep 24.

Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States of America. Electronic address:

Background: Fibrous dysplasia (FD) is a rare disorder of expansile fibro-osseous lesions that may be associated with extraskeletal features as part of McCune-Albright syndrome (MAS). Optic disc edema is a potentially serious ophthalmologic finding that has been rarely reported in patients with FD/MAS. The purpose of this study was to investigate the prevalence and potential clinical associations of optic disc edema in a large cohort.

Methods: Clinical records were reviewed from subjects in an ongoing FD/MAS natural history study. Computed Tomography scans were evaluated for the presence of structural craniofacial abnormalities associated with optic disc edema, including Chiari I malformation and space-occupying lesions. Craniomorphometric analyses were performed to determine optic canal diameter and intracranial volume. Statistical analyses were performed to compare clinical and radiographic features between subjects with and without optic disc edema.

Results: Optic disc edema was diagnosed in 7/187 subjects, for a prevalence of 3.7%. All subjects with optic disc edema were diagnosed before age 18 years and had mild, non-progressive disease. Radiographic structural abnormalities, including Chiari I malformation, aneurysmal bone cysts, and arachnoid cysts, were associated with higher odds of optic disc edema (odds ratio [OR] 24.3; 95% confidence interval [CI], 4.2 to 121.4; p < 0.01) (OR 18.0; 95% CI, 3.4 to 108.2; p < 0.01). Treatment with leuprolide, a gonadotropin releasing hormone analog, was also associated with optic disc edema (OR 26.0; 95% CI 3.3 to 177.5; p < 0.05). There was no significant association of optic disc edema with other MAS endocrinopathies, medications, optic canal diameter, or intracranial volume.

Conclusion: Optic disc edema is an uncommon but potentially serious complication of craniofacial FD, which may occur more frequently in pediatric patients and those with structural craniofacial abnormalities. The potential association of leuprolide therapy with optic disc edema in this population warrants further study.
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http://dx.doi.org/10.1016/j.bone.2020.115661DOI Listing
February 2021

Utility of Optical Coherence Tomography in the Diagnosis and Management of Optic Neuropathy in Patients with Fibrous Dysplasia.

J Bone Miner Res 2020 11 24;35(11):2199-2210. Epub 2020 Aug 24.

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

Optic neuropathy (ON) is a highly disabling complication of fibrous dysplasia (FD). The optimal test for identifying and monitoring ON in FD is unknown. Optical coherence tomography (OCT) is an imaging modality that detects retinal nerve fiber layer (RNFL) thinning, a sign of optic nerve atrophy. The purpose of this study was to (i) assess the ability of OCT RNFL thickness measurements to identify ON in FD; (ii) compare the performance of RNFL thickness to computed tomography measurements; and (iii) examine changes in RNFL thickness over time to assess disease progression. A retrospective cohort study was performed to assess subjects (n = 70) who underwent neuro-ophthalmologic examination, including OCT. The diagnostic utility of RNFL thickness was determined using receiver operator characteristic (ROC) curve analysis, and the accuracy was compared with computed tomography measurements. The relationship between RNFL thickness and age was assessed cross-sectionally, using generalized estimating equation methodology, and longitudinally, using a generalized mixed model. Eleven subjects were identified with ON. RNFL thickness identified ON (area under curve = 0.997, p < 0.0001) with sensitivity and specificity of 100% and 95%, respectively, when using the diagnostic criterion of ≤71 μm. RNFL thickness outperformed computed tomography measurements of optic canal narrowing and optic nerve stretch. Subjects with ON exhibited a greater decrease in RNFL thickness with each year of age (-0.70 μm/year, p < 0.001) than subjects with normal vision (-0.16 μm/year, p < 0.05). When assessed longitudinally, subjects with normal vision demonstrated an increase in RNFL thickness until approximately age 20 years that decreased thereafter. In contrast, subjects with ON exhibited an earlier decrease in RNFL thickness during adolescence. In conclusion, RNFL thickness of ≤71 μm accurately identified ON in this population. By establishing the difference in rate of RNFL thinning in patients with and without ON, clinicians may distinguish between patients at risk for ON and intervene before irreversible damage. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4129DOI Listing
November 2020

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

The Clinical Spectrum of McCune-Albright Syndrome and Its Management.

Horm Res Paediatr 2019 19;92(6):347-356. Epub 2019 Dec 19.

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

McCune-Albright syndrome (MAS) is a rare, mosaic disorder presenting along a broad clinical spectrum. Disease arises from somatic-activating GNAS mutations, leading to constitutive Gαs activation and ligand-independent signaling of the Gαs-coupled protein receptor. The phenotype is largely determined by location and extent of tissues in which the GNAS mutation is expressed, as well as the pathophysiologic effects of Gαs activation within these tissues. Patients pre-sent clinically with a variable combination of fibrous dysplasia of bone (FD), café-au-lait skin macules, and hyperfunctioning endocrinopathies. In bone, Gαs leads to impaired differentiation of skeletal stem cells and formation of discrete, expansile FD lesions, resulting in fractures, pain, and functional impairment. A systematic approach to diagnosis and management is critically important to optimize outcomes for patients with FD/MAS. There are no medical therapies capable of altering the disease course in FD; however, screening and treatment for endocrinopathies can mitigate some skeletal morbidities. This review summarizes current understanding of MAS pathophysiology, describes the spectrum of clinical features, and includes a detailed discussion of the recommended approach to diagnosis and management.
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http://dx.doi.org/10.1159/000504802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302983PMC
July 2020

The skeletal phenotype of intermediate GM1 gangliosidosis: Clinical, radiographic and densitometric features, and implications for clinical monitoring and intervention.

Bone 2020 02 6;131:115142. Epub 2019 Nov 6.

Department of Genetics and Metabolism, Rare Disease Institute, Children's National Medical Center, Washington, DC, United States of America. Electronic address:

GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in GLB1 encoding a lysosomal β-galactosidase. This disease is a continuum from the severe infantile form with rapid neurological decline to the chronic adult form, which is not life-limiting. The intermediate or type 2 form can be further classified into late infantile and juvenile forms. The frequency and severity of skeletal outcomes in late infantile and juvenile patients have not been characterized. Our goals are to describe the radiological skeletal abnormalities, bone mineral density (BMD), and frequency of fractures in patients with intermediate GM1 gangliosidosis. We evaluated 13 late infantile and 21 juvenile patients as part of an ongoing natural history study. Average time from onset of symptoms to diagnosis was 1.9 and 6.3 years for late infantile and juvenile patients, respectively. All late infantile patients had odontoid hypoplasia and pear-shaped vertebral bodies, the frequency of which was significantly different than in patients with juvenile disease (none and 14%, respectively). Juvenile patients had irregular endplates of the vertebral bodies (15/21), central indentation of endplates (10/21), and squared and flat vertebral bodies (10/21); all allowed radiographic differentiation from late infantile patients. Lumbar spine, femoral neck, and total hip BMD were significantly decreased (-2.1, -2.2, and -1.8 Z-scores respectively). Lumbar spine BMD peaked at 19 years, while distal forearm BMD peaked at 30 years. Despite low BMD, no patients exhibited fractures. We have demonstrated that all late infantile patients have some degree of odontoid hypoplasia suggesting the need for cervical spine evaluation particularly prior to anesthesia, whereas juvenile patients had variable skeletal involvement often affecting activities of daily living. Type 2 GM1 gangliosidosis patients have skeletal abnormalities that are both an early indication of their diagnosis, and require monitoring and management to ensure the highest possible quality of life.
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http://dx.doi.org/10.1016/j.bone.2019.115142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937522PMC
February 2020

Age-Related Changes and Effects of Bisphosphonates on Bone Turnover and Disease Progression in Fibrous Dysplasia of Bone.

J Bone Miner Res 2019 04 15;34(4):653-660. Epub 2019 Jan 15.

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

Fibrous dysplasia (FD) is a mosaic disease in which bone is replaced with fibro-osseous tissue. Lesions expand during childhood, reaching final burden by age 15 years. In vitro data suggest that disease activity decreases in adulthood; however, there is no clinical data to support this concept. Bone turnover markers (BTMs) have been used as markers of disease activity in FD; however, the natural history of BTM changes, the effects of antiresorptive treatment, and their association to clinical outcomes have not been described. The goals of this study are to describe 1) the natural history of FD disease activity and its association with pain; 2) the impact of bisphosphonates on the natural history of BTMs; and 3) the effect of bisphosphonates on progression of FD burden during childhood. Disease burden scores and alkaline phosphatase, osteocalcin, NTx, FGF23, and RANKL levels from 178 subjects in an FD/MAS natural history study were reviewed, including 73 subjects treated with bisphosphonates. BTMs, RANKL, and FGF23 demonstrated a sustained reduction with age. Bisphosphonate treatment did not significantly impact this age-dependent decrease in BTMs. Pain was more prevalent and severe in adults compared with children and was not associated with BTMs. In children, the progression of disease burden was not affected by bisphosphonates. In conclusion, FD is associated with an age-dependent decline in bone turnover and other markers of disease activity. Pain, in contrast, is more frequent and severe in adults with FD and is not related to bone turnover. Bisphosphonate treatment does not significantly impact the age-dependent decrease in bone turnover, nor does it prevent the progression of FD disease burden in children. These findings, in association with the established adverse effects of antiresorptives, should be considered when evaluating use and response to bisphosphonates in patients being treated for FD and in any study using BTMs as surrogate endpoints. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983318PMC
April 2019

Activation of RANK/RANKL/OPG Pathway Is Involved in the Pathophysiology of Fibrous Dysplasia and Associated With Disease Burden.

J Bone Miner Res 2019 02 29;34(2):290-294. Epub 2018 Nov 29.

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

Fibrous dysplasia of bone (FD) is a mosaic disease caused by mutations in GNAS. Constitutive activation of the α-subunit of the G stimulatory protein (Gαs) leads to dysregulated proliferation of bone marrow stromal cells (BMSCs), generating expansile lesions of fibrotic tissue and abnormal bone. Local bone remodeling regulation by BMSCs is also altered, and FD tissue is characterized by abundant osteoclast-like cells that may be essential for lesion expansion. Animal models show local expression of RANKL in bone lesions, and treatment with the RANKL neutralizing antibody denosumab decreased lesion expansion rate in a patient with aggressive FD. However, the role of RANKL/osteoprotegerin (OPG) in FD pathophysiology is not yet understood. We measured serum levels of RANKL, OPG, and inactive RANKL-OPG complexes in FD patients of known disease burden and in healthy volunteers (HVs). RANK, RANKL, and Ki67 immunohistochemistry were assessed in FD tissue. Cultured FD and HV BMSCs were stimulated with prostaglandin E (PGE ) and 1,25 vitamin D to increase RANKL expression, and media levels of RANKL and OPG were measured. Osteoclastogenic induction by FD or HV BMSCs was assessed in co-cultures with HV peripheral monocytes. FD patients showed a 16-fold increase in serum RANKL compared to HVs. OPG was moderately increased (24%), although RANKL/OPG ratio was 12-fold higher in FD patients than in HVs. These measurements were positively correlated with the skeletal burden score (SBS), a validated marker of overall FD burden. No differences in serum inactive RANKL-OPG complexes were observed. In FD tissue, RANKL+ and Ki67+ fibroblastic cells were observed near RANK+ osteoclasts. High levels of RANKL were released by FD BMSCs cultures, but were undetectable in HV cultures. FD BMSC released less OPG than HV BMSCs. FD, but not HV BMSCs, induced osteoclastogenesis in monocyte co-cultures, which was prevented by denosumab addition. These data are consistent with the role of RANKL as a driver in FD-induced osteoclastogenesis. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983320PMC
February 2019

Chiari I Malformation and Basilar Invagination in Fibrous Dysplasia: Prevalence, Mechanisms, and Clinical Implications.

J Bone Miner Res 2018 11 3;33(11):1990-1998. Epub 2018 Aug 3.

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

Fibrous dysplasia (FD) is a mosaic disorder of benign fibro-osseous lesions, which may be associated with extraskeletal features as part of McCune-Albright syndrome (MAS). Cranial base abnormalities, including Chiari I malformation (CM1), in which the cerebellum extends below the foramen magnum, and secondary basilar invagination (BI), in which the odontoid prolapses into the posterior cranial fossa, are potentially serious complications of metabolic bone disorders. The purpose of this study was to determine the prevalence, natural history, and risk factors for CM1 and BI in patients with FD/MAS, and to determine mechanisms of cranial base deformities. Clinical and radiographic data from subjects in an FD/MAS natural history study were evaluated and compared to normal controls. In 158 patients with craniofacial FD, 10 (6.3%) cases of CM1 and 12 (7.6%) cases of BI were diagnosed. No cranial base abnormalities were identified in 10 control subjects. Craniomorphometric and volumetric analyses identified cranial constriction and cranial settling as the primary mechanisms of cranial base abnormalities, whereas intracranial hypertension was a contributing factor in a minority of subjects. Longitudinal analyses found progression of odontoid position with age, but no progression of tonsillar position. No endocrinopathies were associated with CM1. MAS endocrinopathies associated with BI included hyperthyroidism (odds ratio [OR] 12.0; 95% confidence interval [CI], 2.9 to 55.6; p < 0.01), precocious puberty (OR 5.6; 95% CI, 1.2 to 26.0; p < 0.05), and hypophosphatemia (OR 7.7; 95% CI, 1.9 to 27.0; p < 0.01). Scoliosis was associated with both CM1 (OR 4.8; 95% CI, 1.1 to 22.8; p < 0.05) and BI (OR = infinity; 95% CI, 4.7 to infinity; p < 0.01). This study successfully characterized cranial base abnormalities in FD/MAS and the pathophysiological connection between them. These findings support routine screening for cranial base abnormalities in patients with craniofacial FD, as well as aggressive management of contributory risk factors. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218312PMC
November 2018

Letter to the Editor Regarding "Optical Coherence Tomography in the Management of Skull Base Fibrous Dysplasia with Optic Nerve Involvement".

World Neurosurg 2018 06;114:427-428

Skeletal Disease and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA. Electronic address:

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http://dx.doi.org/10.1016/j.wneu.2018.02.166DOI Listing
June 2018
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