Rachel I Gafni

The National Institute of Diabetes and Digestive and Kidney Diseases, 베서스다, Maryland, United States

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Publications (30)155.73 Total impact

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    ABSTRACT: Context: Denosumab is a humanized monoclonal antibody to RANKL used primarily for post-menopausal osteoporosis and skeletal-related events from metastatic cancer. Its safety in children has not been established. Objective: To investigate the effects of denosumab treatment on skeletal growth and histology. Design: Observational case report with radiologic and histopathological analyses. Setting: Clinical Research Center Patients: A 9-year-old boy with fibrous dysplasia treated with a 7-month course of denosumab. Intervention: Histologic analyses were performed and compared on growth plates from limbs that had been amputated before and 17 months after denosumab treatment. Main Outcome Measures: Skeletal radiographs and bone histopathology from before and after treatment. Results: After initiating denosumab sclerotic metaphyseal bands appeared on radiographs. Post-treatment radiographs revealed migration of the bands away from the growth plates, consistent with continued linear growth. Histologically, the bands were composed of horizontally-arranged trabeculae containing calcified cartilage. This cartilage appeared to derive from unresorbed primary spongiosa as a result of osteoclast inhibition by denosumab, similar to what has been observed with bisphosphonates. By 17 months post-treatment active bone resorption and formation had returned, as evidenced by the presence of active osteoclasts in resorption pits and osteoid surfaces. Conclusions: Further studies are needed to determine the safety of denosumab on the growing skeleton. However in this child there was continued epiphyseal activity both during and after treatment, and reversal of bone turnover suppression after treatment discontinuation, suggesting that denosumab did not have significant adverse effects on growth.
    The Journal of Clinical Endocrinology and Metabolism 12/2014; DOI:10.1210/jc.2013-3081 · 6.31 Impact Factor
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    ABSTRACT: Purpose of review Abnormalities in bone health are increasingly recognized in the pediatric population. Although the methodologies for assessing bone mineral density were originally developed for adults, great strides have been made in recent years, improving their applicability to children. Understanding these technologies, their interpretation, utility, and limitations is critical when assessing a child or adolescent with a suspected abnormality in bone mineral density. Recent findings Improved normative databases that address some of the confounding variables in the growing and maturing child have solidified dual-energy X-ray absorptiometry as the preferred method for the assessment of bone mineral density in children. Consensus statements by expert panels now provide specific guidance to clinicians seeking to evaluate children with fractures or at risk for fractures. Although still primarily a research tool, continued development of quantitative computed tomography applications in pediatrics suggests there may be a complementary role for clinical use in the future. Summary In the child or adolescent with a significant fracture history or a potential for fractures because of an underlying cause, clinicians now have guidelines and normative data to better focus their evaluation. Likewise, researchers can use this information to improve clinical trial design and interpretation of results.
    Current Opinion in Obstetrics and Gynecology 08/2014; 26(5). DOI:10.1097/GCO.0000000000000100 · 2.37 Impact Factor
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    ABSTRACT: Context: Leptin alters bone and mineral metabolism in rodents, but this has not been verified in humans. Patients with congenital generalized lipodystrophy (CGL) have low leptin due to deficient adipose mass and serve as models of leptin deficiency and replacement. Objective: To study the effects of recombinant human methionyl leptin (metreleptin) on bone mineral content (BMC) and mineral metabolism. Design and Setting: An open-label nonrandomized study at the National Institutes of Health. Patients: Thirty-one patients with CGL (ages 4.3 to 46.7 y). Intervention: Metreleptin (0.06 to 0.24 mg/kg/d) for 6 months to 11 years. Outcome Measures: BMC was assessed by dual-energy x-ray absorptiometry. SD scores (SDS) for BMC were calculated based on height, race, sex, and age using population normative data. Calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at baseline and follow-up. Results: At baseline, patients demonstrated significantly increased total body less head BMC (mean SDS, 1.8 ± 0.7), height (mean SDS, 1.3 ± 1.3), and lean mass index, defined as lean body mass per height squared (mean SDS, 1.5 ± 0.83), vs population normative data. No change in total body less head BMC was observed after metreleptin. Lean mass index decreased with metreleptin. Serum calcium decreased with metreleptin, but remained within normal limits. No changes were seen in phosphorus, PTH, or vitamin D. Conclusions: In contrast to rodent models, CGL patients have increased BMC in the leptin-deficient state, which does not change with leptin replacement. The high BMC in these patients is partially explained by high lean mass and tall stature.
    Journal of Clinical Endocrinology &amp Metabolism 07/2014; 99(8):jc20141353. DOI:10.1210/jc.2014-1353 · 6.31 Impact Factor
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    ABSTRACT: Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease.
    Journal of dental research 04/2014; 93(7). DOI:10.1177/0022034514529150 · 4.14 Impact Factor
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    ABSTRACT: Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder characterized by congenital calcification of large and medium sized arteries, associated with early myocardial infarction, heart failure, and stroke, and premature death. Most cases of GACI are caused by mutations in the ENPP1 gene. We first studied two siblings with GACI from a non-consanguineous family without mutations in the ENPP1 gene. To search for disease-causing mutations, we identified genomic regions shared between the two affected siblings but not their unaffected parents or brother. The ABCC6 gene, which is mutated in pseudoxanthoma elasticum (PXE), resided within a small region of homozygosity shared by the affected siblings. Sequence analysis of ABCC6 revealed that the two affected siblings were homozygous for the missense mutation p.R1314W. Subsequently, ABCC6 mutations were identified in five additional GACI families with normal ENPP1 sequences. Genetic mutations in ABCC6 in patients with PXE are associated with ectopic tissue mineralization in the skin and arterial blood vessels. Thus, our findings provide additional evidence that the ABCC6 gene product inhibits calcification under physiologic conditions and confirm a second locus for GACI. In addition, our study emphasizes the potential utility of shared homozygosity mapping to identify genetic causes of inherited disorders.Journal of Investigative Dermatology accepted article preview online, 5 September 2013. doi:10.1038/jid.2013.370.
    Journal of Investigative Dermatology 09/2013; 134(3). DOI:10.1038/jid.2013.370 · 6.37 Impact Factor
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    ABSTRACT: Pathologically elevated serum levels of FGF23, a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain, and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia, and osteomalacia are associated with pathologic Ras activation, and may provide insight in the heretofore limited understanding of the regulation of FGF23.
    Human Molecular Genetics 09/2013; DOI:10.1093/hmg/ddt429 · 6.68 Impact Factor
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    ABSTRACT: Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and post-operative biochemical changes in 31 subjects with TIO. All had failed either initial, or re-localization (in case of recurrence or metastases at outside institutions). Functional imaging with (111) Indium- octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and (18) fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT,MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20/31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16/20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14/16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10/12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were: sensitivity=0.95, specificity=0.64, PPV=0.82 and NPV=0.88 for octreo-SPECT; sensitivity=0.88, specificity=0.36, PPV=0.62 and NPV=0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1-5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D(3) (1,25D) rose and exceeded the normal range. In this systematic approach to TIO tumor localization Octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation. © 2013 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 06/2013; 28(6). DOI:10.1002/jbmr.1881 · 6.59 Impact Factor
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    ABSTRACT: Objective: Tumoral calcinosis (TC) is a rare entity characterized by hydroxyapatite crystals tumorous masses usually in periarticular areas, induced by systemic hyperphosphatemia and hypervitaminosis D. Orofacial findings have been poorly described in the primary hyperphosphatemic subtype of TC. In this study, we analyzed and characterized orofacial phenotypic markers in a series of patients with tumoral calcinosis. Methods: Four patients with familial tumoral calcinosis were evaluated retrospectively using medical and dental records. Clinical history was reviewed and orofacial findings were retrieved from intra-oral and extra-oral examinations and from interpretation of periapical and panoramic radiographs. Results: Geographic and racial diversity was present among our patient group despite the high predominance of TC in Africa reported in the literature (2 Caucasians from Middle East and North America, 2 Africans from Sub-Saharan Africa and North America). Intra-oral phenotypic findings included: calcifications in pulp chambers and along root canals of primary and permanent dentition (n=4), short and blunted roots on permanent dentition (n=3), taurodontism (n=1), cementosis (n=1), retained primary teeth (n=2), and mandibular exostosis (n=1). Extra-oral examination revealed the following: calcification of sublingual and submandibular salivary glands (n=1), and temporomandibular joint (TMJ) tenderness and pain (n=1). The TMJ pain was related to an internal derangement of the disc, which limited the mandibular range of motion upon opening and laterotrusion. Conclusions: This case series suggests that tumor calcinosis patients may present with not only several abnormalities in tooth development and eruption, but also calcified masses affecting salivary glands and the TMJ disc. Thus, a careful and comprehensive intra-oral and extra-oral examination is required, as well as soft and hard tissue imaging of teeth, salivary glands and the TMJ.
    IADR/AADR/CADR General Session and Exhibition 2013; 03/2013
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    ABSTRACT: The Hajdu-Cheney syndrome is a very rare disease that affects several organ system, leading to severe osteoporosis and other abnormalities. We describe clinical and genetic findings of nine patients with this disease. INTRODUCTION: The Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant disorder characterized by severe osteoporosis, acroosteolysis of the distal phalanges, renal cysts, and other abnormalities. Recently, heterozygous mutations in NOTCH2 were identified as the cause of HCS. METHODS: Nine patients with typical presentations of HCS took part in this study: five affected patients from two small families and four sporadic cases. Peripheral blood DNA was obtained and exome sequencing performed in one affected individual per family and in all four sporadic cases. Sanger sequencing confirmed mutations in all patients. RESULTS: One of the identified mutations was introduced in a plasmid encoding NOTCH2. Wild-type and mutant NOTCH2 were transiently expressed in HEK293 cells to assess intracellular localization after ligand activation. Deleterious heterozygous mutations in the last NOTCH2 exon were identified in all patients; five of the six mutations were novel. CONCLUSION: Consistent with previous reports, all mutations are predicted to result in a loss of the proline/glutamic acid/serine/threonine sequence, which harbors signals for degradation, therefore suggesting activating mutations. One of the six mutations furthermore predicted disruption of the second nuclear localization signal of NOTCH2, but the mutant revealed normal nuclear localization after transfection, which is consistent with the proposed gain-of-function mechanism as the cause of this autosomal dominant disease. Our findings confirm that heterozygous NOTCH2 mutations are the cause of HCS and expand the mutational spectrum of this disorder.
    Osteoporosis International 02/2013; 24(8). DOI:10.1007/s00198-013-2298-5 · 4.17 Impact Factor
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    ABSTRACT: Context:Nephrocalcinosis is a complication of hypoparathyroidism and other metabolic disorders. Imaging modalities include ultrasonography (US) and computed tomography (CT). Few studies have compared these modalities, and standard clinical practice is not defined.Objective:The objective of the study was to determine the preferred method for assessing nephrocalcinosis.Design:The design of the study was a retrospective, blinded analysis.Setting:The study was conducted at a clinical research center.Patients:Twenty-two hypoparathyroid subjects and 7 controls participated in the study.Interventions:Contemporaneous renal US and CT images were reviewed in triplicate by 4 blinded radiologists. Nephrocalcinosis was classified using a 0-3 scale with 0 meaning no nephrocalcinosis and 3 meaning severe nephrocalcinosis.Main Outcome Measures:Intraobserver, interobserver, and interdevice agreements were measured.Results:Intraobserver agreement was high, with an overall weighted kappa of 0.83 for CT and 0.89 for US. Interobserver agreement was similar between modalities, with kappas of 0.74 for US and 0.70 for CT. Only moderate agreement was found between US and CT scores, with an intermodality kappa of 0.47 and 60% concordance. Of discordant pairs, 81% had higher US scores and only 19% had higher CT scores. Of nephrocalcinosis seen on US and not CT, 45%, 46%, and 9% were grades 1, 2, and 3, respectively. Overall, US scores were higher than CT with a cumulative odds ratio (95% confidence interval) of 5.97 (2.60, 13.75) (P < .01). In controls, 100% of US ratings were 0, and 95% of CT ratings were 0.Conclusions:US is superior to CT for assessment of mild to moderate nephrocalcinosis in patients with hypoparathyroidism. This finding, in combination with its low cost, lack of radiation, and portability, defines US as the preferred modality for assessment of nephrocalcinosis.
    The Journal of Clinical Endocrinology and Metabolism 01/2013; 98(3). DOI:10.1210/jc.2012-2747 · 6.31 Impact Factor
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    ABSTRACT: Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates and is regulated by blood levels of phosphate and active vitamin D. Post-translational glycosylation by the enzyme GALNT3 and subsequent processing by furin have been demonstrated to be a regulated process that plays a role in regulating FGF23 levels. In physiologic states, FGF23 signaling is mediated by an FGF receptor and the coreceptor, Klotho. Recent work identifying a role for iron/hypoxia pathways in FGF23 physiology and their implications are discussed. Beyond its importance in primary disorders of mineral metabolism, recent work implicates FGF23 in renal disease-associated morbidity, as well as possible roles in cardiovascular disease and skeletal fragility.
    Trends in Endocrinology and Metabolism 08/2012; 23(12). DOI:10.1016/j.tem.2012.07.002 · 8.87 Impact Factor
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    ABSTRACT: Parathyroid hormone (PTH) has variable actions on bone. Chronically increased PTH is catabolic and leads to osteoporosis; yet intermittent administration is anabolic and increases bone mass. PTH deficiency is associated with decreased bone remodeling and increased bone mass. However, the effects of PTH replacement therapy on bone in hypoparathyroidism are not well known. We discontinued calcitriol therapy and treated 5 hypoparathyroid subjects (2 adults and 3 adolescents) with synthetic human PTH 1-34 (hPTH 1-34), injected two to three times daily for 18 months, with doses individualized to maintain serum calcium at 1.9 to 2.25 mmol/L. Biochemical markers and bone mineral density (BMD) were assessed every 6 months; iliac-crest biopsies were performed before and after 1 year of treatment. hPTH 1-34 therapy significantly increased bone markers to supranormal levels. Histomorphometry revealed that treatment dramatically increased cancellous bone volume and trabecular number and decreased trabecular separation. Changes in trabecular width were variable, suggesting that the increase in trabecular number was due to the observed intratrabecular tunneling. Cortical width remained unchanged; however, hPTH 1-34 treatment increased cortical porosity. Cancellous bone remodeling was also stimulated, inducing significant changes in osteoid, mineralizing surface, and bone formation rate. Similar changes were seen in endocortical and intracortical remodeling. BMD Z-scores were unchanged at the spine and femoral neck. Total hip Z-scores increased; however, total body BMD Z-scores decreased during the first 6 months of treatment and then stabilized, remaining significantly decreased compared to baseline. Radial Z-scores also decreased with treatment; this was most pronounced in the growing adolescent. Daily hPTH 1-34 therapy for hypoparathyroidism stimulated bone turnover, increased bone volume, and altered bone structure in the iliac crest. These findings suggest that treatment with hPTH 1-34 in hypoparathyroid adults and adolescents has varying effects in the different skeletal compartments, leading to an increase in trabecular bone and an apparent trabecularization of cortical bone.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 08/2012; 27(8):1811-20. DOI:10.1002/jbmr.1627 · 6.59 Impact Factor
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    ABSTRACT: Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)-regulating protein, α-subunit of the Gs stimulatory protein (G(s) α). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF-κB ligand (RANKL) is a cell-surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD-like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal-related events from bone metastases. We present the case of a 9-year-old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross-linked C-telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 07/2012; 27(7):1462-70. DOI:10.1002/jbmr.1603 · 6.59 Impact Factor
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    ABSTRACT: Fibroblast growth factor-23 (FGF23) is a phosphate- and vitamin D-regulating hormone derived from osteoblasts/osteocytes that circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by O-glycosyl transferase N-acetylgalactosaminyltransferase 3 (ppGalNAcT3) and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. Elevated iFGF23 levels are observed in a number of hypophosphatemic disorders, such as X-linked, autosomal recessive, and autosomal dominant hypophosphatemic rickets, whereas low iFGF23 levels are found in the hyperphosphatemic disorder familial tumoral calcinosis/hyperphosphatemic hyperostosis syndrome. Fibrous dysplasia of bone (FD) is associated with increased total FGF23 levels (cFGF23 + iFGF23); however, classic hypophosphatemic rickets is uncommon. Our results suggest that it can be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in the small G-protein G(s) α that results in increased cyclic adenosine monophosphate (cAMP) levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels and ppGalNacT3 and furin activities. Analysis of blood specimens from patients with FD confirmed that the elevated total FGF23 levels are the result of proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells (BMSCs) from patients with FD demonstrated that BMSCs harboring the causative G(s) α mutation had higher cAMP levels, lower ppGalNAcT3, and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 05/2012; 27(5):1132-41. DOI:10.1002/jbmr.1546 · 6.59 Impact Factor
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    ABSTRACT: Recent advances in understanding the epidemiology, genetics, diagnosis, clinical presentations, skeletal involvement, and therapeutic approaches to hypoparathyroidism led to the First International Workshop on Hypoparathyroidism that was held in 2009. At this conference, a group of experts convened to discuss these issues with a view towards a future research agenda for this disease. This review, which focuses primarily on hypoparathyroidism in the adult, provides a comprehensive summary of the latest information on this disease. © 2011 American Society for Bone and Mineral Research
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2011; 26(10):2317 - 2337. DOI:10.1002/jbmr.483 · 6.59 Impact Factor
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    Alison M Boyce, Rachel I Gafni
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    ABSTRACT: Evaluation of the child with fractures is challenging, as no clear guidelines exist to distinguish traumatic from pathological fractures. Although most fractures in childhood are benign, recurrent fractures may be associated with a wide variety of primary skeletal diseases as well as secondary causes, necessitating a careful history and physical exam to guide the evaluation. There is no "gold standard" for the evaluation and treatment of children with fractures and low bone mineral density (BMD); therefore, the diagnosis of osteoporosis in a pediatric patient should be made using a combination of clinical and radiographic features. Interpretation of bone densitometry in growing patients presents a unique set of challenges because areal BMD measured by dual-energy x-ray absorptiometry depends on multiple dynamic variables. Interpretation of pediatric dual-energy x-ray absorptiometry should be based on Z-scores (sd scores compared to age, sex, and ethnicity-matched controls), using normative databases specific to the brand of densitometer and the patient population. Given the skeleton's ability to recover from low BMD through modeling and remodeling, optimizing management of underlying conditions leading to bone fragility is the initial step. Conservative measures including calcium and vitamin D supplementation and weight-bearing physical activity are important interventions that should not be overlooked. The use of bisphosphonates in children and adolescents is controversial due to lack of long-term efficacy and safety data and should be limited to clinical trials and compassionate therapy in children with significantly compromised quality of life. Close monitoring is required, and further study is necessary to assess their long-term safety and efficacy in children.
    The Journal of Clinical Endocrinology and Metabolism 07/2011; 96(7):1943-52. DOI:10.1210/jc.2010-2546 · 6.31 Impact Factor
  • Rachel I. Gafni, Jeffrey Baron
    Bone 07/2009; 45. DOI:10.1016/j.bone.2009.04.016 · 4.46 Impact Factor
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    ABSTRACT: 5 of 6 children infected with human immunodeficiency virus (HIV) receiving Tenofovir disoproxil fumarate (TDF) experienced absolute decreases in bone mineral density (BMD). 2 pre-pubertal subjects experienced >6% BMD decreases. 1 subject was the smallest child and experienced a 27% decrease, necessitating withdrawal of TDF. Subsequently, her BMD recovered. Monitoring of children infected with HIV who require treatment with TDF is warranted.
    The Journal of pediatrics 04/2008; 152(4):582-4. DOI:10.1016/j.jpeds.2007.12.020 · 3.74 Impact Factor
  • Rachel I Gafni, Jeffrey Baron
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    ABSTRACT: During childhood and adolescence, bone mass acquisition occurs primarily through skeletal growth. It is widely assumed that bone mass acquisition throughout childhood is an important determinant of the risk of osteoporosis in late adulthood; bone mass is thought to resemble a bank account in which deposits persist indefinitely. However, several well-controlled clinical studies suggest that increasing bone mass acquisition during childhood will have only transient effects. A likely explanation is that bone mass is governed by a homeostatic system that tends to return to a set point after any perturbation and, therefore, bone mass depends primarily on recent conditions, not those in the distant past. Indeed, in an animal model, we have shown evidence that bone mass acquisition in early life has no effect on bone mass in adulthood, in part because many areas of the juvenile skeleton are replaced in toto through skeletal growth. Therefore, it should not be assumed that alterations in childhood bone mass acquisition will affect bone mass many decades later in late adulthood. This issue remains open and the solution may depend on the type of childhood condition (for example calcium intake versus exercise) and its magnitude, timing, and duration. To date, both animal studies and clinical studies suggest that much of the effect of early bone mass acquisition does not persist.
    PEDIATRICS 04/2007; 119 Suppl 2:S131-6. DOI:10.1542/peds.2006-2023D · 5.30 Impact Factor
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    ABSTRACT: Hypoparathyroidism is characterized clinically by the presence of hypocalcemia and hyperphosphatemia due to inadequate supply or effectiveness of circulating parathyroid hormone (PTH). It may be present either as an isolated finding or as a component of a more complex developmental, metabolic, or endocrinologic syndrome. While the most common cause of hypoparathyroidism continues to be surgical destruction1, several genetic etiologies have been identified that help define the molecular basis for less common causes. These genetic disorders can result in impaired embryologic development of the parathyroids, disordered synthesis or secretion of PTH, autoimmune destruction of the parathyroid gland, or inappropriate end-organ response to PTH (Table 1).
    02/2007: pages 159-178;

Publication Stats

965 Citations
155.73 Total Impact Points

Institutions

  • 2014
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      베서스다, Maryland, United States
  • 2003–2013
    • National Institutes of Health
      • • Branch of Craniofacial and Skeletal Diseases
      • • Branch of HIV and AIDS Malignancy
      • • Section on Growth and Development
      Maryland, United States
  • 2011
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      • Program in Developmental Endocrinology and Genetics (PDEGEN)
      Роквилл, Maryland, United States
  • 2007
    • University of Maryland, Baltimore
      • Department of Pediatrics
      Baltimore, Maryland, United States
  • 2006
    • George Washington University
      Washington, Washington, D.C., United States
  • 2000–2002
    • National Institute of Child Health and Human Development
      Maryland, United States