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1. AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity

Author

Caroline M. Gorvin, Angela Rogers, Benoit Hastoy, Andrei I. Tarasov, Morten Frost, Silvia Sposini, Asuka Inoue, Michael P. Whyte, Patrik Rorsman, Aylin C. Hanyaloglu, Gerda E. Breitwieser, and Rajesh V. Thakker

Subjects
endosomal signaling, GPCR, lcsh:Biology (General), hypercalcemia, clathrin-mediated endocytosis, calcium signaling, lcsh:QH301-705.5, adaptor protein-2, G proteins
Abstract

Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic signaling via multiple G-protein pathways remain unknown. Here, we investigated the effects of disease-causing mutations of the adaptor protein-2 σ subunit (AP2σ) on signaling by the class C GPCR calcium-sensing receptor (CaSR). These AP2σ mutations increase CaSR PM expression yet paradoxically reduce CaSR signaling. Hypercalcemia-associated AP2σ mutations reduced CaSR signaling via Gαq/11 and Gαi/o pathways. The mutations also delayed CaSR internalization due to prolonged residency time of CaSR in clathrin structures that impaired or abolished endosomal signaling, which was predominantly mediated by Gαq/11. Thus, compartmental bias for CaSR-mediated Gαq/11 endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling.

Published
2018

3. List of Contributors

Author

David Abraham, Maria Almeida, Elena Ambrogini, Andrew Arnold, Bence Bakos, Clemens Bergwitz, Daniel D. Bikle, John P. Bilezikian, Neil Binkley, Alessandro Bisello, L.F. Bonewald, George Bou-Gharios, Roger Bouillon, Mary L. Bouxsein, Brendan F. Boyce, Steven Boyd, Maria Luisa Brandi, David B. Burr, Laura M. Calvi, Ernesto Canalis, Xu Cao, Geert Carmeliet, Thomas O. Carpenter, Wenhan Chang, Shek Man Chim, Shilpa Choudhary, Sylvia Christakos, Yong-Hee Patricia Chun, Cristiana Cipriani, Roberto Civitelli, Thomas L. Clemens, Michael T. Collins, Caterina Conte, Mark S. Cooper, Jillian Cornish, Serge Cremers, Bess Dawson-Hughes, Benoit de Crombrugghe, Hector F. DeLuca, David W. Dempster, Matthew T. Drake, Patricia Ducy, Frank H. Ebetino, Klaus Engelke, Reinhold G. Erben, David R. Eyre, Charles R. Farber, Marina Feigenson, Mathieu Ferron, Pablo Florenzano, Francesca Fontana, Brian L. Foster, Peter A. Friedman, Seiji Fukumoto, Laura W. Gamer, Thomas J. Gardella, Patrick Garnero, Harry K. Genant, Francesca Giusti, Andy Göbel, David Goltzman, Jeffrey P. Gorski, James Griffith, R. Graham G Russell, Kurt D. Hankenson, Fadil M. Hannan, Stephen E. Harris, Iris R. Hartley, Christine Hartmann, Robert P. Heaney, Geoffrey N. Hendy, Matthew J. Hilton, Lorenz C. Hofbauer, Gill Holdsworth, Yi-Hsiang Hsu, David M. Hudson, Marja Hurley, Karl L. Insogna, Robert L. Jilka, Mark L. Johnson, Rachelle W. Johnson, Glenville Jones, Stefan Judex, Harald Jüppner, Ivo Kalajzic, Gérard Karsenty, Hua Zhu Ke, Sundeep Khosla, Douglas P. Kiel, J. Klein-Nulend, Frank C. Ko, Yasuhiro Kobayashi, Martin Konrad, Paul J. Kostenuik, Christopher S. Kovacs, Richard Kremer, Venkatesh Krishnan, Henry M. Kronenberg, Peter A. Lakatos, Uri A. Liberman, Joseph A. Lorenzo, Conor C. Lynch, Karen M. Lyons, Y. Linda Ma, Christa Maes, Michael Mannstadt, Stavros Manolagas, Robert Marcus, David E. Maridas, Pierre J. Marie, Francesca Marini, Jasna Markovac, T. John Martin, Brya G. Matthews, Antonio Maurizi, Sasan Mirfakhraee, Sharon M. Moe, David G. Monroe, Carolina A. Moreira, Ralph Müller, David S. Musson, Teruyo Nakatani, Dorit Naot, Nicola Napoli, Tally Naveh-Many, Edward F. Nemeth, Thomas L. Nickolas, Michael S. Ominsky, Noriaki Ono, David M. Ornitz, Nicola C. Partridge, Vihitaben S. Patel, J. Wesley Pike, Carol Pilbeam, Lori Plum, John T. Potts, J. Edward Puzas, Tilman D. Rachner, Audrey Rakian, Rubie Rakian, Nora E. Renthal, Julie A. Rhoades (Sterling), Mara Riminucci, Scott J. Roberts, Pamela Gehron Robey, Michael J. Rogers, G. David Roodman, Clifford J. Rosen, Vicki Rosen, David W. Rowe, Janet Rubin, Clinton T. Rubin, Karl P. Schlingmann, Ego Seeman, Markus J. Seibel, Chris Sempos, Dolores M. Shoback, Caroline Silve, Justin Silver, Natalie A. Sims, Frederick R. Singer, Joseph P. Stains, Steve Stegen, Paula H. Stern, Gaia Tabacco, Istvan Takacs, Naoyuki Takahashi, Donovan Tay, Anna Teti, Rajesh V. Thakker, Ryan E. Tomlinson, Francesco Tonelli, Dwight A. Towler, Elena Tsourdi, Chia-Ling Tu, Nobuyuki Udagawa, Connie M. Weaver, Marc N. Wein, Lee S. Weinstein, MaryAnn Weis, Michael P. Whyte, Bart O. Williams, Xin Xu, Shoshana Yakar, Yingzi Yang, Stefano Zanotti, and Hong Zhou

Published
2020
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4. Introduction to Genetics of Skeletal and Mineral Metabolic Diseases

Author

Rajesh V. Thakker, Caroline M Gorvin, Paul J. Newey, and Michael P. Whyte

Subjects
0301 basic medicine, Genetics, medicine.diagnostic_test, 030209 endocrinology & metabolism, Physical examination, Biology, Penetrance, Germline, 03 medical and health sciences, symbols.namesake, 030104 developmental biology, 0302 clinical medicine, Genetic variation, Mendelian inheritance, symbols, medicine, Abnormality, Introduction to genetics, Clinical skills
Abstract

Many skeletal and mineral metabolic diseases have a genetic basis, which may be a germline single gene abnormality (i.e., a monogenic or Mendelian disorder), a somatic single gene defect (i.e., a postzygotic mosaic disorder), or involve several genetic variants (i.e., oligogenic or polygenic disorders). Genetic mutations causing Mendelian diseases usually have a large effect (i.e., penetrance), whereas oligogenic or polygenic disorders are associated with several genetic variations, each of which may have small effects with greater or smaller contributions from environmental factors (i.e., multifactorial disorders). Recognition of monogenic hereditary disorders is of clinical importance, as it may lead to relevant and timely investigations with correct treatment for the patient, and the patient’s relatives. The diagnosis of monogenic skeletal disease requires an awareness of the great diversity of symptoms and signs that may be associated with the disorder and, as ever, clinical skill is required. Thus, the clinician will need to pursue a careful and systematic approach with detailed history and physical examination and appropriate laboratory evaluations that should lead to judicious use of the range of diagnostic tools available. Finally, the clinician will require an appreciation of the increasing number and complexity of molecular genetic tests available to ensure their appropriate use and interpretation. These considerations are reviewed in this chapter.

Published
2018
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6. List of Contributors

Author

John S. Adams, Judith E. Adams, Jawaher A. Alsalem, Paul H. Anderson, Panagiota Andreopoulou, Edith Angellotti, Leggy A. Arnold, Gerald J. Atkins, Antonio Barbáchano, Shari S. Bassuk, Sarah Beaudin, Anna Y. Belorusova, Nancy A. Benkusky, Carlos Bernal-Mizrachi, Ishir Bhan, Harjit P. Bhattoa, Daniel D. Bikle, John P. Bilezikian, Neil C. Binkley, Heike A. Bischoff-Ferrari, Charles W. Bishop, Ida M. Boisen, Fabrizio Bonelli, Adele L. Boskey, Barbara J. Boucher, Roger Bouillon, Manuella Bouttier, Barbara D. Boyan, Danny Bruce, Laura Buburuzan, Andrew J. Burghardt, Thomas H.J. Burne, Mona S. Calvo, Carlos A. Camargo, Jorge B. Cannata-Andia, Margherita T. Cantorna, Carsten Carlberg, Geert Carmeliet, Thomas O. Carpenter, Graham D. Carter, Kevin D. Cashman, Lisa Ceglia, Sylvia Christakos, Kenneth B. Christopher, Rene F. Chun, Fredric L. Coe, Frederick Coffman, Juliet Compston, Cyrus Cooper, Elizabeth M. Curtis, Natalie E. Cusano, Michael Danilenko, G. David Roodman, Bess Dawson-Hughes, Pierre De Clercq, Hector F. DeLuca, Julie Demaret, Marie B. Demay, David W. Dempster, Elaine M. Dennison, Puneet Dhawan, Vassil Dimitrov, Katie M. Dixon, Maryam Doroudi, Shevaun M. Doyle, Adriana S. Dusso, Aleksey Dvorzhinskiy, Peter R. Ebeling, John A. Eisman, Gregory R. Emkey, Ervin H. Epstein Jr., Sol Epstein, Darryl Eyles, Murray J. Favus, David Feldman, Gemma Ferrer-Mayorga, David M. Findlay, James C. Fleet, Brian L. Foster, Renny T. Franceschi, David R. Fraser, Jessica M. Furst, Rachel I. Gafni, Edward Giovannucci, Christian M. Girgis, James L. Gleason, Francis H. Glorieux, Elzbieta Gocek, David Goltzman, José Manuel González-Sancho, Laura A. Graeff-Armas, William B. Grant, Natalie J. Groves, Conny Gysemans, Lasse Bøllehuus Hansen, Nicholas C. Harvey, Catherine M. Hawrylowicz, Colleen E. Hayes, Robert P. Heaney, Geoffrey N. Hendy, Pamela A. Hershberger, Martin Hewison, Michael F. Holick, Bruce W. Hollis, Philippe P. Hujoel, Elina Hyppönen, Karl L. Insogna, Nina G. Jablonski, Martin Blomberg Jensen, David A. Jolliffe, Glenville Jones, Kerry S. Jones, Harald Jüppner, Enikö Kallay, Andrew C. Karaplis, Martin Kaufmann, Mairead Kiely, Tiffany Y, Kim, Martin Konrad, Christopher S. Kovacs, Richard Kremer, Roland Krug, Rajiv Kumar, Noriyoshi Kurihara, Emma Laing, Joseph M. Lane, Dean P. Larner, María Jesús Larriba, Gilles Laverny, Nathalie Le Roy, Seong M. Lee, Michael A. Levine, Richard Lewis, Paul Lips, Thomas S. Lisse, Eva S. Liu, Philip T. Liu, Yan Li, Yan Chun Li, James G. MacKrell, Leila J. Mady, Sharmila Majumdar, Makoto Makishima, Peter J. Malloy, Elizabeth H. Mann, JoAnn E. Manson, Adrian R. Martineau, Rebecca S. Mason, Chantal Mathieu, Toshio Matsumoto, Donald G. Matthews, John J. McGrath, Daniel Metzger, Mark B. Meyer, Denshun Miao, Mathew T. Mizwicki, Rebecca J. Moon, Howard A. Morris, Li J. Mortensen, Alberto Muñoz, Yuko Nakamichi, Carmen J. Narvaez, Faye E. Nashold, Tally Naveh-Many, Carrie M. Nielson, Anthony W. Norman, Yves Nys, Melda Onal, Lubna Pal, Kristine Y. Patterson, Steven Pauwels, Pamela R. Pehrsson, Martin Petkovich, John M. Pettifor, Paul E. Pfeffer, Katherine M. Phillips, J. Wesley Pike, Stefan Pilz, Anastassios G. Pittas, Pawel Pludowski, David E. Prosser, Sri Ramulu N. Pullagura, L. Darryl Quarles, Rithwick Rajagopal, Katherine J. Ransohoff, Saaeha Rauz, Brian J. Rebolledo, Jörg Reichrath, Sandra Rieger, Amy E. Riek, Natacha Rochel, Jeffrey D. Roizen, Janet M. Roseland, Cliff Rosen, Mark S. Rybchyn, Hiroshi Saitoh, Reyhaneh Salehi-Tabar, Anne L. Schafer, Karl P. Schlingmann, Inez Schoenmakers, Zvi Schwartz, Kayla Scott, Christopher T. Sempos, Lusia Sepiashvili, Mukund Seshadri, Elizabeth Shane, Tatiana Shaurova, Irene Shui, Justin Silver, Ravinder J. Singh, Linda Skingle, René St-Arnaud, Jessica Starr, Keith R. Stayrook, Emily M. Stein, Ryan E. Stites, George P. Studzinski, Tatsuo Suda, Fumiaki Takahashi, Naoyuki Takahashi, Jean Y. Tang, Christine L. Taylor, Hugh S. Taylor, Peter J. Tebben, Thomas D. Thacher, Ravi Thadhani, Kebashni Thandrayen, Susan Thys-Jacobs, Dov Tiosano, Roberto Toni, Dwight A. Towler, Donald L. Trump, Nobuyuki Udagawa, André G. Uitterlinden, Aasis Unnanuntana, Jeroen van de Peppel, Bram C.J. van der Eerden, Marjolein van Driel, Johannes P.T.M. van Leeuwen, Natasja van Schoor, An-Sofie Vanherwegen, Aria Vazirnia, Lieve Verlinden, Annemieke Verstuyf, Reinhold Vieth, Carol L. Wagner, Graham R. Wallace, Connie Weaver, JoEllen Welsh, John H. White, Susan J. Whiting, Michael P. Whyte, John J. Wysolmerski, Sachiko Yamada, Olivia B. Yu, Kathryn Zavala, Christoph Zechner, Meltem Zeytinoglu, and Hengguang Zhao

Published
2018
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7. Hypophosphatasia and How Alkaline Phosphatase Promotes Mineralization

Author

Michael P. Whyte

Subjects
0301 basic medicine, medicine.medical_specialty, Osteomalacia, Chemistry, Hypophosphatasia, ALPL, 030209 endocrinology & metabolism, Rickets, medicine.disease, Metabolic bone disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, Inborn error of metabolism, Internal medicine, Asfotase alfa, medicine, Alkaline phosphatase
Abstract

Hypophosphatasia (HPP) is the remarkably informative inborn error of metabolism and metabolic bone disease that features low serum alkaline phosphatase (ALP) activity (hypophosphat asemia ) due to loss-of-function mutation(s) of TNSALP ( ALPL ), the gene that encodes the “tissue nonspecific” (bone/liver) isoenzyme of ALP (TNSALP). Lessons from HPP revealed that TNSALP is a cell-surface phosphohydrolase and showed how it functions. Several phosphocompounds that are TNSALP natural substrates accumulate extracellularly in HPP, including inorganic pyrophosphate (PP i ), an inhibitor of hydroxyapatite (HA) crystal growth, and pyridoxal 5′-phosphate (PLP), the major circulating form of vitamin B 6 . The superabundance of extracellular PP i blocks mineralization of the skeleton after matrix vesicles (MVs) rupture and release their nascent HA crystals. This causes rickets or osteomalacia despite normal or sometimes elevated circulating levels of calcium and phosphorus and adequate vitamin D. Failure of the cementumcovering tooth roots to mineralize leads to premature exfoliation of deciduous teeth. However, HPP spans the greatest range of severity of all skeletal diseases. This is largely explained by autosomal dominant (AD) and autosomal recessive (AR) inheritance from among several hundred, typically missense, mutations of TNSALP . Unless treated, perinatal HPP kills rapidly due to profound skeletal hypomineralization. Infantile HPP presents postnatally, but before age 6 months with rickets, failure-to-thrive, and sometimes hypercalcemia or vitamin B 6 -dependent seizures. Progressive chest deformity often causes lethal pulmonary problems. When severe, childhood HPP features symptomatic rickets, premature loss of deciduous teeth, and chronic muscle weakness. Adult HPP typically presents in middle age with osteomalacia and pseudofractures and sometimes arthropathies involving PP i deposition. Odonto-HPP, likely the most prevalent HPP, features tooth loss without skeletal disease. AR inheritance accounts for the most severely affected patients, whereas AD and rarely AR transmission explain the mild forms. In 2015, substantially effective bone-targeted TNSALP replacement therapy (asfotase alfa) received regulatory approval multinationally, typically for pediatric-onset HPP—the last rickets/osteomalacia to await a medical treatment. Now, for a variety of disorders, excessive ALP activity in diseased tissues is implicated in ectopic mineralization.

Published
2018
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9. Mendelian Disorders of RANKL/OPG/RANK/NF-κB Signaling

Author

Michael P. Whyte

Subjects
musculoskeletal diseases, 0301 basic medicine, medicine.medical_specialty, Osteolysis, biology, Bone disease, business.industry, 030209 endocrinology & metabolism, Osteopetrosis, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, medicine.anatomical_structure, Paget's disease of bone, Osteoprotegerin, RANKL, Osteoclast, Internal medicine, medicine, biology.protein, Osteosarcoma, business
Abstract

Revelation that the RANKL/OPG/RANK/NF-κB signaling pathway is a key modulator of osteoclast (OC) formation and action began in the 1990s with the discoveries of three new members of the tumor necrosis factor (TNF) superfamily (RANKL, OPG, and RANK). Soon after, genetically altered mice disclosed importance for these proteins in bone biology. Binding of RANKL to RANK promotes osteoclastogenesis and increased skeletal remodeling mediated through NF-κB signaling, whereas coupling of RANKL instead to its “decoy receptor” OPG inhibits this pathway. Subsequently, the significance of these proteins for humans was highlighted by the discoveries that mutation of the genes that encode RANKL ( TNFSF11 ), OPG ( TNFRSF11B ), and RANK ( TNFRSF11A ) explain several ultrarare but highly instructive Mendelian diseases that alter osteoclastogenesis and OC action. Those that activate the pathway (familial expansile osteolysis, early-onset Paget’s disease of bone, expansile skeletal hyperphosphatasia, panostotic expansile bone disease, and juvenile Paget’s disease) resemble classic Paget’s disease of bone. Those that deactivate the pathway cause “OC-poor” osteopetrosis due to impaired OC formation. In 2016, neonatal high bone mass became the newest heritable entity of this pathway and revealed the first mutation identified within the five-member NF-κB complex itself. This chapter reviews the clinical and laboratory features as well as the etiology and pathogenesis of these intriguing disorders.

Published
2018
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10. List of Contributors

Author

Cheryl Ackert-Bicknell, Sunita K. Agarwal, Omar M.E. Albagha, Robyn S. Allen, Andrew Arnold, J.H. Duncan Bassett, John F. Bateman, Teresita Bellido, Lynda Bonewald, Eveline Boudin, Mary L. Bouxsein, Brendan F. Boyce, Niambi S. Brewer, Stephanie J. Brewster, Mike Briggs, Edward M. Brown, Matthew A. Brown, David A. Bushinsky, Wayne A. Cabral, Michael T. Collins, Michael R. Convente, Jessica Costa-Guda, Hong-Wen Deng, Olivier Devuyst, Marc K. Drezner, Emma L. Duncan, Ogo I. Egbuna, John A. Eisman, Charles R. Farber, David Feldman, Carlos R. Ferreira, William A. Gahl, Caroline M. Gorvin, Matthew W. Grol, Yan Guo, Kilian Guse, Fadil M. Hannan, Ruo-Han Hao, Ingrid A. Holm, Takashi Igarashi, Christina Jacobsen, Fjola Johannesdottir, Harald Jüppner, Frederick S. Kaplan, Gerard Karsenty, Christopher S. Kovacs, John J. Kuiper, Brendan H. Lee, Gabriela G. Loots, Rik J. Lories, Frank P. Luyten, Peter J. Malloy, Michael Mannstadt, Joan C. Marini, T. John Martin, Walter L. Miller, Orson W. Moe, Paul J. Newey, Tuan V. Nguyen, Kazuo Okamoto, Paola D. Pajevic, Christopher J. Papasian, Siân E. Piret, Stuart H. Ralston, Fernando Rivadeneira, Pamela G. Robey, Clifford J. Rosen, Merry Z.C. Ruan, Steven J. Scheinman, Scott J. Schurman, Aimy Sebastian, Yiping Shen, Eileen M. Shore, Caroline Silve, Natalie A. Sims, Alexandra K. Stanley, Adrianne Stone, Hiroshi Takayanagi, Rajesh V. Thakker, O. Will Towler, André G. Uitterlinden, Ana M. Valdes, Bram C.J. van der Eerden, Wim Van Hul, Jianwen Wei, Marc N. Wein, Lee S. Weinstein, Michael P. Whyte, Graham R. Williams, Lianping Xing, Tie-Lin Yang, Andreas Zankl, Shira G. Ziegler, and Michael J. Zuscik

Published
2018
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11. Heritable Renal Phosphate Wasting Disorders

Author

Michael P. Whyte and Marc K. Drezner

Subjects
Fibroblast growth factor 23, medicine.medical_specialty, Osteomalacia, Autosomal dominant hypophosphatemic rickets, Rickets, Biology, Gene mutation, medicine.disease, Pathogenesis, Hypophosphatemic Rickets, Endocrinology, Internal medicine, medicine, Hypophosphatemia
Abstract

Heritable disorders of disturbed renal phosphate handling are the most common causes of rickets and osteomalacia in developed countries. However, the molecular mechanisms underlying the biochemical abnormalities and abnormal bone/cartilage mineralization in these diseases are complex, and our current models are incomplete, albeit they have grown remarkably over the past decade. Isolated renal phosphate wasting and consequent low serum phosphorus concentrations may result from a variety of genetic disorders that include: autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), and autosomal recessive hypophosphatemic rickets (ARHR). Seminal findings have confirmed a central role for the endocrine molecule, fibroblast growth factor 23 (FGF23), in the pathogenesis of these diseases. Understanding the inter-relationships between the gene mutations underlying these disorders and regulation of FGF23 production and proteolysis has provided new and unanticipated therapeutic targets for management of this constellation of diseases. These advances have resulted from ground-breaking studies in humans and animal models that promise to fuel further successful studies.

Published
2018
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13. Contributors

Author

Lloyd Paul Aiello, Kyriaki S. Alatzoglou, Erik K. Alexander, Carolyn A. Allan, Bruno Allolio, Nobuyuki Amino, Bradley D. Anawalt, Peter Angelos, Valerie A. Arboleda, Richard J. Auchus, Lloyd Axelrod, Rebecca S. Bahn, H.W. Gordon Baker, MD, PhD, FRACP, Shlomi Barak, Randall B. Barnes, Andreas Barthel, Murat Bastepe, Emma K. Beardsley, Paolo Beck-Peccoz, Graeme I. Bell, Wenya Linda Bi, John P. Bilezikian, Manfred Blum, Steen J. Bonnema, Stefan R. Bornstein, Roger Bouillon, Andrew J.M. Boulton, Glenn D. Braunstein, F. Richard Bringhurst, Frank J. Broekmans, Marcello D. Bronstein, Edward M. Brown, Wendy A. Brown, Serdar E. Bulun, Henry B. Burch, Henry G. Burger, Richard O. Burney, Morton G. Burt, Enrico Cagliero, Glenda G. Callender, Maria Luiza Avancini Caramori, Robert M. Carey, Tobias Carling, Francesco Cavagnini, Jerry D. Cavallerano, Etienne Challet, Shu Jin Chan, R. Jeffrey Chang, Roland D. Chapurlat, V. Krishna Chatterjee, Francesco Chiofalo, Luca Chiovato, Kyung J. Cho, Emily Christison-Lagay, Daniel Christophe, George P. Chrousos, John A. Cidlowski, David R. Clemmons, Robert V. Considine, Marco Conti, Georges Copinschi, Kyle D. Copps, Michael A. Cowley, Leona Cuttler, Mehul T. Dattani, Stephen N. Davis, Mario De Felice, Leslie J. De Groot, David M. de Kretser, Ralph A. DeFronzo, Ahmed J. Delli, Marie B. Demay, Michael C. Dennedy, Roberto Di Lauro, Rosemary Dineen, Su Ann Ding, Sean F. Dinneen, Daniel J. Drucker, Jacques E. Dumont, Kathleen M. Dungan, Ian F. Dunn, Michael J. Econs, David A. Ehrmann, Graeme Eisenhofer, Berrin Ergun-Longmire, Erica A. Eugster, Sadaf I. Farooqi, Martin Fassnacht, Bart C.J.M. Fauser, Gianfranco Fenzi, Ele Ferrannini, David M. Findlay, Courtney Anne Finlayson, Delbert A. Fisher, Isaac R. Francis, Mason W. Freeman, Lawrence A. Frohman, Mark Frydenberg, Peter J. Fuller, Jason L. Gaglia, Gianluigi Galizia, Thomas J. Gardella, Katharine C. Garvey, Harry K. Genant, Michael S. German, Evelien F. Gevers, Francesca Pecori Giraldi, Linda C. Giudice, Andrea Giustina, Anna Glasier, Francis H. Glorieux, Allison B. Goldfine, Louis J. Gooren, David F. Gordon, Karen A. Gregerson, Raymon H. Grogan, Milton D. Gross, Ashley B. Grossman, Matthias Gruber, Valeria C. Guimarães, Mark Gurnell, Nadine G. Haddad, Daniel J. Haisenleder, David J. Handelsman, John B. Hanks, Mark J. Hannon, Erika Harno, Matthias Hebrok, Mark P. Hedger, Laszlo Hegedüs, Jerrold J. Heindel, Arturo Hernandez, Maria K. Herndon, Ken K.Y. Ho, Nelson D. Horseman, Ieuan A. Hughes, Christopher J. Hupfeld, Hero K. Hussain, Valeria Iodice, Benjamin C. James, J. Larry Jameson, Glenville Jones, Nathalie Josso, Harald Jüppner, Agata Juszczak, Jeffrey Kalish, Edwin L. Kaplan, Niki Karavitaki, Monika Karczewska-Kupczewska, Ahmed Khattab, David C. Klein, Ronald Klein, Gunnar Kleinau, Michaela Koontz, John J. Kopchick, Peter Kopp, Irina Kowalska, Stephen M. Krane, Knut Krohn, Henry M. Kronenberg, Elizabeth M. Lamos, Andrea Lania, Sue Lynn Lau, Edward R. Laws, John H. Lazarus, Diana L. Learoyd, Harold E. Lebovitz, Åke Lenmark, Edward O. List, Kate Loveland, David A. Low, Paolo E. Macchia, Noel K. Maclaren, Geraldo Madeiros-Neto, Carine Maenhaut, Christa Maes, Katharina M. Main, Carl D. Malchoff, Diana M. Malchoff, Rayaz A. Malik, Susan J. Mandel, Christos S. Mantzoros, Eleftheria Maratos-Flier, Michele Marino, John C. Marshall, T. John Martin, Thomas F.J. Martin, Christopher J. Mathias, Elizabeth A. McGee, Travis McKenzie, Robert I. McLachlan, Juris J. Meier, Shlomo Melmed, Boyd E. Metzger, Heino F.L. Meyer-Bahlburg, Robert P. Millar, Walter L. Miller, Madhusmita Misra, Mark E. Molitch, Molly B. Moravek, Damian G. Morris, Sapna Nagar, Jon Nakamoto, Maria I. New, Lynnette K. Nieman, John H. Nilson, Georgia Ntali, Moira O’Bryan, Stephen O’Rahilly, Kjell Öberg, Jerrold M. Olefsky, Matthew T. Olson, Karel Pacak, Furio Pacini, Shetal H. Padia, Ralf Paschke, Francisco J. Pasquel, Katherine Wesseling Perry, Luca Persani, Louis H. Philipson, Christian Pina, Frank B. Pomposelli, John T. Potts, Charmian A. Quigley, Marcus O. Quinkler, Christine Campion Quirk, Ewa Rajpert-De Meyts, Eric Ravussin, David W. Ray, Samuel Refetoff, Ravi Retnakaran, Rodolfo A. Rey, Christopher J. Rhodes, E. Chester Ridgway, Gail P. Risbridger, Robert A. Rizza, Bruce G. Robinson, Pierre P. Roger, Michael G. Rosenfeld, Robert L. Rosenfield, Peter Rossing, Robert T. Rubin, Ileana G.S. Rubio, Neil B. Ruderman, Jose Russo, Irma H. Russo, Isidro B. Salusky, Nanette Santoro, Kathleen M. Scully, Patrick M. Sexton, Gerald I. Shulman, Paolo S. Silva, Shonni J. Silverberg, Frederick R. Singer, Niels E. Skakkebaek, Malgorzata E. Skaznik-Wikiel, Dorota Skowronska-Krawczyk, Carolyn L. Smith, Philip W. Smith, Roger Smith, Steven R. Smith, Peter J. Snyder, Donald L. St. Germain, René St-Arnaud, Donald F. Steiner, Paul M. Stewart, Marek Strączkowski, Jerome F. Strauss, Dennis M. Styne, Karena L. Swan, Ronald S. Swerdloff, Lyndal J. Tacon, Javier A. Tello, Rajesh V. Thakker, Christopher J. Thompson, Henri J.L.M. Timmers, Jorma Toppari, Michael L. Traub, Michael A. Tsoukas, Robert Udelsman, Guillermo E. Umpierrez, Greet Van den Berghe, Gilbert Vassart, Ashley H. Vernon, Eric Vilain, Theo J. Visser, Paolo Vitti, Geoffrey A. Walford, Christina Wang, Anthony P. Weetman, Nancy L. Weigel, Gordon C. Weir, Roy E. Weiss, Anne White, Kenneth E. White, Morris F. White, Michael P. Whyte, Wilmar M. Wiersinga, Holger S. Willenberg, Joseph I. Wolfsdorf, Fredric E. Wondisford, Ka Kit Wong, John J. Wysolmerski, Mabel Yau, Morag J. Young, Lisa M. Younk, Run Yu, Tony Yuen, Martha A. Zeiger, Bernard Zinman, and R. Thomas Zoeller

Published
2016
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14. Contributors

Author

Robert A. Adler, C.E. Ambrosini, Andrew Arnold, Zubair W. Baloch, Francisco Bandeira, Carlo Bartolozzi, Sanjay Kumar Bhadada, John P. Bilezikian, Jens Bollerslev, Maria Luisa Brandi, Edward M. Brown, Roger Bouillon, Glenda G. Callender, Tobias Carling, Vincenzo Carnevale, Monica Therese B. Cating-Cabral, Filomena Cetani, Luisella Cianferotti, Roberto Civitelli, Bart L. Clarke, Aline Correia, Felicia Cosman, Aline G. Costa, Natalie E. Cusano, Pierre D’Amour, Anthony F. De Giacomo, Marian Dejaeger, David W. Dempster, Marcella Donovan Walker, Richard Eastell, Thomas A. Einhorn, Ghada El-Hajj Fuleihan, Dorothy A. Fink, Lorraine A. Fitzpatrick, Adam N. Freeman, Peter A. Friedman, Thomas J. Gardella, Andrea Giustina, David Goltzman, Didier Hans, Robert P. Heaney, Sarada Jaimunga, Sophie Jamal, Suzanne M. Jan De Beur, Harald Jüppner, Aliya A. Khan, Sundeep Khosla, Gordon L. Klein, Stavroula Kousteni, Christopher S. Kovacs, Richard Kremer, Henry M. Kronenberg, Benjamin Z. Leder, Michael A. Levine, E. Michael Lewiecki, Virginia A. Livolsi, Christa Maes, Michael Mannstadt, Claudio Marcocci, Robert Marcus, Giuliano Mariani, T. John Martin, Salvatore Mazzeo, P. Miccoli, Paul D. Miller, Salvatore Minisola, Deborah M. Mitchell, Jörgen Nordenström, Roberto Pacifici, A. Michael Parfitt, Munro Peacock, John T. Potts Jr, M. Zohair Rahman, Sudhaker D. Rao, Leila Revollo, Jeffrey Roizen, Elisabetta Romagnoli, Domenico Rubello, Mishaela R. Rubin, Isidro B. Salusky, Alfredo Scillitani, Elizabeth Shane, Dolores M. Shoback, Barbara C. Silva, Caroline Silve, Shonni J. Silverberg, Stuart M. Sprague, Elizabeth A. Streeten, Larry J. Suva, Laila Tabatabai, Rajesh V. Thakker, Dwight A. Towler, Robert Udelsman, Tamara Vokes, Robert A. Wermers, Katherine Wesseling-Perry, Michael P. Whyte, and John J. Wysolmerski

Published
2015
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15. Hypophosphatasia

Author

Michael P. Whyte

Subjects
Pediatrics, medicine.medical_specialty, Chemistry, Hypophosphatasia, medicine, medicine.disease
Published
2013
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16. List of Contributors

Author

Omar M.E. Albagha, Andrew Arnold, Paul Baldock, Mary L. Bouxsein, Brendan F. Boyce, Stephanie Jo Brewster, Edward M. Brown, Matthew A. Brown, David A. Bushinsky, Salin A. Chakkalakal, Roderick Clifton-Bligh, William G. Cole, Michael T. Collins, Michael R. Convente, Jessica Costa-Guda, Andria L. Culbert, Hong-Wen Deng, Olivier Devuyst, Marc K. Drezner, Emma L. Duncan, Ogo I. Egbuna, John A. Eisman, David Feldman, Mathieu Ferron, Matti Gild, Yan Guo, Kilian Guse, Ingrid A. Holm, Bryan Hudson, Takashi Igarashi, Christina Jacobsen, Harald Jüppner, Frederick S. Kaplan, Gerard Karsenty, Christopher S. Kovacs, Brendan Lee, Gabriela G. Loots, Rik J. Lories, Vitali Y. Lounev, Frank P. Luyten, Peter J. Malloy, Joan C. Marini, T. John Martin, Walter L. Miller, Orson W. Moe, Tuan V. Nguyen, Franck Oury, Christopher J. Papasian, Dhruval Patel, Bram Perdu, Siân E. Piret, M. Helen Rajpar, Stuart H Ralston, Fernando Rivadeneira, Bruce G Robinson, Merry ZC Ruan, Steven J. Scheinman, Scott J. Schurman, Yiping Shen, Eileen M. Shore, Caroline Silve, Natalie A. Sims, Anil Singh, Allen M. Spiegel, Rajesh V. Thakker, André G. Uitterlinden, Ana M. Valdes, Wim Van Hul, Lee S. Weinstein, Michael P. Whyte, Lianping Xing, Tie-Lin Yang, and Michael J. Zuscik

Published
2013
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17. Genetics of Bone Biology and Skeletal Disease

Author

John A. Eisman, Rajesh V. Thakker, and Michael P. Whyte

Subjects
Feed back, Genetics, Animal model, Statistical genetics, Molecular pathology, Skeletal disease, Bone cell, Disease, Bone biology, Biology
Abstract

This book identifies and analyzes the genetic basis of bone disorders in humans and demonstrates the utility of mouse models in furthering the knowledge of mechanisms and evaluations of treatments. The book is aimed at all students of bone biology and genetics, and with this in mind, it includes general introductory chapters on genetics and bone biology and more specific disease-orientated chapters, which comprehensively summarize the clinical, genetic, molecular genetic, animal model, functional and molecular pathology, diagnostic, counselling and treatment aspects of each disorder. Saves academic, medical, and pharma researchers time in quickly accessing the very latest details on a broad range of genetic bone issues, as opposed to searching through thousands of journal articles. Provides a common language for bone biologists and geneticists to discuss the development of bone cells and genetics and their interactions in the development of disease Researchers in all areas bone biology and genetics will gain insight into how clinical observations and practices can feed back into the research cycle and will, therefore, be able to develop more targeted genomic and proteomic assays For those clinical researchers who are also MDs, correct diagnosis (and therefore correct treatment) of bone diseases depends on a strong understanding of the molecular basis for the disease.

Published
2013
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18. Mendelian Disorders of RANKL/OPG/RANK Signaling

Author

Michael P. Whyte

Subjects
musculoskeletal diseases, medicine.medical_specialty, Regulator, Osteopetrosis, Disease, Biology, medicine.disease, Endocrinology, medicine.anatomical_structure, RANKL, Osteoclast, Internal medicine, medicine, biology.protein, Tumor necrosis factor alpha, Signal transduction, Gene
Abstract

Identification of the RANKL/OPG/RANK signaling pathway as the principal regulator of osteoclast (OC) formation and action began with the discoveries of new members of the tumor necrosis factor (TNF) superfamily (RANKL, OPG, and RANK). Subsequently, genetically altered mice revealed the importance of these molecules for bone biology and helped to show that binding of RANKL to RANK promotes osteoclastogenesis and increases skeletal remodeling, whereas coupling of RANKL to OPG inhibits these processes. The significance of this pathway for humans was then demonstrated by the discoveries that mutations in the genes that encode RANK ( TNFRSF11A ), OPG ( TNFRSF11B ), and RANKL ( TNFSF11 ) explain: (1) several rare mendelian disorders (familial expansile osteolysis, early-onset Paget’s disease of bone, expansile skeletal hyperphosphatasia, and juvenile Paget’s disease) that resemble classic late-onset Paget’s disease of bone featuring enhanced osteoclastogenesis; or (2) forms of osteopetrosis featuring impaired OC formation. This chapter reviews the disease features and genetic bases for these instructive disorders of skeletal biology.

Published
2013
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20. Contributors

Author

Charles S. Abrams, Frank J. Accurso, Nezam H. Afdhal, Cem Akin, Allen J. Aksamit, Qais Al-Awqati, Ban Mishu Allos, David Altshuler, Michael J. Aminoff, Jeffrey L. Anderson, Karl E. Anderson, Larry J. Anderson, Karen H. Antman, Aśok C. Antony, Gerald B. Appel, Frederick R. Appelbaum, William P. Arend, Paul Arguin, James O. Armitage, Cheryl A. Armstrong, M. Amin Arnaout, Robert Arnold, David Atkins, William L. Atkinson, Dennis Ausiello, Bruce R. Bacon, Grover C. Bagby, Barbara J. Bain, Dean F. Bajorin, Mark Ballow, Robert W. Baloh, Jonathan Barasch, Richard L. Barbano, Murray G. Baron, Elizabeth Barrett-Connor, Michael J. Barry, Bruce A. Barshop, John G. Bartlett, Mary Barton, Robert C. Basner, Stephen G. Baum, Daniel G. Bausch, Arnold S. Bayer, Hasan Bazari, John H. Beigel, George A. Beller, Robert M. Bennett, Joseph R. Berger, Paul Berk, Nancy Berliner, James L. Bernat, Philip J. Bierman, Bruce R. Bistrian, Joseph J. Biundo, Charles D. Blanke, Joel N. Blankson, Martin J. Blaser, William A. Blattner, Thomas P. Bleck, William E. Boden, C. Richard Boland, Jean Bolognia, Robert Bonomo, Larry Borish, Patrick J. Bosque, Randall Brand, Itzhak Brook, Enrico Brunetti, David M. Buchner, Pierre A. Buffet, H. Franklin Bunn, Peter A. Calabresi, David P. Calfee, Hugh Calkins, Douglas Cameron, Michael Camilleri, Grant W. Cannon, Maria Domenica Cappellini, Blase A. Carabello, Edgar M. Carvalho, Agustin Castellanos, Naga P. Chalasani, Henry Chambers, Mary Charlson, William P. Cheshire, Patrick F. Chinnery, David C. Christiani, David R. Clemmons, Jeffrey Cohen, Myron S. Cohen, Steven P. Cohen, Steven L. Cohn, Robert Colebunders, Joseph M. Connors, Deborah J. Cook, C. Ralph Corey, Kenneth H. Cowan, William A. Craig, Simon L. Croft, Mary K. Crow, John A. Crump, Mark R. Cullen, Gary C. Curhan, Inger K. Damon, Troy E. Daniels, Nancy Davidson, Lisa M. DeAngelis, Malcolm M. DeCamp, Carlos Del Rio, George D. Demetri, Robert H. Demling, Patricia A. Deuster, Robert B. Diasio, David J. Diemert, Kathleen B. Digre, John M. Douglas, Jeffrey M. Drazen, Stephen C. Dreskin, W. Lawrence Drew, George L. Drusano, Thomas D. DuBose, F. Daniel Duffy, Herbert L. DuPont, Madeleine Duvic, Kathryn M. Edwards, N. Lawrence Edwards, Lawrence H. Einhorn, Ronald J. Elin, George M. Eliopoulos, Perry Elliott, Jerrold J. Ellner, Louis J. Elsas, Dirk M. Elston, Ezekiel J. Emanuel, Gregory F. Erickson, Armin Ernst, Joel D. Ernst, David S. Ettinger, Amelia Evoli, Douglas O. Faigel, Gary W. Falk, Murray J. Favus, Gene Feder, Stephan D. Fihn, Gary S. Firestein, Neil Fishman, Lee A. Fleisher, Marsha D. Ford, Chris E. Forsmark, Vance G. Fowler, Jay W. Fox, Manuel A. Franco, Martyn A. French, Karen Freund, Linda P. Fried, Cem Gabay, Kenneth L. Gage, Robert F. Gagel, John N. Galgiani, Patrick G. Gallagher, Eithan Galun, Leonard Ganz, Guadalupe Garcia-Tsao, Jonathan D. Gates, William M. Geisler, Tony P. George, Dale N. Gerding, M. Eric Gershwin, Morie A. Gertz, Gordon D. Ginder, Jeffrey Ginsberg, Geoffrey S. Ginsburg, Michael Glogauer, John W. Gnann, Matthew R. Golden, Lee Goldman, Ellie J. Goldstein, Lawrence T. Goodnough, Jörg J. Goronzy, Eduardo Gotuzzo, Deborah Grady, Leslie C. Grammer, F. Anthony Greco, Harry B. Greenberg, Peter K. Gregersen, Robert C. Griggs, Lisa M. Guay-Woodford, Richard L. Guerrant, Colleen Hadigan, John D. Hainsworth, Anders Hamsten, Kenneth R. Hande, H. Hunter Handsfield, Göran K. Hansson, Rashidul Haque, Raymond C. Harris, Stephen Crane Hauser, Frederick G. Hayden, Letha Healey, Douglas C. Heimburger, Erik L. Hewlett, David R. Hill, Nicholas S. Hill, L. David Hillis, Jack Hirsh, V. Michael Holers, Steven M. Holland, Steven Hollenberg, Edward W. Hook, Laurence Huang, Leonard D. Hudson, Steven E. Hyman, Michael Iannuzzi, Robert D. Inman, Sharon K. Inouye, Karl L. Insogna, Silvio E. Inzucchi, Eric M. Isselbacher, Ahmedin Jemal, Joanna Jen, Dennis M. Jensen, Michael D. Jensen, Robert T. Jensen, Mariell Jessup, Stuart Johnson, Ralph F. Józefowicz, Stephen G. Kaler, Moses R. Kamya, Hagop Kantarjian, David R. Karp, Daniel L. Kastner, David A. Katzka, Debra K. Katzman, Carol A. Kauffman, Kenneth Kaushansky, Emmet B. Keeffe, Morton Kern, Gerald T. Keusch, David H. Kim, Matthew Kim, Louis V. Kirchhoff, Michael J. Klag, Samuel Klein, David S. Knopman, Tamsin A. Knox, Albert I. Ko, Rami S. Komrokji, Dimitrios P. Kontoyiannis, Barbara S. Koppel, Kevin Korenblat, Bruce R. Korf, Neil J. Korman, Joseph A. Kovacs, Monica Kraft, Christopher M. Kramer, Donna M. Krasnewich, Peter J. Krause, Henry M. Kronenberg, Ernst J. Kuipers, Paul Ladenson, Donald W. Landry, Nancy E. Lane, Anthony E. Lang, Richard A. Lange, George V. Lawry, Thomas H. Lee, William M. Lee, James Leggett, Adam Lerner, Stuart Levin, Stephanie M. Levine, Gary R. Lichtenstein, Henry W. Lim, Aldo A.M. Lima, Andrew H. Limper, Geoffrey S.F. Ling, Alan F. List, William C. Little, Richard F. Loeser, Bennett Lorber, Donald E. Low, Daniel R. Lucey, James R. Lupski, Henry T. Lynch, Jeffrey M. Lyness, Bruce W. Lytle, C. Ronald MacKenzie, Harriet MacMillan, Robert D. Madoff, Mark W. Mahowald, Atul Malhotra, Lionel A. Mandell, Peter Manu, Marsha D. Marcus, Ariane J. Marelli, Maurie Markman, Andrew R. Marks, Kieren A. Marr, Thomas J. Marrie, Paul Martin, Joel B. Mason, Barry M. Massie, Henry Masur, Eric L. Matteson, Toby Maurer, Emeran A. Mayer, Stephen A. McClave, F. Dennis McCool, Charles E. McCulloch, Michael A. McGuigan, John McHutchison, William McKenna, Vallerie McLaughlin, John J.V. McMurray, Mary McNaughton-Collins, Kenneth McQuaid, Frederick W. Miller, Kenneth L. Minaker, Jonathan W. Mink, Daniel R. Mishell, William E. Mitch, Mark E. Molitch, Bruce A. Molitoris, José G. Montoya, Fred Morady, Jeffrey A. Moscow, Andrew H. Murr, Robert J. Myerburg, Stanley Naguwa, Stanley J. Naides, Theodore E. Nash, Avindra Nath, Eric G. Neilson, Lawrence S. Neinstein, Thomas B. Newman, William L. Nichols, Lynnette K. Nieman, Dennis E. Niewoehner, S. Ragnar Norrby, David A. Norris, Susan O’Brien, Francis G. O’Connor, Patrick G. O’Connor, James R. O'Dell, Anne E. O'Donnell, Jae K. Oh, Jeffrey E. Olgin, Jeffrey W. Olin, Walter A. Orenstein, Douglas R. Osmon, Catherine M. Otto, Stephen A. Paget, Mark Papania, Peter G. Pappas, Pankaj Jay Pasricha, David L. Paterson, Carlo Patrono, Jean-Michel Pawlotsky, Richard D. Pearson, Eli N. Perencevich, Trish M. Perl, Michael C. Perry, William A. Petri, Marc A. Pfeffer, Perry J. Pickhardt, Gerald B. Pier, David S. Pisetsky, Marshall R. Posner, Charlene Prather, Basil A. Pruitt, Reed E. Pyeritz, Thomas C. Quinn, Jai Radhakrishnan, Ganesh Raghu, Margaret V. Ragni, Srinivasa N. Raja, S. Vincent Rajkumar, Didier Raoult, Robert W. Rebar, Annette C. Reboli, K. Rajender Reddy, Donald A. Redelmeier, Susan E. Reef, Neil M. Resnick, David B. Reuben, Herbert Y. Reynolds, Emanuel P. Rivers, Robert A. Rizza, Lewis R. Roberts, Jean-Marc Rolain, José R. Romero, G. David Roodman, Clifford Rosen, Karen Rosene-Montella, Philip J. Rosenthal, Marc E. Rothenberg, Hope S. Rugo, James A. Russell, Anil K. Rustgi, Robert A. Salata, Jane E. Salmon, Renato M. Santos, Michael N. Sawka, Andrew I. Schafer, William Schaffner, W. Michael Scheld, Eileen Schneider, Thomas J. Schnitzer, Robert T. Schooley, David L. Schriger, Steven A. Schroeder, Lynn M. Schuchter, Sam Schulman, Lawrence B. Schwartz, Robert S. Schwartz, Carlos Seas, Steven A. Seifert, Julian L. Seifter, Clay F. Semenkovich, Carol E. Semrad, F. John Service, George M. Shaw, Pamela J. Shaw, Robert S. Sherwin, Michael E. Shy, Wilmer L. Sibbitt, Ellen Sidransky, Robert F. Siliciano, Michael S. Simberkoff, David L. Simel, Karl Skorecki, Arthur S. Slutsky, Eric J. Small, Gerald W. Smetana, Frederick S. Southwick, Robert F. Spiera, Stanley M. Spinola, Pawel Stankiewicz, Paul Stark, Lynne S. Steinbach, Martin H. Steinberg, Theodore S. Steiner, David S. Stephens, David A. Stevens, William G. Stevenson, Arthur E. Stillman, James K. Stoller, John H. Stone, Edwin P. Su, Roland W. Sutter, Morton N. Swartz, Ronald S. Swerdloff, Megan Sykes, Thomas A. Tami, Susan M. Tarlo, Victoria M. Taylor, Ayalew Tefferi, Paul S. Teirstein, Sam R. Telford, Margaret Tempero, Michael J. Thun, Nina Tolkoff-Rubin, Antonella Tosti, John J. Treanor, Ronald B. Turner, Arthur C. Upton, Greet Van den Berghe, John Varga, Adrian Vella, Joseph G. Verbalis, Ronald G. Victor, Angela Vincent, Paul A. Volberding, Julie M. Vose, Robert M. Wachter, Edward H. Wagner, Edward E. Walsh, Thomas J. Walsh, Christina Wang, Christine Wanke, Stephen I. Wasserman, Heiner Wedemeyer, Geoffrey A. Weinberg, David A. Weinstein, Robert S. Weinstein, Roger D. Weiss, Martin Weisse, Jeffrey I. Weitz, Samuel A. Wells, Richard P. Wenzel, Victoria P. Werth, Sterling G. West, Cornelia M. Weyand, A. Clinton White, Christopher J. White, Perrin C. White, Richard J. Whitley, Michael P. Whyte, Samuel Wiebe, Jeanine P. Wiener-Kronish, Jennifer E. Wildes, Alexander Wilmer, William Winkenwerder, Joseph I. Wolfsdorf, Gary P. Wormser, John J. Wysolmerski, Myron Yanoff, Neal S. Young, William F. Young, Alan S.L. Yu, Mark L. Zeidel, Peter Zimetbaum, and Justin A. Zivin

Published
2012
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21. Hypophosphatasia

Author

Michael P. Whyte

Subjects
medicine.medical_specialty, Osteomalacia, Hypophosphatasia, Severe disease, Rickets, Biology, medicine.disease, Isozyme, Endocrinology, Internal medicine, medicine, Extracellular, Bone formation, Gene
Abstract

Publisher Summary Hypophosphatasia is the rare, heritable form of rickets or osteomalacia that features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia). Hypophosphatasemia in HPP is explained by a generalized reduction of activity of the “tissue-non-specific” isoenzyme of ALP (TNSALP) caused by loss-of-function mutation(s) within the TNSALP gene. The tissue-specific ALP isoenzyme genes are intact. In HPP, extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi), an inhibitor of mineralization, explains the skeletal disease. Characterization of this inborn error-of-metabolism verified a role for ALP in bone formation. The discoveries of elevated endogenous levels of three phospho compounds in HPP clarified the metabolic basis for this inborn-error-of-metabolism and the physiological role of TNSALP. HPP occurs worldwide. It is especially prevalent for inbred Mennonite families in Manitoba, Canada, where approximately 1 in 2500 newborns manifests severe disease, and approximately 1 in 25 individuals is a carrier. The prognosis for the various forms of HPP typically reflects the severity of the skeletal disease that corresponds with the age at presentation.

Published
2012
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22. Contributors

Author

Steven A. Abrams, John S. Adams, Judith E. Adams, Luciano Adorini, Paul H. Anderson, Lenore Arab, Gerald J. Atkins, Ariane Berdal, Ishir Bhan, Daniel Bikle, John P. Bilezikian, Heike Bischoff-Ferrari, Adele L. Boskey, Roger Bouillon, Barbara D. Boyan, Alex J. Brown, Edward M. Brown, Danny Bruce, Andrew J. Burghardt, Thomas Burne, Mona S. Calvo, Carlos A. Camargo, Margherita Cantorna, Carsten Carlberg, Thomas O. Carpenter, Matthew W. Carson, Lisa Ceglia, Hong Chen, Songcang Chen, Sylvia Christakos, Fredric L. Coe, Juliet Compston, Heide S. Cross, Natalie E. Cusano, Bess Dawson-Hughes, Pierre De Clercq, Hector DeLuca, Michael Danilenko, Valentin David, Hector F. Deluca, Marie B. Demay, Francisco J.A. de Paula, Vianney Descroix, Puneet Dhawan, Katie M. Dixon, Harald Dobnig, Jeffrey A. Dodge, Eve Donnelly, Maryam Doroudi, Diane R. Dowd, Marc K. Drezner, Adriana S. Dusso, Peter R. Ebeling, Thomas Edouard, Guy Eelen, John A. Eisman, Tina Epps, Ervin H. Epstein, Sol Epstein, Darryl Eyles, Mary C. Farach-Carson, Murray J. Favus, David Feldman, David M. Findlay, James C. Fleet, Renny T. Franceschi, Ryoji Fujiki, David G. Gardner, Adit A. Ginde, Edward Giovannucci, Denis J. Glenn, Francis H. Glorieux, Elzbieta Gocek, David Goltzman, José Manuel González-Sancho, Clare Gordon-Thomson, Conny Gysemans, Karen E. Hansen, Carol A. Haussler, Mark R. Haussler, Colleen E. Hayes, Robert P. Heaney, Christian Helvig, Geoffrey N. Hendy, Martin Hewison, Arnold Lippert Hirsch, Michael F. Holick, Bruce W. Hollis, Elizabeth Holt, Jui-Cheng Hsieh, Karl L. Insogna, Candace Johnson, Glenville Jones, Peter W. Jurutka, Heidi J. Kalkwarf, Shigeaki Kato, Steven A. Kliewer, H. Phillip Koeffler, Hannelie Korf, Alexander Kouzmenko, Christopher S. Kovacs, Barbara E. Kream, Richard Kremer, Aruna V. Krishnan, Roland Krug, Noboru Kubodera, Rajiv Kumar, Emma M. Laing, Joseph M. Lane, María Jesús Larriba, Seong Min Lee, Richard D. Lewis, Yan Li, Yan Chun Li, Jane B. Lian, Alexander C. Lichtler, Paul Lips, Philip T. Liu, Thomas S. Lisse, Yanfei L. Ma, Paul N. MacDonald, Leila Mady, Mario Maggi, Sharmila Majumdar, Makoto Makishima, Peter J. Malloy, David J. Mangelsdorf, Jonathan M. Mansbach, JoAnn E. Manson, Rebecca S. Mason, Chantal Mathieu, Christopher G. Mayne, Timothy M. McAlindon, John McGrath, Mark B. Meyer, Mathew T. Mizwicki, Muriel Molla, Martin Montecino, Dino Moras, Annamaria Morelli, Howard A. Morris, Alberto Muñoz, Mark S. Nanes, Faye E. Nashold, Tally Naveh-Many, Wei Ni, Corwin D. Nelson, Anthony W. Norman, Fumiaki Ohtake, Ryoko Okamoto, Olivia I. Okereke, Lubna Pal, Martin Petkovich, John M. Pettifor, J. Wesley Pike, Anastassios G. Pittas, Lori A. Plum, David E. Prosser, L. Darryl Quarles, Brian J. Rebolledo, Jörg Reichrath, Natacha Rochel, Clifford J. Rosen, F. Patrick Ross, Philip Sambrook, Daniel R. Schmidt, Ryan D. Schoch, Gary G. Schwartz, Zvi Schwartz, Vanessa Sequeira, Elizabeth Shane, M. Kyla Shea, Justin Silver, Robert U. Simpson, Linda Skingle, Eduardo Slatopolsky, Harald Sourij, Justin A. Spanier, Bonny L. Specker, René St-Arnaud, Keith R. Stayrook, Emily M. Stein, Gary S. Stein, Janet L. Stein, George P. Studzinski, Fumiaki Takahashi, Jean Y. Tang, Hugh S. Taylor, Peter Tebben, Ravi Thadhani, Natalie W. Thiex, William R. Thompson, Susan Thys-Jacobs, Dov Tiosano, Dwight A. Towler, Donald Trump, André G. Uitterlinden, Aasis Unnanuntana, Maurits Vandewalle, Marjolein van Driel, Johannes P.T.M. van Leeuwen, Andre J. van Wijnen, Natasja van Schoor, Lieve Verlinden, Annemieke Verstuyf, Reinhold Vieth, Connie M. Weaver, Barrie M. Weinstein, JoEllen Welsh, John H. White, G. Kerr Whitfield, Susan J. Whiting, Michael P. Whyte, John J. Wysolmerski, Sachiko Yamada, and Ian Yip

Published
2011
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23. Approach to the Patient with Metabolic Bone Disease

Author

Michael P. Whyte

Subjects
medicine.medical_specialty, Osteomalacia, medicine.diagnostic_test, business.industry, Rickets, Physical examination, Bioinformatics, medicine.disease, Metabolic bone disease, Surgery, medicine, Etiology, Vitamin D and neurology, Medical history, Intensive care medicine, business, Genetic testing
Abstract

Publisher Summary Metabolic bone disease encompasses a considerable number and variety of conditions. Although these disorders are often rare, several are epidemic in various regions of the world. Some can be life threatening; others can be incidental findings. Cumulatively, the number of individuals with clinically important metabolic bone disease is significant. This chapter emphasizes a number of considerations for the approach to the patient with metabolic bone disease, particularly those with disturbances in vitamin D homeostasis. The complex interaction of the many exogenous and endogenous factors impact vitamin D homeostasis. Demonstration of concern for, and commitment to, the patient begins with a complete medical history and thorough physical examination that wins their confidence and trust. Such rapport will likely be essential for effective management of what will often prove to be a chronic disorder. Physical examination is crucial not only for diagnosis, but to uncover structural skeletal problems. Information gathered by the medical history and physical examination is the guide to the myriad of biochemical, radiological, and other technologies that can assist to establish the etiology and pathogenesis and to set the stage for subsequent treatment and follow-up. Effective therapies are available for derangements of vitamin D homeostasis, but the pharmaceuticals vary significantly in potency, duration of effect, and cost. Once the proper clinical foundation is in place, the physician is usually gratified by a patient that he/she has greatly helped.

Published
2011
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24. Contributors

Author

Lloyd Paul Aiello, Erik K. Alexander, Carolyn A. Allan, Bruno Allolio, Peter Angelos, Sree Appu, Richard J. Auchus, Joseph Avruch, Lloyd Axelrod, Rebecca S. Bahn, H.W.G. Baker, Randall B. Barnes, Murat Bastepe, John D. Baxter, Paolo Beck-Peccoz, Graeme I. Bell, John P. Bilezikian, Stephen R. Bloom, Manfred Blum, Steen J. Bonnema, Diego Botero, Roger Bouillon, Andrew J.M. Boulton, Glenn D. Braunstein, F. Richard Bringhurst, Frank J. Broekmans, Marcello D. Bronstein, Edward M. Brown, Chuong Bui, Col. Henry B. Burch, Henry G. Burger, Richard O. Burney, John B. Buse, Peter C. Butler, Paolo Cappabianca, Maria Luiza Avancini Caramori, Robert M. Carey, Esther Carlton, David Carmody, Jose F. Caro, Francesco Cavagnini, Jerry Cavallerano, Luigi M. Cavallo, Shu Jin Chan, R. Jeffrey Chang, Roland D. Chapurlat, V. Krishna Chatterjee, Luca Chiovato, Kyung J. Cho, Daniel Christophe, Teng-Teng Chung, John A. Cidlowski, Adrian J.L. Clark, Peter E. Clark, David R. Clemmons, Robert V. Considine, Georges Copinschi, Kyle D. Copps, C. Hamish Courtney, Leona Cuttler, Melita L. Daley, Mehul Dattani, Stephen N. Davis, Oreste de Divitiis, Mario De Felice, Ralph A. DeFronzo, Leslie J. De Groot, David de Kretser, Ahmed J. Delli, Pierre D. Delmas, Marie B. Demay, Paul Devroey, Roberto Di Lauro, Sean F. Dinneen, Jacques E. Dumont, Kathleen M. Dungan, Daniel J. Drucker, Michael J. Econs, David A. Ehrmann, Graeme Eisenhofer, Gregory F. Erickson, Barbro Eriksson, Eric Espiner, Felice Esposito, Victoria Esser, Erica A. Eugster, Sadaf Farooqi, Martin Fassnacht, Bart C.J.M. Fauser, Gianfranco Fenzi, Ele Ferrannini, David M. Findlay, Courtney Finlayson, Delbert A. Fisher, Maguelone G. Forest, Daniel W. Foster, Mason Wright Freeman, Mark Frydenberg, Peter Fuller, Robert F. Gagel, Jason L. Gaglia, Gianluigi Galizia, Chuanyun Gao, Thomas J. Gardella, Bruce D. Gaylinn, Harry K. Genant, Michael S. German, Mohammad A. Ghatei, Linda C. Giudice, Anna Glasier, Francis H. Glorieux, Javier González-Maeso, Louis J. Gooren, David F. Gordon, Karen A. Gregerson, Milton D. Gross, Ashley Grossman, Valéria C. Guimarães, Mark Gurnell, Nadine Haddad, Daniel J. Haisenleder, David J. Handelsman, John B. Hanks, Mark John Hannon, Simon W. Hayward, Matthias Hebrok, Laszlo Hegedüs, Georg Hennemann, Maria K. Herndon, Peter Hindmarsh, Ken K.Y. Ho, Nelson D. Horseman, Mara J. Horwitz, Mimi Hu, Ieuan A. Hughes, Christopher J. Hupfeld, Hero K. Hussain, Peter Illingworth, J. Larry Jameson, Nathalie Josso, Harald Jüppner, Jeffrey Kalish, Edwin L. Kaplan, Jeffrey B. Kerr, Ronald Klein, Meyer Knobel, Efstratios Kolibianakis, John J. Kopchick, Peter Kopp, Márta Korbonits, Melvyn Korobkin, Stephen M. Krane, Knut Krohn, Henry M. Kronenberg, John M. Kyriakis, Sue Lynn Lau, John H. Lazarus, Diana L. Learoyd, Harold E. Lebovitz, Paul Lee, Åke Lernmark, Laura J. Lewis-Tuffin, Zhi-Liang Lu, Paolo Emidio Macchia, Noel K. Maclaren, Carine Maenhaut, Christa Maes, Katharina M. Main, Carl D. Malchoff, Diana Mark Malchoff, Rayaz A. Malik, Susan J. Mandel, Christos Mantzoros, Eleftheria Maratos-Flier, Stefania Marchisotta, Michele Marinò, John C. Marshall, Thomas F.J. Martin, T. John Martin, Gabriel Á. Martos-Moreno, Christopher J. Mathias, Michael Mauer, Elizabeth A. McGee, Neil J. McKenna, Robert I. McLachlan, Geraldo Medeiros-Neto, Juris J. Meier, Shlomo Melmed, Boyd E. Metzger, Robert Millar, Walter L. Miller, Madhusmita Misra, Mark E. Molitch, David D. Moore, Damian G. Morris, Allan U. Munck, Jon Nakamoto, Anikó Náray-Fejes-Tóth, Ralf Nass, David M. Nathan, Maria I. New, Carolyn Nguyen, Lynnette K. Nieman, John H. Nilson, Jeffrey A. Norton, Robert H. Oakley, Kjell Öberg, Jerrold M. Olefsky, Stephen O’Rahilly, Umut Ozcan, Karel Pacak, Furio Pacini, Shetal H. Padia, Ralf Paschke, Adam Pawson, Alison C. Peck, Francesca Pecori Giraldi, Luca Persani, Richard L. Phelps, Louis H. Philipson, Kevin Phillips, Aldo Pinchera, Frank B. Pomposelli, John T. Potts, Charmian A. Quigley, Marcus Quinkler, Christine Campion Quirk, Miriam T. Rademaker, Ewa Rajpert-De Meyts, Eric Ravussin, David W. Ray, Nancy King Reame, Samuel Refetoff, Ravi Retnakaran, Rodolfo A. Rey, Christopher J. Rhodes, E. Chester Ridgway, Gail P. Risbridger, Robert A. Rizza, Bruce Robinson, Pierre P. Roger, Michael G. Rosenfeld, Robert L. Rosenfield, James H. Rosing, Peter Rossing, Robert T. Rubin, Neil Ruderman, Irma H. Russo, Jose Russo, Wael Antoine Salameh, Isidoro B. Salusky, Mary H. Samuels, Richard J. Santen, Nanette Santoro, Virginia D. Sarapura, Stuart C. Sealfon, Patrick M. Sexton, Gerald I. Shulman, Paolo S. Silva, Shonni J. Silverberg, Frederick R. Singer, Niels E. Skakkebaek, Dorota Skowronska-Krawczyk, Carolyn L. Smith, Philip W. Smith, Roger Smith, Steven R. Smith, Peter J. Snyder, Richard Stanhope, René St-Arnaud, Donald F. Steiner, Adam Stevens, Andrew F. Stewart, Paul M. Stewart, Donald L. St. Germain, Jim Stockigt, Jerome F. Strauss, Lillian Marie Swiersz, Lyndal J. Tacon, Shahrad Taheri, Rajesh V. Thakker, Chris Thompson, Michael O. Thorner, Henri J.L.M. Timmers, Jorma Toppari, Cristina Traggiai, Michael L. Traub, Yolanda Tseng, Fred W. Turek, Eve Van Cauter, Greet Van den Berghe, André C. Van Steirteghem, Gilbert Vassart, Eric Vilain, Theo J. Visser, Michael P. Wajnrajch, Gary Wand, Paul Webb, Anthony P. Weetman, Nancy L. Weigel, Gordon C. Weir, Roy E. Weiss, Katherine Wesseling-Perry, Anne White, Kenneth E. White, Morris F. White, Michael P. Whyte, Wilmar M. Wiersinga, Joseph I. Wolfsdorf, and Bernard Zinman

Published
2010
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25. Hypophosphatasia

Author

Michael P. Whyte

Subjects
Osteomalacia, medicine.medical_specialty, Hypophosphatasia, Rickets, Aplasia, Biology, medicine.disease, Hypoplasia, Endocrinology, stomatognathic system, Asfotase alfa, Internal medicine, medicine, Alkaline phosphatase, Dental cementum
Abstract

Publisher Summary This chapter focuses on the role of alkaline phosphatase (ALP) in hypophosphatasia. ALPs are found in nearly all plant and animal species and in humans, four ALP isoenzymes are encoded by four separate genes. Three of the isoenzymes are expressed in a tissue-specific distribution and are called intestinal, placental, and germ cell (placental-like) ALP. The fourth ALP isoenzyme is ubiquitous, but is especially abundant in hepatic, skeletal, and renal tissue (liver/bone/kidney ALP) and is known as tissue-nonspecific ALP (TNSALP). The TNSALP gene is located near the end of the short arm of chromosome 1 and is greater than 50 kb and contains 12 exons, 11 of which are translated to form the 507 amino acid nascent enzyme. Despite the presence of relatively high levels of TNSALP in bone, liver, kidney, and adrenal tissue in healthy individuals the effect of hypophosphatasia centers on the skeleton and dentition. The most pernicious form of hypophosphatasia is expressed in utero and can cause stillbirth. Profound skeletal hypomineralization results in caput membraneceum, and limbs that are shortened and deformed during gestation and at birth. Some affected neonates survive several days or weeks, but then suffer from increasing respiratory compromise because of rachitic disease of the chest and because of lungs that are hypoplastic. Infantile hypophosphatasia presents before the age of 6 months where the postnatal development often seems normal, until the onset of poor feeding and inadequate weight gain, and the clinical manifestations of rickets are recognized. The cranial sutures appear to be wide, but actually reflect hypomineralization of the skull and often there is a “functional” craniosynostosis. Childhood hypophosphatasia is especially variable in its clinical expression where premature loss of deciduous teeth results from aplasia, hypoplasia, or dysplasia of dental cementum.

Published
2008
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26. Rare Bone Diseases

Author

Michael P. Whyte

Subjects
Bone growth, Pathology, medicine.medical_specialty, Bone density, Bone disease, business.industry, Cartilage formation, medicine.disease, Bone remodeling, Resorption, Pathogenesis, Skeletal disorder, medicine, business
Abstract

This chapter summarizes information concerning genetic as well as local and systemic factors involved in the etiology and pathogenesis of rare bone diseases where data from assays of biochemical markers of skeletal remodeling are accumulating. For such disorders, bone turnover assessed biochemically can shed light on the nature of the skeletal perturbation and help to design, evaluate, and monitor treatment. However, systemic or focal derangements in bone growth, modeling, and remodeling and cartilage formation and degradation can be occurring and lead to generalized or regional ostopenia (bone density below the normal) or increases in skeletal mass. Biochemical markers of skeletal formation or resorption provide summative values reflecting the impact of a global disturbance or a partly localized lesion. Hence, the type and extent of the pathologic process in individual patients merits consideration when interpreting results from such assays. This is best illustrated by the common focal skeletal disorder, Paget's bone disease.

Published
2006
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27. Contributors

Author

Kristina Åkesson, Sari L. Alatalo, Susan J. Allison, Ziyad Al Aly, Paul A. Baldock, John P. Bilezikian, Neil Binkley, Jean-Jacques Body, Jean-Philippe Bonjour, Adele L. Boskey, Roger Bouillon, Kim Brixen, Peter Bruckner, Geert Carmeliet, Ian M Clark, Peter Croucher, Pierre D. Delmas, David W. Dempster, Jean-Pierre Devogelaer, Marc K. Drezner, Richard Eastell, Guy Eelen, Erik Fink Eriksen, Lorraine A. Fitzpatrick, Ghada El-Hajj Fuleihan, Edith M. Gardiner, Patrick Garnero, Renate E. Gay, Steffen Gay, Francis H. Glorieux, Mary B. Goldring, Steven R. Goldring, David Goltzman, Esther A. González, Andreas Grauer, Caren M. Gundberg, Tim Hardingham, John R. Harrison, Dick Heinegård, M.H. Helfrich, Herbert Herzog, M.A. Horton, Philippa Hulley, Harald Jüppner, Helena Kaija, S. Khosla, Marius E. Kraenzlin, Barbara E. Kream, Carolina A. Moreira Kulak, Johannes P.T.M. van Leeuwen, Gary L. Lensmeyer, Jane B. Lian, Joseph A. Lorenzo, Pilar Lorenzo, Christa Maes, Daniel-Henri Manicourt, Klaus von der Mark, Kevin J. Martin, T. John Martin, Christian Meier, Joyce B.J. van Meurs, José Luis Millán, David G. Monroe, Jean E. Mulder, Gillian Murphy, Kim E. Naylor, Michel Neidhart, Tuan V. Nguyen, Satoru K. Nishimoto, Lila O.T. Patrikainen, Huibert A.P. Pols, Lawrence G. Raisz, Stuart Ralston, Frank Rauch, Ian R. Reid, Juha Risteli, Leila Risteli, Fernando Rivadeneira, René Rizzoli, Simon P. Robins, Clifford J. Rosen, Mishaela R. Rubin, Graham Russell, Tore Saxne, Heinrich Schmidt-Gayk, Ego Seeman, Markus J. Seibel, Elizabeth Shane, Shonni J. Silverberg, Peter A. Simkin, Natalie A. Sims, Ethel Siris, Thomas C. Spelsberg, Gary S. Stein, Eugene J.-M. A. Thonar, André G. Uitterlinden, H. Kalervo Väänänen, Annemieke Verstuyf, Pirkko T. Vihko, Michael P. Whyte, and Hua Zhou

Published
2006
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28. List of Contributors

Author

Steven A. Abrams, John S. Adams, Judith E. Adams, Luciano Adorini, Paul H. Anderson, Gerald J. Atkins, Jane E. Aubin, Isabelle Bailleul-Forestier, Julia Barsony, Thomas K. Barthel, Norman H. Bell, Ariane Berdal, Joel J. Bergh, Jacqueline L. Berry, Daniel D. Bikle, John P. Bilezikian, Ernst Binderup, Lise Binderup, Nicholas J. Bishop, Ilse Bogaerts, Ricardo L. Boland, Adele L. Boskey, Roger Bouillon, Barbara D. Boyan, Philippe Brachet, Alex J. Brown, Edward M. Brown, Carsten Carlberg, Geert Carmeliet, Thomas O. Carpenter, Marie-Claire Chapuy, Fredriech K.W. Chan, Tai C. Chen, Sylvia Christakos, Margaret Clagett-Dame, Thomas L. Clemens, Je-Yong Choi, Fredric L. Coe, Kay Colston, Juliet E. Compston, Nancy E. Cooke, Clara Crescioli, Heide S. Cross, Michael Danilenko, Jean-Luc Davideau, Michael Davies, Hector F. DeLuca, Marie B. Demay, Puneet Dhawan, Carlos Encinas Dominguez, Diane R. Dowd, Marc K. Drezner, Thomas W. Dunlop, Adriana S. Dusso, Richard Eastell, Michael J. Econs, John Eisman, Sol Epstein, Erik Fink Eriksen, Luis M. Esteban, Dan Faibish, Yue Fang, Mary C. Farach-Carson, Murray J. Favus, David Feldman, David Findlay, Christian Frank, Leonard P. Freedman, Ryuji Fujiki, Masafumi Fukagawa, Robert F. Gagel, Emmanuel Garcion, Edith M. Gardiner, Marielle Gascon-Barré, Edward Giovannucci, Henning Glerup, Francis H. Glorieux, Wagn O. Godtfredsen, David Goltzman, Soraya Gutierrez, Conny Gysemans, Bernard P. Halloran, Carol A. Haussler, Mark R. Haussler, Robert P. Heaney, Johan Heersche, Helen L. Henry, Pamela A. Hershberger, Martin Hewison, Richard A. Heyman, Kanji Higashio, Michael F. Holick, Bruce W. Hollis, Ronald L. Horst, Jui-Cheng Hsieh, Karl L. Insogna, Elizabeth T. Jacobs, Amjad Javed, Glenville Jones, Candace S. Johnson, Peter W. Jurutka, Mehmet Kahraman, S. Kaleem Zaidi, Heidi J. Kalkwarf, Shigeaki Kato, Anne-Marie Kissmeyer, Hirochika Kitagawa, Lilia M.C. Koberle, H. Phillip Koeffler, Ruth Koren, Barbara E. Kream, Richard Kremer, Aruna V. Krishnan, Noboru Kubodera, Rajiv Kumar, Kiyoshi Kurokawa, Christopher J. Laing, Jacques Lemire, Frédéric Lézot, Yan Chun Li, Jane B. Lian, Alexander C. Lichtler, Paul Lips, Yan Liu, Paul MacDonald, Hubert Maehr, Mario Maggi, Peter J. Malloy, David J. Mangelsdorf, Chantal Mathieu, Brian May, Andrew P. Mee, Pierre J. Meunier, Toshimi Michigami, Martin Montecino, Dino Moras, Roberta Morosetti, Howard A. Morris, Daniel L. Motola, Josephia Muindi, Shigeo Nakajima, Tally Naveh-Many, Philippe Naveilhan, Isabelle Neveu, Anthony W. Norman, Anders Nykjaer, James O'Kelly, John L. Omdahl, Peter Ordentlich, Keiichi Ozono, A. Michael Parfitt, Donna M. Peehl, Sara Peleg, Xiaorong Peng, John M. Pettifor, J. Wesley Pike, Elizabeth A. Platz, Lori A. Plum, Shirwin Pockwinse, Huibert A.P. Pols, Anthony A. Portale, Gary H. Posner, Mehrdad Rahmaniyan, Amiram Ravid, G. Satyanarayana Reddy, Jörg Reichrath, Timothy A. Reinhardt, Alfred A. Reszka, B. Lawrence Riggs, Natacha Rochel, Mishaela R. Rubin, Andrew F. Russo, Philip Sambrook, Adina E. Schneider, Gary G. Schwartz, Zvi Schwartz, Jiali Shen, Nirupama K. Shevde, Rafal R. Sicinski, Justin Silver, Eduardo A. Slatopolsky, Bonny L. Specker, René St-Arnaud, Gary S. Stein, Janet L. Stein, Paula H. Stern, George P. Studzinski, Tatsuo Suda, Amelia L.M. Sutton, Peter Tebben, Harriet S. Tenenhouse, Michelle L. Thatcher, Susan Thys-Jacobs, Dwight A. Towler, Donald L. Trump, André G. Uitterlinden, Milan R. Uskoković, Sami Väisänen, Hugo Van Baelen, Sophie Van Cromphaut, Johannes P.T.M. van Leeuwen, Joyce B.J. van Meurs, Andre J. van Wijnen, Christel Verboven, Reinhold Vieth, Robert H. Wasserman, JoEllen Welsh, G. Kerr Whitfield, Michael P. Whyte, Thomas Willnow, Didier Wion, Hisataka Yasuda, Daniel Young, and Chi Zhang

Published
2005
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29. Contributors

Author

Carolyn Becker, John P. Bilezikian, Albert C. Clairmont, Bess Dawson-Hughes, Marc K. Drezner, Murray J. Favus, Ignac Fogelman, Harry K. Genant, David Goltzman, Susan L. Greenspan, Sari Halpert, Hunter Heath III, Frederick S. Kaplan, Michael Kleerekoper, Winston Koo, Craig B. Langman, Edgar V. Lerma, Marjorie Luckey, Barbara P. Lukert, Velimir Matkovic, Betsy McClung, Michael McClung, Paul D. Miller, Dorothy A. Nelson, Eric Orwoll, Socrates E. Papapoulos, John M. Pettifor, S. Abbas Raza, Elizabeth Shane, Jay R. Shapiro, Frederick R. Singer, Ethel S. Siris, Paul D. Sponseller, Line Vautour, Michelle P. Warren, Nelson Watts, and Michael P. Whyte

Published
2005
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30. Hypophosphatasia

Author

Michael P. Whyte

Subjects
medicine.medical_specialty, Kidney, business.industry, Hypophosphatasia, Rickets, Aplasia, medicine.disease, Hypoplasia, Craniosynostosis, Endocrinology, medicine.anatomical_structure, stomatognathic system, Internal medicine, medicine, Alkaline phosphatase, Dental cementum, business
Abstract

Publisher Summary This chapter focuses on the role of alkaline phosphatase (ALP) in hypophosphatasia. ALPs are found in nearly all plant and animal species and in humans, four ALP isoenzymes are encoded by four separate genes. Three of the isoenzymes are expressed in a tissue-specific distribution and are called intestinal, placental, and germ cell (placental-like) ALP. The fourth ALP isoenzyme is ubiquitous, but is especially abundant in hepatic, skeletal, and renal tissue (liver/bone/kidney ALP) and is known as tissue-nonspecific ALP (TNSALP). The TNSALP gene is located near the end of the short arm of chromosome 1 and is greater than 50 kb and contains 12 exons, 11 of which are translated to form the 507 amino acid nascent enzyme. Despite the presence of relatively high levels of TNSALP in bone, liver, kidney, and adrenal tissue in healthy individuals the effect of hypophosphatasia centers on the skeleton and dentition. The most pernicious form of hypophosphatasia is expressed in utero and can cause stillbirth. Profound skeletal hypomineralization results in caput membraneceum, and limbs that are shortened and deformed during gestation and at birth. Some affected neonates survive several days or weeks, but then suffer from increasing respiratory compromise because of rachitic disease of the chest and because of lungs that are hypoplastic. Infantile hypophosphatasia presents before the age of 6 months where the postnatal development often seems normal, until the onset of poor feeding and inadequate weight gain, and the clinical manifestations of rickets are recognized. The cranial sutures appear to be wide, but actually reflect hypomineralization of the skull and often there is a “functional” craniosynostosis. Childhood hypophosphatasia is especially variable in its clinical expression where premature loss of deciduous teeth results from aplasia, hypoplasia, or dysplasia of dental cementum.

Published
2002
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31. Autoimmune Hypoparathyroidism

Author

Michael P. Whyte

Subjects
Autoimmune disease, Pathology, medicine.medical_specialty, business.industry, Thyroid disease, Alopecia totalis, Dystrophy, Disease, Autoimmune polyendocrinopathy, medicine.disease, medicine.disease_cause, Autoimmune Polyendocrinopathy Syndrome, Autoimmunity, Hypoparathyroidism, Addison's disease, Immunology, medicine, Adrenal insufficiency, Chronic mucocutaneous candidiasis, business, Primary Hypoparathyroidism, pernicious anemia
Abstract

This chapter highlights the autoimmune aspects of hypoparathyroidism. Hypoparathyroidism occurs as a component of an autosomal recessive disorder that features hypofunction of one or more endocrine glands as well as a variety of additional problems because of autoimmune disease. Initially termed polyglandular autoimmune syndrome, type 1 or autoimmune polyendocrinopathy is often designated as autoimmune polyendocrinopathy syndrome, type 1 (APS1). It is an autosomal recessive disease characterized by: (1) autoimmune polyendocrine deficiencies, (2) chronic mucocutaneous candidiasis, and (3) ectodermal dystrophies. In addition, there can be pernicious anemia, hepatitis, intestinal malabsorption, splenic atrophy, or gallstones, and a large proportion of patients develop squamous-cell carcinoma of the oral mucosa. The major features of APS1: (1) hypoparathyroidism, (2) adrenal insufficiency, and (3) chronic mucocutaneous candidiasis. The pathogenesis of APS1—that is, the autoimmune destruction of endocrine tissues, is understood at a molecular level and the defective gene has been identified. Although immune dysfunction also occurs in the DiGeorge anomaly, dysembryogenesis rather than autoimmunity causes the associated hypoparathyroidism. However, there are other less well-characterized syndromes with hypoparathyroidism in which autoimmunity may be a pathogenetic factor.

Published
2001
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32. Contributors

Author

Joseph M. Alexander, Andrew Arnold, Jane E. Aubin, Cristina Bandeira, Francisco Bandeira, John P. Bilezikian, F. Richard Bringhurst, Arthur E. Broadus, Edward M. Brown, Ernesto Canalis, Gustav Celdas, Naibedya Chattopadhyay, Michael Chorev, Thomas L. Clemens, Jack W. Coburn, Arthur Conigrave, L.J. Deftos, David W. Dempster, Gerard M. Doherty, John L. Doppman, Robert W. Downs, Marc K. Drezner, Murray J. Favus, Lorraine A. Fitzpatrick, Ghada El-Hajj Fuleihan, Robert F. Gagel, Paul G. Gauger, Emily L. Germain-Lee, David Goltzman, Esther A. González, Andrew Grey, Luiz Griz, David Heath, Hunter Heath, Johan N.M. Heersche, Janet M. Hock, Karl Insogna, Suzanne M. Jan de Beur, Harald Jüppner, Andrew C. Karaplis, Sundeep Khosla, Michael Kleerekoper, Vanessa A. Klugman, Richard Kremer, Henry M. Kronenberg, Kaechoong Lee, Michael A. Levine, Virginia A. LiVolsi, Sverker Ljunghall, Ewa Lundgren, Geisa Macedo, Lawrence Mallette, Robert Marcus, John T. Martin, Kevin J. Martin, Stephen J. Marx, Urszula Masiukiewicz, L.J. Melton, Xunwu Meng, Saroj K. Mishra, Ambrish Mithal, Maryann Mitnick, Jean E. Mulder, Gregory R. Mundy, Inaam A. Nakchbandi, M. T. Audrey Nguyen, Robert A. Nissenson, Babatunde Oyajobi, Charles Y.C. Pak, A. Michael Parfitt, May Parisien, William M. Philbrick, John T. Potts, Lawrence G. Raisz, D. Sudhaker Rao, Jonas Rastad, B.L. Riggs, Michael Rosenblatt, Robert K. Rude, Isidro B. Salusky, Markus J. Seibel, Gino V. Segre, Elizabeth Shane, Yifan Shi, Caroline Silve, Shonni J. Silverberg, Eduardo Slatopolsky, Andrew F. Stewart, John L. Stock, Gordon J. Strewler, R.V. Thakker, Norman W. Thompson, Robert Udelsman, Lee S. Weinstein, Samuel A. Wells, Michael P. Whyte, and John J. Wysolmerski

Published
2001
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34. Osteoprotegerin deficiency and aneurysm formation: Case report of iliac artery aneurysms in Juvenile Paget's disease

Author

Brandon T. Gaston, Elizabeth L. Chou, Aman B. Patel, Mark E. Lindsay, Steven Mumm, Michael P. Whyte, and Abhisekh Mohapatra

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701, Surgery, RD1-811
Abstract

Background: Juvenile Paget's disease (JPD, OMIM #239,000) is a rare heritable disorder of the skeleton usually caused by bi-allelic loss-of-function mutation(s) of the tumor necrosis factor receptor superfamily member, 11B gene (TNFRSF11B), resulting in deficiency of the encoded protein osteoprotegerin (OPG). Deficiency of this signaling molecule leads to osteoclast activation and accelerated bone turnover. Vascular complications of JPD include intracranial carotid artery and brachial artery aneurysms. Iliac artery aneurysms have not been described in these patients. Case presentation: We report an 18-year-old man with JPD and bilateral common iliac artery aneurysms discovered incidentally during endovascular treatment of an intracranial internal carotid artery aneurysm (iICA). CT imaging showed a fusiform right common iliac artery aneurysm measuring 2.1 cm, and a fusiform left common iliac artery aneurysm measuring 1.8 cm. To our knowledge, our case is the first report of JPD associated with iliac artery aneurysms. Conclusions: Our experience supports an emerging association between OPG deficiency and arterial aneurysms. JPD from OPG deficiency requires surveillance for aortic and peripheral vasculopathies.

Published
2022
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35. Transformative public policy design? The lifeworld of early postcolonial social policy in Ghana

Author

Michael Kpessa-Whyte

Subjects
Science
Abstract

Based on the experience of advanced industrialized countries, social policies are portrayed as responses to the crises of capitalist industrialization. But this claim cannot explain the development of social policies, albeit limited in scope, in African countries in the early postcolonial era where policy makers undertook ambitious social development programs although their countries were comparatively underdeveloped. This article examines the approach to socio-economic development in the early postcolonial era (1950s to mid 1960s) in Ghana and argues that policymakers at the time adopted a transformative view of social policy and used it strategically as an integral part of modernization efforts to serve multiple purposes simultaneously. Consequently, social programs such as education and health were conceptualized as essential for human and societal progress hence, they were provided on the basis of social citizenship, whereas other such as old age income security and housing were designed to address new vulnerabilities that arise when a person is disconnected from traditional support systems due to processes of social change.

Published
2021
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