Text-Atlas of Skeletal Age Determination

The authors would like to dedicate this book to the memory of Roberto Passariello, a great scientist, a great leader, and above all a great friend.

Text-Atlas of Skeletal Age DeterminationMRI of the Hand and Wrist in ChildrenEDITED BY

Ernesto Tomei, MD (Editor-in-Chief)Associate Professor of RadiologyDepartment of Radiology, Oncology and Anatomy PathologySapienza University of RomeRome, Italy

Sofia Battisti, MDClinical Research ScholarMR Section, Department of RadiologyUniversity of North CarolinaChapel Hill, North Carolina, USA;Resident RadiologyDepartment of Radiology Campus Bio-medico of RomeRome, Italy

Milvia MartinoDepartment of Radiology, Oncology and Anatomy PathologySapienza University of RomeRome, Italy

Daniel B. Nissman, MD MPH MSEEClinical Assistant Professor of RadiologyDepartment of Radiology, Musculoskeletal SectionUNC School of MedicineChapel HillNorth Carolina, USA

Richard C. Semelka, MDProfessor of Radiology; Director of Magnetic Resonance Services; Vice Chair of Quality and SafetyDepartment of RadiologyUNC School of MedicineChapel HillNorth Carolina, USA

Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved

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Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data

Text-atlas of skeletal age determination : MRI of the hand and wrist in children / edited by Ernesto Tomei, Sofia Battisti, Milvia Martino, Daniel B. Nissman, and Richard C. Semelka p. ; cm. – (Current clinical imaging) Includes bibliographical references and index. ISBN 978-1-118-69227-1 (cloth : alk. paper) I. Tomei, Ernesto, editor. II. Battisti, Sofia, editor. III. Martino, Milvia, editor. IV. Nissman, Daniel B., editor. V. Semelka, Richard C., editor. VI. Series: Current clinical imaging. [DNLM: 1. Age Determination by Skeleton–methods. 2. Hand–growth & development. 3. Bone Development. 4. Child. 5. Magnetic Resonance Imaging–methods. WE 830] QM101 611'.71–dc23 2013043352

Hardback ISBN: 978-1-118-69227-1

Cover image: © Jsheets19/iStockphotoCover design by Wiley

Printed in 9.5/12 pt Palatino by Toppan Best-set Premedia Limited

10 9 8 7 6 5 4 3 2 1

    v

Contents

Contributors, ix

Introduction, xiii

Preface, xv

  1 Anatomic Aspects of Bone Ossification and their Magnetic Resonance Counterparts, 1Guido Carpino, Ernesto Tomei, Richard C. Semelka, and Eugenio Gaudio1.1 Endochondral ossification, 1

1.1.1 Primary center of ossification (fetal life), 1

1.1.2 Growth plate, 11.1.3 Secondary centers of ossification

(later in development), 11.2 Longitudinal bone growth, 21.3 Magnetic resonance aspects of endochondral

ossification, 31.3.1 Bone marrow, 31.3.2 Epiphyseal cartilage, 31.3.3 Growth plate, 4

1.4 Wrist and carpal bones, 5

  2 Bone Age: Medico-legal Issues, 7Serenella Serinelli, Paolo Arbarello, Sofia Battisti, Ernesto Tomei, and Richard C. Semelka2.1 Introduction, 72.2 Medico-legal fields of application, 8

2.2.1 Unaccompanied children in Europe, 82.2.2 Unaccompanied children in the USA, 10

2.3 Criminal law, 102.4 Adoptions, 112.5 Ethical issues, 112.6 Conclusions, 13

  3 Endocrinology, Puberty, and Disorders of Pubertal Development, 17Antonio Radicioni, Gilda Ruga, Sofia Battisti, Richard C. Semelka, Ernesto Tomei, and Andrea Lenzi3.1 Introduction, 173.2 Alterations of the time of onset of puberty, 183.3 Early puberty, 18

3.4 Precocious puberty, 183.4.1 Clinical and diagnostic evaluation, 193.4.2 Therapy, 20

3.5 Late puberty, 203.6 Delayed puberty, 20

3.6.1 Clinical and diagnostic evaluation, 213.6.2 Therapy, 223.6.3 Imaging, 22

  4 MR Assessment of Skeletal Age in Healthy Children, 23Ernesto Tomei, Sofia Battisti, Milvia Martino, and Richard C. Semelka4.1 Introduction, 234.2 State of the art of age estimation

methods, 234.2.1 MR skeletal imaging of the wrist

and hand, 254.3 Conclusions, 54

  5 Maturation of Individual Bones of the Hand and Wrist in Healthy Children, 57Milvia Martino, Sofia Battisti, Richard C. Semelka, and Ernesto Tomei5.1 Grading system of MR images to assess

skeletal estimation, 575.2 MR images of maturation of individual

bones, 605.3 Details of MRI maturation scoring

system, 605.4 Notes on the use of the bone maturation

tables, 615.5 Conclusions, 61

  6 Musculoskeletal Findings in Young Athletes, 77Sofia Battisti, Milvia Martino, Alessandro Sartori, Ernesto Tomei, and Richard C. Semelka6.1 Introduction, 776.2 Athletics associated with delayed bone

aging, 796.3 Athletics associated with premature (advanced)

bone aging, 806.4 Athletics associated with specific forms of

overuse trauma, 83

vi    Contents

  7 Bone Marrow Maturation in Healthy and Diseased States, 85Sofia Battisti, Ernesto Tomei, Antonello Rubini, Milvia Martino, Andrea Laghi, and Richard C. Semelka7.1 Introduction, 857.2 Healthy bone marrow and the role of magnetic

resonance, 857.3 Bone marrow disorders, 87

7.3.1 Bone marrow reconversion, 887.3.2 Bone marrow infiltration/replacement/

deposition, 897.3.3 Bone marrow depletion/failure, 90

  8 Nutrition and Growth, 93Silvia Migliaccio, Sofia Battisti, Alessandro Pinto, Lorenzo Maria Donini, Ernesto Tomei, and Richard C. Semelka8.1 Introduction, 938.2 Anorexia nervosa, 948.3 Obesity, 96

  9 MRI Skeletal Age Estimation in Celiac Disease, 99Monica Montuori, Maria Bavestrelli, Margherita Bonamico, Milvia Martino, Richard C. Semelka, and Ernesto Tomei9.1 General aspects, 999.2 Therapy, 1019.3 Imaging, 102

10 Growth Failure and Pediatric Inflammatory Bowel Disease, 105Marina Aloi, Salvatore Cucchiara, Milvia Martino, Richard C. Semelka, and Ernesto Tomei10.1 General aspects, 105

10.1.1 Disruption of the GH–IGF-1 axis, 10510.1.2 IGF-1-independent mechanisms, 10610.1.3 Tumor necrosis factor, 10610.1.4 Chronic corticosteroid therapy, 106

10.2 Imaging of individuals with childhood onset IBD, 107

11  Adult Bone Diseases That Begin in Childhood, 109Salvatore Minisola, Vincenzo Carnevale, Najwa Al Ansari, Ernesto Tomei, and Richard C. Semelka11.1 General aspects, 10911.2 Imaging, 114

12 Skeletal Findings in Neurometabolic Disease, 117Mario Mastrangelo, Sara Bertino, Sofia Battisti, Richard C. Semelka, Ernesto Tomei, and Vincenzo Leuzzi12.1 Introduction, 11712.2 Phenylketonuria, 117

12.2.1 General aspects, 11712.2.2 Growth, bone maturation, and the role of

bone MRI in phenylketonuria, 118

12.3 Niemann–Pick type C disease, 11912.3.1 General aspects, 11912.3.2 Growth, bone maturation, and the role of

bone MRI in Niemann–Pick type C disease, 121

13 Skeletal Findings in Genetic Disease, 123Luigi Tarani, Natascia Liberati, Chiara Mancini, Francesca Mancini, Michela Martini, Chiara Mattiucci, Giovanni Parlapiano, Leonardo Pimpolari, Richard C. Semelka, and Fiorenza Colloridi13.1 Introduction, 12313.2 Assessment of growth, 123

13.2.1 Anthropometric measures, 12413.2.2 Measurement of skeletal and biologic

maturation, 12413.2.3 Staging of pubertal development, 124

13.3 Growth disorders, 12513.3.1 Syndromes associated with

disharmonious short growth, 12513.3.2 Overgrowth syndromes, 12713.3.3 Imaging of subjects with genetic causes

for abnormal growth, 130

14 Skeletal Findings in Pediatric Oncology Patients, 133Anna Clerico, Giulia Varrasso, Carlo Alberto Cappelli, Milvia Martino, Richard C. Semelka, and Ernesto Tomei14.1 Introduction and diseases, 13314.2 Imaging, 135

15 Bone Mineral Density Measured with DXA Method in Pediatric Inflammatory Bowel Diseases, 137Carlina V. Albanese and Richard C. Semelka15.1 Introduction, 13715.2 Effects on bone metabolism in pediatric

IBD, 13715.2.1 IBD and alteration of bone mass in

pedriatic age patients, 13715.2.2 IBD and growth failure, 138

15.3 DXA in pediatric age patients, 13815.4 Conclusions, 141

16 MRI of the Symptomatic Hand and Wrist, 143Daniel B. Nissman, 14316.1 Introduction, 14316.2 Protocols, 14316.3 Clinical examples, 143

16.3.1 Trauma, 14316.3.2 Infection, 14516.3.3 Arthritis, 14516.3.4 Masses, 145

17 Magnetic Resonance Imaging Principles and Techniques, 149Daniel B. Nissman and Brian M. Dale17.1 Introduction, 14917.2 Principles of MRI, 149

Contents    vii

17.2.1 Magnetic resonance, 14917.2.2 Imaging, 15017.2.3 Safety, 151

17.2.3.1 Magnetic forces, 15117.2.3.2 Heating, 15117.2.3.3 Sound, 15117.2.3.4 Tissue stimulation, 152

17.2.4 Pulse sequences, 152

17.3 MRI techniques, 15217.3.1 Soft tissue contrast in musculoskeletal

MRI, 15217.3.2 Low field versus high field MRI, 154

Index, 155

A color plate section falls between pages 144 and 145

    ix

Contributors

Najwa Al Ansari, MDResident at Department of Radiology, Oncology and Anatomy

PathologySapienza University of RomeRome, Italy

Carlina V. Albanese, MDAssociate Professor of RadiologyHead of Osteoporosis UnitDepartment of Radiological Sciences, Oncology and PathologySapienza University of RomeRome, Italy

Marina Aloi, MDPediatric Gastroenterology and Liver UnitDepartment of PediatricsSapienza University of RomeRome, Italy

Paolo Arbarello, MDFull Professor of Forensic Medicine;Director of the Forensic Medicine Section in the Department of

Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of Rome;Director of Postgraduate course in Forensic MedicineSapienza University of Rome;President of SIMLA (Italian Society of Forensic Medicine)Rome, Italy

Sofia Battisti, MDClinical Research ScholarMR Section, Department of RadiologyUniversity of North CarolinaChapel Hill, North Carolina, USA;Resident RadiologyDepartment of Radiology Campus Bio-medico of RomeRome, Italy

Maria Bavestrelli, MDDepartment of Pediatrics and Infantile NeuropsychiatrySapienza University of RomeRome, Italy

Sara Bertino, MDChild Neurology DivisionDepartment of Pediatrics and Child Neurology and PsychiatrySapienza University of RomeRome, Italy

Margherita Bonamico, MDAssociate ProfessorDepartment of Pediatrics and Infantile NeuropsychiatrySapienza University of RomeRome, Italy

Carlo Alberto Cappelli, MDOncology UnitDepartment of PediatricsSapienza University of RomeRome, Italy

Vincenzo Carnevale, MDInternal Medicine Unit,Casa Sollievo della Sofferenza HospitalIRCCS, San Giovanni Rotondo (FG)Italy

Guido Carpino, MDDepartment of Motor, Human and Health SciencesUniversity of Rome Foro ItalicoRome, Italy

Anna Clerico, MD PhDAssociate ProfessorOncology UnitDepartment of PediatricsSapienza University of RomeRome, Italy

Fiorenza ColloridiAssistant ProfessorDepartment of PediatricsClinical Genetics UnitSapienza University of RomeRome, Italy

Salvatore Cucchiara, MDFull ProfessorPediatric Gastroenterology and Liver UnitDepartment of PediatricsSapienza University of RomeRome, Italy

x    Contributors

Brian M. Dale, PhDZone Research ManagerMR R&D CollaborationsSiemens Medical Solutions, Inc.Morrisville, North Carolina, USA

Lorenzo Maria Donini, MDAssociate ProfessorSection of Medical Pathophysiology, Endocrinology and NutritionDepartment of Experimental MedicineSapienza University of Rome;Unit of Endocrinology Section of Health SciencesUniversity of Rome Foro ItalicoRome, Italy

Eugenio Gaudio, MDFull ProfessorDepartment of Anatomical, Histological, Forensic Medicine and

Orthopedic SciencesSapienza University of RomeRome, Italy

Andrea Laghi, MDAssociate Professor of RadiologyDepartment of Radiology, Oncology and Anatomy PathologySapienza University of RomeRome, Italy;Director, Tecniche Diagnostiche AvanzateInstituto Chirurgico Ortopedico TraumatologicoLatina, Italy

Andrea Lenzi, MDFull ProfessorDepartment of Experimental MedicineSection of Medical Pathophysiology, Food Science and EndocrinologySapienza University of RomeRome, Italy

Vincenzo Leuzzi, MDChild Neurology DivisionDepartment of Pediatrics and Child Neurology and PsychiatrySapienza University of RomeRome, Italy

Natascia Liberati, studentDepartment of PediatricsClinical Genetics UnitSapienza University of RomeRome, Italy

Chiara Mancini, MDDepartment of PediatricsClinical Genetics UnitSapienza University of RomeRome, Italy

Francesca Mancini, MDDepartment of PediatricsClinical Genetics UnitSapienza University of RomeRome, Italy

Michela Martini, MDDepartment of PediatricsClinical Genetics UnitSapienza University of RomeRome, Italy

Milvia MartinoDepartment of Radiology, Oncology and Anatomy PathologySapienza University of RomeRome, Italy

Mario Mastrangelo, MD PhDChild Neurology DivisionDepartment of Pediatrics and Child Neurology and PsychiatrySapienza University of RomeRome, Italy

Chiara Mattiucci, MDDepartment of PediatricsClinical Genetics UnitSapienza University of RomeRome, Italy

Silvia Migliaccio, MDSection of Medical Pathophysiology, Endocrinology and NutritionDepartment of Experimental MedicineSapienza University of Rome;Unit of Endocrinology Section of Health SciencesUniversity of Rome Foro ItalicoRome, Italy

Salvatore Minisola, MDFull ProfessorDepartment of Internal MedicinePoliclinico Umberto I HospitalSapienza University of RomeRome, Italy

Monica Montuori, MD PhDDepartment of Pediatrics and Infantile NeuropsychiatrySapienza University of RomeRome, Italy

Daniel B. Nissman, MD MPH MSEEClinical Assistant Professor of RadiologyDepartment of Radiology, Musculoskeletal SectionUNC School of MedicineChapel Hill, North Carolina, USA

Giovanni Parlapiano, studentDepartment of PediatricsClinical Genetics UnitSapienza University of RomeRome, Italy

Leonardo Pimpolari, MDDepartment of PediatricsClinical Genetics UnitSapienza University of RomeRome, Italy

Contributors    xi

Alessandro Pinto, MDSection of Medical Pathophysiology, Endocrinology and NutritionDepartment of Experimental MedicineSapienza University of Rome;Unit of Endocrinology Section of Health SciencesUniversity of Rome Foro ItalicoRome, Italy

Antonio Radicioni, MDProfessor, Department of Experimental MedicineSection of Medical Pathophysiology, Food Science and EndocrinologySapienza University of RomeRome, Italy

Antonello Rubini, MDDepartment of Radiology, Oncology and Anatomy PathologySapienza University of RomeRome, Italy

Gilda Ruga, MDDepartment of Experimental MedicineSection of Medical Pathophysiology, Food Science and EndocrinologySapienza University of RomeRome, Italy

Alessandro Sartori, MDResident at Department of Radiology, Oncology and Anatomy

PathologySapienza University of Rome,Rome, Italy

Richard C. Semelka, MDProfessor of Radiology;Director of Magnetic Resonance Services;Vice Chair of Quality and SafetyDepartment of RadiologyUNC School of MedicineChapel Hill, North Carolina, USA

Serenella Serinelli, MDResident in Forensic MedicineSapienza University of RomeRome, Italy

Luigi Tarani, MDProfessor, Department of PediatricsClinical Genetics UnitSapienza University of RomeRome, Italy

Ernesto Tomei, MDAssociate Professor of RadiologyDepartment of Radiology, Oncology and Anatomy PathologySapienza University of Rome,Rome, Italy

Giulia Varrasso, MDOncology UnitDepartment of PediatricsSapienza University of RomeRome, Italy

    xiii

Introduction

The radiographic examination of the hand and wrist was initially used to study skeletal development, correlating skeletal and chronologic age in order to verify potential growth and whether a need for intervention was neces-sary. In recent years, the reasons for this examination has expanded beyond assessment of development, into such areas as the law, sports, and delving more deeply into nonimaging specialties, including pediatric endocrinol-ogy, gastroenterology, hematology, oncology, genetics, and metabolics.

The increase in the interest and importance of imaging in these evaluations, combined with the awareness of the potential harm from X-rays, especially in young individu-als, has prompted the scientific community to consider diagnostic modalities that do not involve ionizing radia-tion. In addition to avoiding the use of radiation, MRI has the additional potentially tremendous value, because its intrinsic high soft tissue contrast resolution, of providing unique information on the bone marrow, cartilage, and muscles and soft tissues.

In this text-atlas, the editors and collaborators describe their early and ground-breaking work into the use of MRI to evaluate bone, bone marrow, and cartilage, to assess MR skeletal age both in normal subjects and in individu-als with disease. The chapters that illustrate normal bone age present strategies comparable to both traditional Greulich and Pyle and Tanner and Whitehouse approaches, but with far greater information, due to the capacity of MRI to reveal the appearance of all the developing musculoskeletal tissues. Chapters written by a variety of clinical specialist experts also point the direction towards greater integration of MRI findings into management of patients with a full range of disease processes. The potential applications in safe use of detailed imaging in children seems endless, and for this reason it is a great pleasure for me to present this work as a longtime col-league and friend of Professor Tomei.

Professor Roberto Passariello

    xv

Preface

The unmatched soft tissue contrast resolution of MRI has been recognized since the inception of clinical MRI in the mid 1980s. Also recognized since the early days is the tremendous ability of MRI to reveal the various compo-nents of the musculoskeletal system, including bone marrow, ligaments, tendons, and cartilage. Although MRI has been widely used for evaluating the changes in bone in the growing skeleton of children, there is relatively little work attempting to provide a comprehensive vision on assessing skeletal age throughout childhood. In this book we formalize our 3-year experience with using MRI to evaluate skeletal age in healthy subjects and in children with a variety of underlying diseases, including genetic disease, cancer, celiac disease, and Crohn disease. A low field open magnet (0.2 Tesla) was used for this study; coronal 3D spin echo T1-weighted images with a slice thickness of 1.3 mm were acquired.

We have used the left wrist and hand of children to assess skeletal age, basing this upon the convention used originally by Greulich and Pyle and subsequently by Tanner and Whitehouse. Building upon their work, we have not only studied the development of ossified bone, but now, thanks to the soft tissue resolving capacity of MRI, we have expanded our assessment to include carti-lage and bone marrow, and their changes with matura-tion. By this means we believe that this approach will be the most accurate means by which to determine skeletal age, based on the variety of information assessed and the detail that can be visualized. Determination of skeletal age is not only important for children who may experi-ence what appears to be either delayed or premature growth, but also to verify the age of individuals, which also has medicolegal implications. We include in this book a new field of research, the effects of physical activ-ity and excess physical activity as a potential area of con-siderable importance for athletic pursuits.

The key aspect of this work is our efforts to categorize and systematize the observations of normal development of bones, describing in detail the various stages of matu-ration of cartilage, ossification centers, and bone marrow. These evaluations were not previously accessible in vivo until detailed evaluation by MRI. This forms the frame-work for our early development of the Tomei skeletal aging system.

We have addressed a variety of different disease pro-cesses that can result in delayed growth and also prema-ture growth. In this edition we introduce evaluating delay or prematurity from the concept of growth abnormality with usual pattern of development, growth abnormality with abnormal pattern of development, and growth abnormality with development of abnormal bones.

Sir Isaac Newton is credited with remarking: “If I have seen further it is by standing on the shoulders of giants,” by this same fashion we credit our predecessors who determined skeletal age by using imaging studies.

In working with young children, safety is of paramount importance. We believe this is one of the compelling strengths of MRI, because no ionizing radiation is used. At the same time, because children make up the source material of the book, we were very careful to obtain approval from the institutional ethics committee, but most importantly from the parents and other care-givers. Additionally, some of the studies in patients with various clinical diseases were for clinical reasons and not research.

Lastly, we wish to acknowledge the work of our MR technologists in performing these studies, with special thanks to Antonio Moscato and Roberto Fringuelli, and to Serena Sposato, who is in charge of medical records for the Department of Radiology at La Sapienza.

Ernesto Tomei, Sofia Battisti, Milvia Martino, Daniel B. Nissman, and Richard C. Semelka

1

CHAPTER 1

Anatomic Aspects of Bone Ossification and their Magnetic Resonance CounterpartsGuido Carpino1, Ernesto Tomei2, Richard C. Semelka3, and Eugenio Gaudio4

1Department of Motor, Human and Health Sciences, University of Rome Foro Italico, Rome, Italy2Department of Radiology, Oncology and Anatomy Pathology, Sapienza University of Rome, Rome, Italy3Department of Radiology, UNC School of Medicine, Chapel Hill, North Carolina, USA4Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy

1.1 Endochondral ossification

Endochondral ossification is the process by which a bone develops from a pre-existing model composed of hyaline cartilage. It begins around the sixth week of fetal develop-ment and continues into the individual’s twenties. Most bones of the body, including the vertebrae, ribs, sternum, scapula, pelvis, and bones of the limbs, develop in this way [1,2].

Ossification proceeds in the following fashion: the center of the cartilage model is invaded by mesenchymal stem cells which form the primary center of ossification. Later, at each end of the cartilage model, secondary centers of ossification appear (Figure 1.1). These centers of ossification gradually encroach on the remaining carti-lage, ultimately replacing it completely (except at the articular surfaces) by the time skeletal maturity is reached [1,3,4]. The cartilage model is important as the source of longitudinal bone growth. The ossification of the cartilage model is a well-organized process which could be subdi-vided into several phases [1,3,4].

1.1.1 Primary center of ossification (fetal life)Chondrocytes at the center of the cartilaginous model (the diaphysis) begin to increase in number and size. The chondrocytes’ hypertrophy is followed by their apopto-sis, matrix calcification, and vascular invasion. The blood vessels bring with them mesenchymal stem cells that will give rise both to osteoblasts and osteoclasts. The invading cells stimulate the removal of the calcified cartilage and its replacement by trabecular bone and bone marrow.

1.1.2 Growth plateAs the bone marrow cavity expands toward the epiphy-ses, the chondrocytes at the epiphyseal margin proliferate

rapidly, forming longitudinal columns of flattened cells. Thus, the primary growth plate is interposed between the cartilaginous epiphysis and the newly generated bone (bone marrow cavity). The growth plate is composed of zones of resting, proliferative, maturing, and hyper-trophic chondrocytes, and of calcification.Zone of resting cartilage. This region, farthest from the

marrow cavity, consists of typical hyaline cartilage that as yet shows no sign of transforming into bone.

Zone of cell proliferation. A little closer to the marrow cavity, chondrocytes multiply and arrange themselves into longitudinal columns of flattened lacunae.

Zone of cell hypertrophy. Next, the chondrocytes cease to divide and begin to hypertrophy.

Zone of calcification and bone deposition. Minerals are deposited in the matrix between the columns of lacunae and calcify the cartilage. Apoptosis of hypertrophic chondrocytes occurs. Each column is converted into a longitudinal channel, which is immediately invaded by blood vessels and marrow from the marrow cavity. Osteoblasts line up along the walls of these channels and begin depositing concentric lamellae of matrix, while osteoclasts dissolve the temporarily calcified cartilage.Within the growth plate, chondrocyte proliferation

(zone of cell proliferation) is balanced by chondrocyte apoptosis and the replacement of the calcified cartilage with bone (zone of bone deposition). In this way, the width of the growth plate during development is main-tained while the bone increases in length [1,3,4].

1.1.3 Secondary centers of ossification (later in development)Roughly spherical secondary centers of ossification form within the cartilaginous epiphyses. The secondary ossifi-cation center becomes hollowed out by the same process

Text-Atlas of Skeletal Age Determination: MRI of the Hand and Wrist in Children, First Edition. Edited by Ernesto Tomei, Sofia Battisti, Milvia Martino, Daniel B. Nissman, and Richard C. Semelka.© 2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.