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BO N E DY SPL ASI A S
BONE DYSPLASIAS
An Atlas of Genetic Disorders of Skeletal Development

FOURTH EDITION

Jürgen W. Spranger, MD
Paula W. Brill, MD
Christine Hall, MD
Gen Nishimura, MD
Andrea Superti-​Furga, MD
Sheila Unger, MD

1
 1
Oxford University Press is a department of the University of Oxford. It furthers
the University’s objective of excellence in research, scholarship, and education
by publishing worldwide. Oxford is a registered trade mark of Oxford University
Press in the UK and certain other countries.

Published in the United States of America by Oxford University Press

198 Madison Avenue, New York, NY 10016, United States of America.

© Oxford University Press 2018

First edition: W.B. Saunders 1974

Second edition: Urban & Fischer 2002
Third edition: Oxford University Press 2012

All rights reserved. No part of this publication may be reproduced, stored in

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You must not circulate this work in any other form

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CIP data is on file at the Library of Congress

ISBN 978–​0–​19–​062665–​5

This material is not intended to be, and should not be considered, a substitute for medical or other professional
ad­vice. Treatment for the conditions described in this material is highly dependent on the individual circumstances.
And, while this material is designed to offer accurate information with respect to the subject matter covered and to be
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Printed by Sheridan Books, Inc., United States of America

 CONTENTS

Foreword xi 4.3 Spondyloepiphyseal Dysplasia Congenita

John M. Opitz (MIM 183900) 72

Acknowledgments xiii 4.4 Spondylo-​epi-​metaphyseal Dysplasia,

Strudwick Type (MIM 183900, 184250,
Introduction xv 184253) 80
4.5 Kniest Dysplasia (MIM 156550) 85
1. ACHONDROPLASIA AND RELATED FGFR3 CONDITIONS 1
4.6 Spondyloepiphyseal Dysplasia, Stanescu
1.1 Thanatophoric Dysplasia, Types 1 and 2
Type (MIM 616538) 90
(MIM 187600, 187601) 1
4.7 Spondyloperipheral Dysplasia (MIM 271700) 92
1.2 Achondroplasia (MIM 100800) 5
4.8 Spondyloepiphyseal Dysplasia with Short
1.3 Hypochondroplasia (MIM 146000) 12
Metatarsals (MIM 609162) 95
1.4 SADDAN (Severe Achondroplasia with
4.9 Stickler Dysplasia (MIM 108300, 604841) 97
Developmental Delay and Acanthosis
Nigricans) (MIM 616482) 19 4.10 Fibrochondrogenesis (MIM 228520) 101
4.11 Oto-​Spondylo-​Megaepiphyseal Dysplasia
2. PSEUDOACHONDROPLASIA AND DOMINANT (MIM 184840, 277610, 215150) 103
EPIPHYSEAL DYSPLASIA 23
2.1 Pseudoachondroplasia (MIM 177170) 23 5. MUCOPOLYSACCHARIDOSES AND OLIGOSACCHARIDOSES 109

2.2 Multiple Epiphyseal Dysplasias, Autosomal 5.1 Dysostosis Multiplex 109

Dominant (MIM 132400, 614135, 600204, 5.2 Mucopolysaccharidosis IV (MIM 253000,
600969, 607078) 27 253010) 117
5.3 Mucolipidosis II (MIM 252500) 124
3. DYSPLASIAS WITH PREDOMINANT METAPHYSEAL
INVOLVEMENT 33 5.4 Mucolipidosis III (MIM 252600, 252605) 129
3.1 Metaphyseal Chondrodysplasia, Schmid Type 6. METATROPIC DYSPLASIA AND OTHER TRPV4-​RELATED
(MIM 156500) 33
SKELETAL DYSPLASIAS 135
3.2 Cartilage-​Hair Hypoplasia (MIM 250250, 6.1 Metatropic Dysplasia (MIM 156530, 168400) 135
607095) 37
6.2 Spondyloepiphyseal Dysplasia, Maroteaux
3.3 Metaphyseal Dysplasia, Spahr Type Type (MIM 184095) 143
(MIM 250400) 41
6.3 Spondylometaphyseal Dysplasia, Kozlowski
3.4 Metaphyseal Anadysplasia (MIM 602111, Type (MIM 184252) 146
613073) 44
6.4 Brachyolmia, Autosomal Dominant
3.5 Shwachman Syndrome (MIM 260400) 50
(MIM 113500) 151
3.6 Metaphyseal Chondrodysplasia, Jansen Type 6.5 Familial Digital Arthropathy with
(MIM 156400) 54
Brachydactyly (MIM 606835) 154
3.7 Eiken Dysplasia (MIM 600002) 58
7. SPONDYLO-​EPI-​METAPHYSEAL AND SPONDYLO-​
3.8 CINCA (Chronic Infantile Neurologic
METAPHYSEAL DYSPLASIAS 157
Cutaneous and Articular Syndrome)
(MIM 607115) 61 7.1 Achondrogenesis Type 1A (MIM 200600) 157
7.2 Odontochondrodysplasia (MIM 184260) 160
4. SPONDYLO​EPIPHYSEAL DYSPLASIA CONGENITA
AND RELATED TYPE 2/​TYPE 11 COLLAGEN 7.3 Schneckenbecken Dysplasia (MIM 269250) 163
DISORDERS 65 7.4 Opsismodysplasia (MIM 258480) 165
4.1 Achondrogenesis II, Hypochondrogenesis 7.5 Spondylometaphyseal Dysplasia—​
(MIM 200610) 65 Sedaghatian Type (MIM 250220) 169
4.2 Platyspondylic Dysplasia, Torrance Type 7.6 Spondyloenchondrodysplasia (SPENCD;
(MIM 151210) 68 MIM 607944) 172

v
 7.7 Spondyloepimetaphyseal Dysplasia, 8.16 Steel Syndrome (MIM 615155) 302
PAPSS2 Type, and Brachyolmia, Autosomal
Recessive Type (MIM 271530, 271630) 175 9. FILAMIN-​ASSOCIATED DYSPLASIAS/​DYSOSTOSES AND
RELATED DISORDERS 307
7.8 Dyggve-​Melchior-​Clausen Dysplasia
(MIM 223800) 178 9.1 Otopalatodigital Syndrome Type I
7.9 Spondylometaepiphyseal Dysplasia, (MIM 311300) 307
Short Limb-​Abnormal Calcification Type 9.2 Otopalatodigital Syndrome Type II
(MIM 271665) 183 (MIM 304120) 314
7.10 Spondylometaphyseal Dysplasia with 9.3 Melnick-​Needles Osteodysplasty
Cone-​Rod Dystrophy (MIM 608940) 189 (MIM 309350) 320
7.11 Dyssegmental Dysplasia (MIM 224400, 9.4 Frontometaphyseal Dysplasia (MIM 305620,
MIM 244110) 194 617137) 326
7.12 Schwartz-​Jampel Syndrome (MIM 255800) 199 9.5 Boomerang Dysplasia/​Atelosteogenesis
7.13 Spondyloepiphyseal Dysplasia Tarda, Type I (MIM 112310, 108720) 331
X-​Linked (MIM 313400) 205 9.6 Atelosteogenesis Type III (MIM 108721) 335
7.14 Aggrecan-​Associated Skeletal Dysplasias 9.7 Larsen Syndrome, Autosomal Dominant
(MIM 608361, 612813) 209 (MIM 150250) 339
7.15 Wolcott-​Rallison Syndrome (MIM 226980) 214 9.8 Spondylocarpotarsal Synostosis Syndrome
7.16 Schimke Immunoosseous Dysplasia (MIM 272460) 344
(MIM 242900) 218 9.9 Frank-​Ter Haar Syndrome (MIM 249420) 346
7.17 Progressive Pseudo-​Rheumatoid Dysplasia
10. PUNCTATE CALCIFICATION GROUP 351
(MIM 208230) 222
7.18 Spondylometaphyseal Dysplasia, Corner 10.1 Greenberg Dysplasia (MIM 215140) 351
Fracture Type (MIM 184255) 228 10.2 Chondrodysplasia Punctata Conradi,
7.19 Sponastrime Dysplasia (MIM 271510) 230 Hünermann Type (MIM 302960) 353

7.20 CODAS Syndrome (MIM 600373) 233
7.21 NANS Deficiency (MIM 610442) 236
7.22 Spondylo-​Epi-​Metaphyseal Dysplasia
with Immune Deficiency and Developmental
Disability, EXTL3-​Deficient Type
(MIM 617425) 240
8. DIASTROPHIC DYSPLASIA AND RELATED CONDITIONS,
AND DYSPLASIAS WITH JOINT DISLOCATIONS 245
8.1 Achondrogenesis, Type IB (MIM 600972) 245
10.3 CHILD (Congenital Hemidysplasia with
Ichthyosiform Erythroderma and Limb
Defects) Syndrome (MIM 308050) 357
10.4 Chondrodysplasia Punctata, Rhizomelic Type
(MIM 215100, 222765, 600121) 360
10.5 Chondrodysplasia Punctata,
Brachytelephalangic Type (MIM 302950,
602497) 363
10.6 Chondrodysplasia Punctata, Autosomal
Dominant Type (MIM 118650) 368

8.2 Atelosteogenesis, Type 2 (MIM 256050) 247 10.7 Chondrodysplasia Punctata, Tibia-​
Metacarpal Type (MIM 118651) 371
8.3 Diastrophic Dysplasia (MIM 222600) 250
10.8 Keutel Syndrome (MIM 245150) 375
8.4 Multiple Epiphyseal Dysplasia, Recessive
Type (rMED; MIM 226900) 256 11. SHORT-​
RIB (±POLYDACTYLY) DYSPLASIAS 379
8.5 Desbuquois Dysplasia (MIM 251450) 260 11.1 Asphyxiating Thoracic Dysplasia
8.6 Chondrodysplasia with Joint Dislocations, (MIM 208500) 380
IMPAD1/​gPAPP Type (MIM 614078) 266 11.2 Ellis Van Creveld Syndrome (MIM 255500) 385
8.7 Catel-​Manzke Syndrome (MIM 616145) 270 11.3 Short Rib (±Polydactyly) Syndrome,
8.8 Chondrodysplasia with Congenital Joint Saldino-​Noonan and Verma-​Naumoff Types
Dislocations, CHST3 Type (MIM 143095) 272 (MIM 613091) 390

8.9 Temtamy Preaxial Brachydactyly Syndrome 11.4 Short Rib (±Polydactyly) Syndrome,
(MIM 605282) 276 Majewski Type (MIM 263520) 394

8.10 B4GALT7 Deficiency (MIM 130070) 279 11.5 Short Rib (±Polydactyly) Syndrome, Beemer-​
Langer Type (MIM 269860) 396
8.11 B3GAT3 Deficiency (MIM 245600) 281
11.6 Cranioectodermal Dysplasia (MIM 218330) 398
8.12 XYLT1 Deficiency (MIM 251450) 284
11.7 Mainzer-​Saldino Syndrome (MIM 266920) 403
8.13 Spondyloepimetaphyseal Dysplasia with
Joint Laxity, Beighton Type (MIM 271640) 287 11.8 Axial Spondylometaphyseal Dysplasia
(MIM 602271) 406
8.14 Spondyloepimetaphyseal Dysplasia
with Joint Laxity, Leptodactylic Type 12. RHIZO-​
MESOMELIC DYSPLASIAS 409
(MIM 603546) 292
12.1 Omodysplasia, Autosomal Recessive
8.15 Pseudodiastrophic Dysplasia (MIM 264180) 298 (MIM 258315, 268250) 409

vi C ontents
 12.2 Robinow Syndrome (MIM 180700, 14.8 Idiopathic Juvenile Osteoporosis
616331, 616894, 268310) 412 (MIM 259750) 526
12.3 Dyschondrosteosis (MIM 127300) 419 14.9 Bruck Syndrome (MIM 259450, 609220,
12.4 Mesomelic Dysplasia, Langer Type 610968) 529
(MIM 249700) 422 14.10 Cole-​Carpenter Syndrome (MIM 112240,
12.5 Mesomelic Dysplasia, Kantaputra Type 616294) 532
(MIM 156232) 425 14.11 Stüve-​Wiedemann Syndrome (MIM 601559) 535
12.6 Mesomelic Dysplasia, Werner Type 14.12 Osteoporosis-​Pseudoglioma Syndrome
(MIM 188740, 135750) 429 (MIM 259770) 540
12.7 Mesomelic Dysplasia, Reardon-​Kozlowski 14.13 Spondyloocular Dysplasia (MIM 605822) 543
Type (MIM 249710) 432 14.14 Geroderma Osteodysplasticum
12.8 Mesomelic Dysplasia, Nievergelt-​ (MIM 231070) 545
Savarirayan Type (MIM 163400, 605274) 435 14.15 Calvarial Doughnut Lesions-​Osteoporosis
12.9 Mesomelic Dysplasia with Acral Syndrome (MIM 126550) 548
Synostoses (MIM 600383) 439 14.16 Gnathodiaphyseal Dysplasia (MIM 166260) 552

13. ACROMESOMELIC AND ACROMELIC DYSPLASIAS/​ 15. DYSORDERS WITH DEFECTIVE MINERALIZATION 557
DYSOSTOSES 443
15.1 Hypophosphatasia (MIM 146300, 241500,
13.1 Acromesomelic Dysplasia, Maroteaux Type 251510) 557
(MIM 602875) 443
15.2 Neonatal Severe Primary
13.2 Grebe Dysplasia (MIM 200700, 201250, Hyperparathyroidism (MIM 239200) 564
228900) 447
15.3 Hereditary Rickets (MIM 307800, 193100,
13.3 Brachydactyly A1 (MIM 112500) 453 241520, 613312, 241530, 264700,
13.4 Brachydactyly B (MIM 113000) 455 600081, 277440, 600785, 300554,
13.5 Brachydactyly C (MIM 113100) 457 612089) 568

13.6 Brachydactyly D (MIM 113200) 460 16. DENSE BONE DYSPLASIAS WITH NORMAL
13.7 Brachydactyly E (MIM 113300, 613380) 462 BONE SHAPE 575

13.8 Brachydactyly, Christian Type (MIM 112450) 465 16.1 Osteopetroses 575

13.9 Tricho-​Rhino-​Phalangeal Dysplasia, Type I 16.2 Raine Dysplasia (MIM 259775) 577
(MIM 190350) 467 16.3 Infantile Osteopetrosis (MIM 259700,
13.10 Tricho-​Rhino-​Phalangeal Dysplasia, Type II 259710, 259720, 611490) 580
(MIM 150230) 471 16.4 Osteopetrosis, Intermediate (MIM 259710,
13.11 Acrocapitofemoral Dysplasia (MIM 607778) 473 611497) 584

13.12 Albright Hereditary Osteodystrophy (MIM 16.5 Osteopetrosis, Late Onset Forms (MIM
103580, 600430, 612462, 612463) 475 607634, 166660) 587

13.13 Acrodysostosis (MIM 101800, 614613) 481 16.6 Osteopetrosis with Renal Tubular Acidosis
(MIM 259730) 591
13.14 Geleophysic Dysplasia (MIM 231050) 484
16.7 Dysosteosclerosis (MIM 224300) 596
13.15 Acromicric Dysplasia (MIM 102370) 487
16.8 Pyknodysostosis (MIM 265800) 601
13.16 Myhre Syndrome (MIM 139210) 490
16.9 Osteomesopyknosis (MIM 166450) 604
13.17 Soft Syndrome (MIM 614813) 494
16.10 Osteopetrosis, Lymphedema, Ectodermal
14. OSTEOGENESIS IMPERFECTA AND OTHER Dysplasia, Immune Defect (MIM 300301) 607
DISORDERS WITH DECREASED BONE DENSITY 497 16.11 Osteopoikilosis (MIM 166700) 611
14.1 Osteogenesis Imperfecta 497 16.12 Melorheostosis (MIM 155950) 613
14.2 Osteogenesis Imperfecta, Type I 16.13 Osteopathia Striata with Cranial Sclerosis
(MIM 116200) 501 (MIM 300373) 616
14.3 Osteogenesis Imperfecta, Type IIA
(MIM 166210) 506 17. DENSE BONE DYSPLASIAS WITH META-​
DIAPHYSEAL MODELING DEFECTS 621
14.4 Osteogenesis Imperfecta, Type IIC 509
17.1 Blomstrand Chondrodysplasia (MIM 215045) 621
14.5 Osteogenesis Imperfecta, Type III/​IIB
(MIM 259420) 511 17.2 Infantile Cortical Hyperostosis (MIM 114000) 623

14.6 Osteogenesis Imperfecta, Type IV 17.3 Dysplastic Cortical Hyperostosis Type

(MIM 166220) 517 Kozlowski-​Tsuruta 627
14.7 Osteogenesis Imperfecta, Type V 17.4 Osteoectasia with Hyperphosphatasia
(MIM 610967) 521 (MIM 239000) 629

C ontents vii
 17.5 Endosteal Hyperostosis, van Buchem Type 19.10 Genochondromatosis (MIM 137360) 750
(MIM 239100, 269500) 634 19.11 Metachondromatosis (MIM 156250) 753
17.6 Camurati-​Engelmann Disease (MIM 131300) 639
20. POLYTOPIC DYSOSTOSES 757
17.7 Ghosal Hematodiaphyseal Dysplasia
(MIM 231095) 644 20.1 Campomelic Dysplasia (MIM 211990,
17.8 Lenz-​Majewski Hyperostotic Dysplasia 114290) 757
(MIM 151050) 647 20.2 Cousin Dysplasia (MIM 260660) 762
17.9 Hypertrophic Osteoarthropathy, Autosomal 20.3 Spondylo-​Megaepiphyseal-​Metaphyseal
Recessive (MIM 259100) 653 Dysplasia (MIM 613330) 765
17.10 Pachydermoperiostosis, Autosomal 20.4 Cleidocranial Dysplasia (MIM 119600) 767
Dominant (MIM 167100) 656 20.5 Yunis-​Varon Syndrome (MIM 216340) 773
17.11 Sclerosteo-​Cerebellar Syndrome 20.6 CDAGS (MIM 603116) 776
(MIM 213002) 660
20.7 Nail-​Patella Syndrome (MIM 161200) 779
17.12 Craniodiaphyseal Dysplasia (MIM 122860,
218300) 663 20.8 Ischio-​Pubic-​Patellar Dysplasia (MIM 147891) 782

17.13 Craniometaphyseal Dysplasia (MIM 20.9 Ischiospinal Dysostosis (MIM 608020) 785
123000, 218400) 666 20.10 Cerebro-​Costo-​Mandibular Syndrome
17.14 Craniometadiaphyseal Dysplasia, Wormian (MIM 117650) 790
Bone Type (MIM 269300) 670 20.11 SAMS Syndrome (MIM 602471) 793
17.15 Pyle Disease (MIM 265900) 673
21. DISORDERS WITH PRENATAL SHORT STATURE
17.16 Metaphyseal Dysplasia, Braun-​Tinschert AND SLENDER BONES 795
Type (MIM 605946) 676
21.1 3M Syndrome (MIM 273750, 612921,
17.17 Oculodentoosseous Dysplasia 614205) 795
(MIM 164200) 679
21.2 Kenny-​Caffey Syndrome (MIM 127000) 798
17.18 Tricho-​Dento-​Osseous Dysplasia
(MIM 190320) 683 21.3 Osteocraniostenosis (OCS; MIM 602361) 802

17.19 Diaphyseal Medullary Stenosis with Bone 21.4 Microcephalic Osteodysplastic Primordial
Malignancy (MIM 112250) 685 Dwarfism, Types 1 and 3 (MIM 210710,
210730) 804
18. OSTEOLYSES 689 21.5 Microcephalic Osteodysplastic Primordial
18.1 Familial Expansile Osteolysis (MIM 174810) 689 Dwarfism, Type 2 (MIM 210720) 807

18.2 Hyaline Fibromatosis (MIM 228600) 692 21.6 IMAGE (Intrauterine Growth Retardation,
Metaphyseal Dysplasia, Adrenal Hypoplasia
18.3 Mandibuloacral Dysplasia (MIM 248370, Congenita, and Genital Anomalies)
608612) 695 Syndrome (MIM 614732) 812
18.4 Progeria (MIM 176670) 699
22. OVERGROWTH/​ACCELERATED SKELETAL
18.5 Winchester-​Torg Syndrome (MIM 259600) 703
MATURATION SYNDROMES (SELECTED) 815
18.6 Hajdu-​Cheney Osteolysis (MIM 102500) 707
22.1 Marshall-​Smith Syndrome (MIM 602535) 815
18.7 Multicentric Carpal-​Tarsal Osteolysis
(MIM 166300) 711
22.2 Moreno-​Nishimura-​Schmidt Overgrowth
Syndrome (MIM 608811) 820
19. DISORDERS CAUSED BY DISORGANIZATION 22.3 Weaver Syndrome (MIM 277590) 824
OF SKELETAL CONSTITUENTS 717 22.4 CNP-​Overexpression Overgrowth Syndrome
19.1 Fibrous Dysplasia (MIM 174800) 717 (MIM 615923) 826
19.2 Cherubism (MIM 118400) 723
23. CRANIOSYNOSTOSIS SYNDROMES 829
19.3 Progressive Osseous Heteroplasia
(MIM 166350) 725 23.1 Apert Syndrome (MIM 101200) 829

19.4 Multiple Cartilaginous Exostoses 23.2 Pfeiffer Syndrome (MIM 101600, 136350) 834
(MIM 133700, 133701, 600209) 728 23.3 Antley-​Bixler Syndrome (MIM 201750) 837
19.5 Osteoglophonic Dysplasia (MIM 166250) 732 23.4 Saethre-​Chotzen Syndrome (MIM 101400) 840
19.6 Fibrodysplasia Ossificans Progressiva 23.5 Baller-​Gerold Syndrome (MIM 218600,
(MIM 135100) 737 266280) 843
19.7 Dysplasia Epiphysealis Hemimelica 23.6 Carpenter Syndrome (MIM 201000,
(MIM 127800) 741 614970) 848
19.8 Enchondromatosis (MIM 166000) 744 23.7 Muenke Syndrome (MIM 602849) 851
19.9 Metaphyseal Chondromatosis with 23.8 Bent Bone Dysplasia-​FGFR2 Type
2-​Hydroxyglutaric Aciduria 748 (MIM 614592) 853

viii C ontents
 24. SPONDYLOCOSTAL DYSOSTOSES 857 25.5 Femoral-​Facial Syndrome (MIM 134780) 876
25.6 Femur-​Fibula-​Ulna Syndrome (MIM 228200) 880
25. LIMB APLASIAS AND HYPOPLASIAS (SELECTED) 863
25.7 Poland Syndrome (MIM 173800) 883
25.1 Al-​Awadi Raas-​Rothschild Syndrome (MIM
276820, 228930) 863 25.8 Nager Syndrome (MIM 154400, 201170) 886
25.2 Roberts/​SC Phocomelia Syndrome (MIM
26. DISORDERS WITH DEFECTIVE JOINT FORMATION 889
268300, 269000) 866
26.1 Multiple Synostoses Syndrome (MIM
25.3 Ectrodactyly, Ectodermal Dysplasia, and
186500, 186570, 610017, 612961) 889
Cleft Lip/​Palate Syndrome (MIM 129900,
604292) 869 26.2 Liebenberg Syndrome (MIM 186550) 894
25.4 Split-​Hand/​Foot Malformation with Long
Bone Deficiency (MIM 119100, 610685,
612576) 872 Index 897

C ontents ix
 FOREWORD
Ten years ago, Victor A. McKusick, renowned pioneer of
North American medical genetics, encyclopedist, cardiolo-
gist, and expert at the human disorders of connective tissue
(especially the Marfan syndrome) wrote the preface for the
second edition of the magisterial Spranger et al. Atlas on
Bone Dysplasias.
It was McKusick who in 1968 initiated the annual
Conferences on the Clinical Delineation of Birth Defects,
the first five at John Hopkins Hospital. In 1968, two days
were devoted to the skeletal dysplasias with input and discus-
sion by Maurice Lamy, Jürgen W. Spranger, David Rimoin,
Judith G. Hall, John Dorst, Leonard O. Langer, and Hans
Zellweger, among others. Centers of excellence were flour-
ishing or being established in Los Angeles, Seattle—​later
Vancouver, Baltimore, Kiel, Paris, and Madison (briefly with
Jürgen Spranger, Len Langer, Enid F. Gilbert, and myself
“under one roof ”). Extremely active working relationships
were established between these and other European experts
including Maurice Lamy, Pierre Maroteaux (Paris), Andres
Giedion (Zürich), K. Kozlowski (Australia), G. Camera
(Italy), Jiri Kučera (Prague), and many others. After the
thalidomide disaster, Widukind Lenz (Münster) became
an outstanding authority on the limb dysostoses.
Sadly, Dr. McKusick did not live to write a revision of
his preface for this edition.
Early efforts in this field were primarily nosological with
delineation of an ever-​increasing number of entities, subse-
quently lumped with or split from others, few remaining as
originally set out (achondroplasia!). Definition of skeletal
dysplasias as causal entities was then, and to some extent still
is, based on family structure (e.g., the spectacular pedigree
of the first family segregating for the Nievergelt syndrome),
presence or absence of parental consanguinity, clinical
manifestations, and paternal age (Penrose, achondroplasia).
As noted by McKusick, these efforts culminated in
several early monographs, for example, by Mørch (1941)
and A. Birch-​Jensen (1949) on defects of upper limbs
in Copenhagen, Hobaek (Norway, 1961), Lamy and
Maroteaux (Paris), Rubin (United States, 1964), and Grebe
(1964); other earlier contributors were members of the
Galton Laboratory, also R.R. Gates in London (1946), and
Hanhart in Switzerland. Refinements of radiologic tech-
nique, bone histology, and histochemistry and collagen
chemistry led to a gradual improvement of nosology and a
deeper understanding of pathogenesis.
While some (Müller-​ Hill, 1984) have expressed
concerns about the provenance of some of Grebe’s material,
others have, unwittingly, profited from collaboration with
Grebe (Grebe and Wiedemann 1953). Wiedemann was a
pediatrician with a strong interest in skeletal dysplasias and
other human constitutional anomalies. Wiedemann’s small
text on the great constitutional anomalies of the skeleton
(1960) appeared while Jürgen Spranger was house officer in
Wiedemann’s department in Kiel (1961–​1974).
At a meeting of the European Society of Radiology in
Paris in 1968, a group of experts considered nosology in
the skeletal dysplasias with Spranger making the funda-
mental biological distinction between skeletal dysplasia
and dysostoses. The first edition of the Langer, Spranger,
and Wiedemann book was a milestone in this field com-
bining clinical, radiologic, genetic, and histologic advances
on the eve of a major molecular reshaping of our under-
standing based, in part, on Spranger’s important concept of
the families of skeletal dysplasias identified on the basis of
roentgenological and pathogenetic criteria (think: type II
collagenopathies, i.e., COL2A1 disorders: achondrogenesis
type 2, platyspondylic lethal dysplasia [Torrance] in humans
and mice, hypochondrogenesis, spondyloepiphyseal dys-
plasia, spondyloepimetaphyseal dysplasia [SEMD], SEMD
Strudwick type, Kniest dysplasia, spondyloperipheral dys-
plasia, Stickler syndrome type 1, vitreoretinopathy and
phalangeal epiphyseal dysplasia, and so on.)
The present group of collaborators on this edition of
Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal
Development, all have decades of experience in this field.
Besides Jürgen Spranger (pediatrician, geneticist, and skel-
etal radiologist), there is Paula W. Brill (New York), whose
interest in the field was inspired by Leonard O. Langer
and John Dorst, and who collaborated on the second and
third editions. Dr. Brill is currently Professor Emerita of
Radiology at Weill Cornell Medical College, where she
previously served as chief of Pediatric Radiology. Gen
Nishimura (Tokyo) claims he was drawn to the field by an
earlier version of this book; he is widely regarded as one
of the world’s finest diagnosticians of skeletal dysplasias;
as head of Pediatric Imaging at Tokyo’s Metropolitan
xi
Children’s Medical Center he contributed substantially to
this revision, particularly the dysostoses.
Sheila Unger, who trained with the late David Rimoin,
and Andrea Superti-​ Furga, who learned from Andres
Giedion and Jürgen Spranger, are well-​known to all readers
of the American Journal of Medical Genetics as compilers
of the Nomenclature of Skeletal Dysplasias, now incor-
porated into this revision, complementing each other as
pediatricians and medical geneticists with an emphasis on
skeletal development, as well as the organizers of the annual
Skeletal Dysplasia Course that has attracted so many young
talents to this field.
Palaeontologists working with an organism’s best pre-
served tissues, bone and teeth, are to an ever-​increasing
measure able to infer age, growth, and function from di-
rect and indirect evidence, even from material that may be
as old as the Devonian, some 360 million years ago. Form,
growth, and function are more easily inferred in a recently
stillborn fetus (e.g., with campomelic “dysplasia”) on the
basis of prenatal ultrasonography, physical and radiological
examination, histological studies of gonads, examination
of growth plate and brain, as well as structure of the domi-
nantly inherited SOX9 gene mutations in fetus and parents.
If neither parent has the infant’s mutation, is the recurrence
risk as low as the mutation rate at the gene? No, because
of germinal mosaicism. Thus, dear reader, please note the
word “genetic” in the title of this book.
But the greatest challenges are presented to the clinician
caring for a child with a previously apparently undescribed
skeletal dysplasia (there are still many, but check Spranger
et al., 2012 first!), but nowadays perhaps exome sequencing
may uncover a phylogenetically ancient gene that must have
been present in LUCA (i.e., the last universal common
ancestor of the archaea, bacteria, and eukaryotes) and may
provide a homologous condition (“animal model”) in a
xii
more or less closely related species. But the greatest clin-
ical skill is required to perform phenotype analysis in such
a child so astutely as to infer prognosis and required care.
And, toward that end, this revision of the Langer, Spranger,
and Wiedemann classic will be enormously useful.
John M. Opitz
University of Utah, Salt Lake City
April 2012
B IB LIOGR APH Y
Birch-​Jensen A (1949) Congenital deformities of the upper
extremities. Copenhagen: Ejnar Munksgaard.
Cocchi U (1964) Krankheiten des skeletsystem. In: Humangenetik,
vol. 2, ed. Becker PE. Stuttgart: Thieme: 113–​178.
Grebe H, Wiedemann HR (1953) Intrafamiliarität einiger typischer
Missbildungen. Acta Genet Med Gemellol 2:203–​224.
Grebe H (1955) Chondrodysplasie. Rome: Analecta Genetica/​Istituto
Gregorio Mendel.
Grebe H (1964) Missbildungen der Gliedmaßen. In: Humangenetik,
vol. 2, ed. Becker PE. Stuttgart: Thieme: 179–​343.
Hobaek A (1961) Problems of hereditary chondrodysplasias.
Oslo: Oslo University Press.
Lamy M, Maroteaux P (1961) Les chondrodystrophies génotypiques.
Paris: Expansion Scientifique Française.
Mørch ET (1941) Chondrodystrophic dwarfes [sic] in Denmark.
Opera ex domo Biologiae Hereditariae Humanae Universitatis
Hafniensis. Munksgaard, Kopenhagen.
Müller-​Hill B (1984) Tödliche Wissenschaft. Die Aussonderung
von Juden, Zigeunern und Geisteskranken 1933–​ 1955.
Reinbeck: Reinbeck-​Verlag.
Rubin P (1964) Dynamic classification of bone dysplasias. Chicago: Year
Book Publishers.
Spranger JW, Winterpacht A, Zabel B (1994) Type II
collagenopathies. Europ J Pediatr 153:56–​65.
Warman ML, Cormier-​Daire V, Hall C, et al. (2011) Nosology
and classification of genetic skeletal disorders: 2010 revision. Am J
Med Genet 155A:943–​968.
Wiedemann HR (1960) Die grossen konstitutionskrankheiten des
skeletts. Stuttgart: G. Fischer Verlag.
F oreword
 ACKNOWLEDGMENTS
Friends and physicians who helped to write the first edi-
tion of this atlas have been acknowledged in it. Much of
its material was used in the second and third editions, and
we continue to express our thanks to them. The second and
third edition could not have been completed without the
continued encouragement, help, and advice from Roger
Stevenson and his staff at the Greenwood Genetics Center,
which became a second academic home to JS.
The Children’s Hospital of the University of Freiburg,
Germany, now houses the Mainz Bone Dysplasia Registry
containing much of the material used in this book. Bernhard
Zabel, Ekkehard Lausch, and their staff in Freiburg pro-
vided the support and friendship needed to gather the ex-
perience and compose a new edition. The authors are part
of an international skeletal dysplasia network (ESDN)
that assists colleagues in need of a diagnosis. Part of the
new material stems from ESDN and is used with permis-
sion of the submitting colleagues. Other cases were shown
to the authors on a personal basis and are part of extensive
electronic databases created by GN in Tokyo and ASF in
Lausanne.
Physicians whom we approached to contribute films
from published cases are acknowledged in the legends.
Colleagues who shared with us their personal experience
and allowed us to use material from their unpublished cases
are gratefully acknowledged in the following list of names:
Y. Alanay, Ankara; B. Albrecht, Essen; G. Alzen, Giessen;
D. Amor, Melbourne; D. Babbit, Milwaukee; P. Beighton,
Cape Town; D. Binstadt, Springfield; M. Blick; O. Caglayan,
Izmir; Dr. Cavalcanti, Campinas; J. Charrow, Chicago;
D. Chitayat, Toronto; R. Cohen, Oakland; M. Crone,
Belfast; Dr. Diaz-Bonnet, San Juan; V. Cormier-Daire,
Paris; A. Crosby, London: J. Dorst, Baltimore; S. Dunbar,
Cincinnati; O. Eklöf, Stockholm; A. Fabretto, Trieste;
R. Faqueih, Rihyadh; S. Fellingham, Tiervlei; B. Frame,
Detroit; S. Garn, Ann Arbor; A. Geiberger, Stockholm;
A. Giedion, Zürich; R. Gorlin, Minneapolis; G. Greenway,
Dallas; K. H. Gustavson, Uppsala; N. Haga, Tokyo;
J. Hall, Vancouver; C. Hall, London; E. Harms, Münster;
A. Hatamochi, Tochigi; R. Hernandez, Ann Arbor;
J. J. Ho, Syracuse; J. Hoeffel, Nancy; D. Horn, Berlin;
A. Jabra, Baltimore; B. Kammer, Urbana; A. E. Kan, Sidney;
O. H. Kim, Suwon; H. Kitoh, Nagoya; A. Kovanlikaya,
New York; K. Kozlowski, Sidney; K. Kretschmar,
Marshfield; K. Kuo, Chicago; G. Laborte, Bayonne;
R. Lachman, Los Angeles; D. Lassrich, Hamburg; J. Lauzon,
Calgary; S. W. Lee, Seoul; M. LeMerrer, Paris; M. Levine,
Torrance; S. Loh, Bandung; R. Markowitz, Philadelphia;
P. Maroteaux, Versailles; W. McAlister, St. Louis;
P. Meinecke, Hamburg; M. Millar, Chicago; G. Mortier,
Antwerp; S. Nampothiri, Cochin; Dr. Nayanar, Sidney;
H. Ohashi, Saitama; I. Ohyama, Tokyo; J. M. Opitz,
Salt Lake City; H. Pagan-Saez, San Juan; A. Parson,
New Zealand; J. Pina-Neto, Reibeirao Preto; H. Refior,
München; M. Reither, Kassel; A. Richards, Cambridge;
O. Ritting, Salzburg; S. P. Robertson, Dunedin; M. Robinow,
Yellow Springs; S. Sane, Minneapolis; J. Sauvegrain, Paris;
R. Savarirayan, Melbourne; A. Schlesinger, Houston;
D. Sillence, Parramatta; A. Stern, Ann Arbor; C. Stoll,
Strassburg; J. Stolte-Dijkstra, Groningen; L. Swishuk,
Galveston; B. ter Haar, Nijmegen; P. Toering, Odense;
H Toshiyuki Kagawa; M. Uhl, Freiburg; F. Unger, Dayton;
F. van Buchem, Utrecht; H. Vega; P. Verloes, Liege;
R. Winchester, New York; S. Yoo, Seoul; I. W. Young,
Loma Linda.
J.W. Spranger, P.W. Brill, C. Hall, G. Nishimura,
S. Unger, A. Superti-Furga
xiii
 INTRODUCTION
HIS TOR IC AL PERSPECTI VE

SHORT STATURE, DWARFS, LILLIPUTIANS, AND siblings, in accordance with the paternal age effect on de
SUPERSTITIOUS BELIEFS novo FGFR3 mutations). The strong aura surrounding little
people, dwarfs, or Lilliputians is surprising and in contrast
Disorders of bone are part of humankind’s genetic burden.
to the notion that the genetic difference between an indi-
Their existence in prehistory is documented by archaeo-
vidual with achondroplasia (or pseudoachondroplasia, or
logical findings. A large number of paintings, engravings,
spondylo-​epiphyseal dysplasia congenita) and a normal-​
and sculptures depict short-​statured individuals, often in
stature individual is a single nucleotide at heterozygosity.
great detail (Enderle et al., 1994). Individuals with consti-
Although medical descriptions of rare cases can be
tutional diseases of the skeleton attract attention because
found in the seventeenth and eighteenth centuries, it was
of their smaller size, because of deformities, and/​or because
only in the nineteenth century that physicians and scientists
of the disproportion between body parts. Individuals with
began to approach affected individuals more systematically
achondroplasia, a common skeletal short-​stature condi-
and to describe the aberrant growth pattern by observation
tion, have short arms and legs, a head that is usually larger
of anatomy and pathology. In 1878, the French physician
than normal, and a typical facial appearance with a prom-
Parrot described an individual with short-​limb dwarfism
inent forehead and a sunken nasal bridge. They are usually
and coined the name achondroplasia, but in 1886, in his
healthy (at least as children and young adults) and are said
treatise on child diseases, he expressed the belief that achon-
to be witty. Although there are no scientific data to con-
droplasia was a manifestation of congenital syphilis (Parrot,
firm the latter claim, their personal perspective on life
1878, 1886). In 1892, the German pathologist Eduard
may lead to particular insights. Perhaps for these reasons,
Kaufmann studied the macroscopy and pathology of a series
individuals with achondroplasia (along with individuals
of 13 stillborns with what was then called “fetal rickets” and
with other deformities) have often played special social
concluded that there were at least three different patterns
roles in human societies, from being members of royal
of anatomical changes; this was the first recognition of het-
courts to participating in circus shows or other public
erogeneity and attempt at classification (Kaufmann, 1892).
entertainment. Short-​ statured individuals have also fu-
Regarding achondroplasia, it is interesting to note that even
eled the fantasy of writers, and indirectly of the public,
as late as in 1912, the Danish physician Murk Jansen (who
like in Jonathan Swift’s Gulliver’s Travels. The misconcep-
also described the metaphyseal dysplasia that still bears his
tion of a separate race (such that of the Lilliputians) was
name) supported the view that it was due to intrauterine
frequent in the past and still lingers even in the present.
fetal restriction: reduced growth as a consequence of “ex-
Around the turn of the twentieth century, in Paris, there
ternal pressure” applied to the fetus ( Jansen, 1912).
existed an institution called le jardin d’acclimatation where
Around the beginning of the twentieth century, the
short-​statured individuals (with diverse diagnoses ranging
use of x-​rays to investigate medical conditions, particularly
from achondroplasia to growth hormone deficiency) were
those affecting the skeleton, opened the way to the recog-
offered a place to live; perhaps this was an act of charity but
nition of several “new” conditions as defined by their pe-
certainly also one of segregation (Bloch, 1909). The halo
culiar, and sometimes specific, radiographic appearance.
around individuals with short stature, deformity, or dispro-
Among these conditions (the list is not exhaustive by far)
portion has thus stood in the way of a scientific or med-
are osteopetrosis (Albers-​Schönberg, 1904), melorheostosis
ical approach to the definition of their conditions, so much
(Léri & Ioanni, 1922), diaphyseal dysplasia (Camurati,
so that still, in 1886, when the French physician Joseph
1922; Engelmann, 1929), dyschondrosteosis (Leri & Weill,
Marie Jules Parrot described a short-​limbed patient and
1929), osteopoikilosis (Ledoux-​Lebard et al., 1916), Pyle
coined the name achondroplasie, he believed that achon-
disease (Cohn, 1933; Pyle, 1931), infantile hyperostosis
droplasia was a manifestation of rickets and that rickets
(Caffey, 1946), and many others. In 1917, Hunter described
itself was a consequence of hereditary syphilis (Parrot,
two brothers with a “rare disease” affecting the skeleton
1886). As late as 1912, the Dutch orthopedist Murk Jansen
(now known as mucopolysaccharidosis type 2), and in 1919
supported the concept that achondroplasia was caused by
Gertrud Hurler described two unrelated patients with sim-
“amnion-​pressure” ( Jansen, 1912). Another popular be-
ilar features including corneal clouding and mental retar-
lief was that achondroplasia was caused by “weak semen”
dation (later defined as mucopolysaccharidosis type I). In
(this latter belief may have been prompted by the observa-
1929, Luis Morquio reported on a siblingship with a form of
tion that achondroplasia individuals are often the youngest

xv
“familial osseous dystrophy” characterized by platyspondyly
and short trunk (Morquio, 1929); the report was followed
by a large number of related observations, and “Morquio
disease” (now mucopolysaccharidosis type IV) became
the prototypic form of short-​trunk dwarfism. Two distinct
forms of “multiple epiphyseal dysplasia” were described in
1937 (Ribbing, 1937) and in 1947 (Fairbanks, 1947); we
know today that at least six different genetic forms exist.
Identification and delineation of new conditions based on
specific radiographic signs, often in combination with spe-
cific clinical findings, flourished throughout the twentieth
century and still today constitutes the basis for the identifi-
cation of the pathogenic gene(s).
C H R O M O S O M E S , LY S O S O M E S , A N D E N Z Y M E S
The years following World War II saw a rapid advancement
of biochemistry and genetics. Following the implementation
of rickets prophylaxis with vitamin D, hypophosphatasia
was recognized as a “genetic form of rickets” associated with
low alkaline phosphatase activity (Rathbun, 1948). In the
1950s, a new cellular organelle was identified, the lysosome,
that contained a number of different hydrolytic enzymes (de
Duve, 1959; de Duve et al., 1955). This led to the discovery
that some of the previously identified clinical syndromes
were caused by genetic deficiencies of individual enzymes.
In 1952, Brante reported evidence of mucopolysaccharide
material in “gargoylism,” and by 1957, experimental evi-
dence established that Hurler disease was characterized
by impaired degradation of mucopolysaccharides (Brante,
1952; Dorfman & Lorincz, 1957). Biochemistry had
joined the field of genetic skeletal diseases for good. In the
late 1950s, the correct number of chromosomes in humans
was finally determined; this triggered the recognition of
the aneuploidies (trisomies 21, 13, and 18, monosomy X,
and others) in rapid sequence. With chromosomes and
enzymes, laboratory tests could help medical geneticists
and pediatricians confirm a diagnosis and explore the phe-
notypic variability of the individual disorders. Thanks to
these advancements, the field of medical genetics gained at-
tention and importance.
THE GOLDEN 1960S
The discovery of chromosomal and biochemical bases for
their clinical observations must have reassured pediatricians
and geneticists that what they were observing was real,
and this freed their minds. It was no longer necessary
to be conservative by forcing different observations into
one category; whereas the 1950s were still hesitant and
saw new entities such as “recessive achondroplasia” and
“pseudoachondroplasia,” the 1960s saw the full delinea-
tion of achondroplasia (Maroteaux & Lamy, 1964; Langer
et al., 1967) and flourished with newly recognized entities
xvi
that were given new names, such as diastrophic dysplasia
(Lamy et al., 1960), familial metaphyseal dysostosis (Spahr
et al., 1961), cartilage-​hair hypoplasia (McKusick et al.,
1965), spondylo-​epiphyseal dysplasia congenita (Spranger
& Wiedemann, 1966), tricho-​ rhino-​phalangeal syn-
drome (Giedion, 1966), metatropic dysplasia (Maroteaux
et al., 1966), spondylometaphyseal dysplasia (Kozlowski,
Maroteaux, & Spranger, 1967), and more (the list is ar-
bitrary and not exhaustive). This freedom to recognize
genetic disorders in the 1960s culminated in the Birth
Defects Conferences, a first series of which was organized
between 1969 and 1971 at the Johns Hopkins Hospital;
the proceedings, two of which are dedicated to dysostoses
and skeletal dysplasias, are still a pleasure to read because of
the richness in new observations as well as the freshness of
the presentations and discussions.
ATLASES AND CLASSIFICATIONS
In 1951, the British orthopedic surgeon Thomas Fairbank
published an Atlas of Generalized Affections of the Skeleton
(Fairbank, 1951). Sir Fairbank was interested in genetic
bone disorders; in 1947, he had described a form of “dys-
plasia epiphysealis multiplex” (Fairbank, 1947). Although
rudimentary by today’s standards, this work was a milestone
in the development of the field of constitutional disorders
of bone. In 1961, Pierre Maroteaux and his mentor
Maurice Lamy published a monography on “genotypic
chondrodystrophies” (Maroteaux & Lamy, 1961). Unlike
the Fairbank atlas, this work did not discuss all genetic skel-
etal conditions but was focused on the “chondrodysplasias.”
The Maroteaux and Lamy classification included eight dif-
ferent groups of bone dysplasias. The literature index of
the monograph lists an impressive number of case reports
from the nineteenth century to the 1950s, demonstrating
the abundance of case reports but also the lack of a system-
atic approach. In 1964, the radiologist Philip Rubin from
Rochester University published his Dynamic Classification
of Bone Dysplasias (Rubin, 1964). Although some of the
diagnoses have changed (e.g., rhizomelic chondrodysplasia
punctata was called “congenital multiple epiphyseal dys-
plasia”), the book was remarkable because it classified
disorders based on the “dynamic pathogenesis” with
speculations on what physiologic process on bone growth
and remodeling was affected. Extensive correlations were
made to what was known at the time about bone modeling.
Rubin modestly wrote that the success of his book would be
measured paradoxically by the rapidity in which its content
would become outdated. In 1974, Jürgen Spranger, Len
Langer, and Hans-​Rudolph Wiedemann published their
Bone Dysplasias: Atlas of Constitutional Disorders of Skeletal
Development, an extensive atlas that was based on the corre-
lation of radiographic, clinical, and genetic data to delineate
conditions (Spranger et al., 1974); in 1975, the radiologists
I ntroduction
Hooshang Taybi and Ralph Lachman published their
Radiology of Syndromes and Skeletal Dysplasias (Taybi
and Lachman, 1975). Both the Spranger and the Taybi-​
Lachman books have been revised periodically and are in
their fourth and fifth editions, respectively.
NOMENCLATURE AND NOSOLOGY
Contemporary to the description of well-​defined disorders
in the late 1950s and 1960s, it became clear that much confu-
sion had been caused by the inhomogeneous denomination
of entities. Clinically different disorders had been reported
under the same name (e.g., “chondrodystrophy”), and indi-
vidual disorders had been reported under different names.
In 1969, in the wake of the Birth Defects Conference on
Skeletal Dysplasias, a group of experts (mainly radiologists)
convened in Paris in 1970 to prepare an “International
Nomenclature of Constitutional Diseases of Bones,” a list
of conditions grouped by their main radiographic or clin-
ical features. This “Paris nomenclature,” compiled by one of
us ( JS), was so welcome that it was published, with minor
variations and comments, in at least five different journals
(e.g., Kozlowski et al., 1969). The 1970 nomenclature un-
derwent revisions in 1977, 1983, 1992, 1997, 2001, 2005,
2010, and 2015 (see Bonafe et al., 2015; Superti-​Furga
et al., 2007; Warman et al., 2011). Following the founda-
tion of the International Society for Skeletal Dysplasias
(ISDS) in 1999, the revisions were prepared by an ad hoc
group within the ISDS; the term nomenclature has been
replaced with nosology. The 2015 revision contains over 450
distinct entities. Notably, recent revisions of the Nosology
have included more dysostoses to reflect the fact that there
is often a common genetic basis, that elements of dysostosis
and dysplasia may occur in the same condition, and that
patients with dysplasias or dysostoses are often seen in the
same clinic. The Nosology should help in the delineation
of new conditions by providing a list of those conditions
that have been recognized as distinct entities on clinical,
radiographic, and genetic grounds. Notwithstanding the
many ties of friendship between the Nosology experts and
the late Victor A. McKusick and the subsequent curators
of the MIM catalogue, there are inconsistencies between
the Nosology and OMIM due to the fact that while OMIM
grows rather appositionally, the Nosology committee does
more pruning of obsolete entities.
Molecular data and the clinical-​ radiographic
classifications: There have been times when skeletal dys-
plasia experts suffered from a dubious reputation. For many
colleagues, it seemed hard to believe that there was a ra-
tionale for preparing long lists of very rare conditions with
Greek-​derived names. Yet, cell biology, biochemistry, and
molecular genetics have confirmed the work of the clinical
and radiographic “stamp collectors”: there is an extraordi-
nary variety of molecular mechanisms at the basis of skeletal
I ntroduction
conditions. Morphogenesis, development, growth, and ho-
meostasis of the skeleton and its over 200 distinct elements
is a complex mechanism with many levels of integration
and control, and because of our ability to recognize mor-
phologic changes in children and adults, as well as in bones
on radiographs, the skeleton is a sensitive reporter. Thus,
whereas biochemical bases of genetic bone disease (such as
the many forms of genetic rickets or the lysosomal storage
disorders) were identified in the 1960s, the 1970s and early
1980s saw the first evidence of “molecular pathology” with
the collagens (collagen 1 and osteogenesis imperfecta, col-
lagen 3 and the Ehlers-​Danlos syndrome type IV, and col-
lagen 2 and chondrodysplasias), and the late 1980s (thanks
to the possibility of molecular cloning and then, particu-
larly, the polymerase chain reaction technique) saw the
underlying gene mutations unravel. In 1983, a multi-​exon
deletion in COL1A1 was identified in lethal osteogenesis
imperfecta (Chu et al., 1983); in 1988, a multi-​exon dele-
tion in COL3A1 was identified in Ehlers-Danlos syndrome
type IV (Superti-​Furga et al., 1988) (not a skeletal condi-
tion, but the “collagen field” was united at that time); and
in 1989, a single-​exon deletion was identified in a family
segregating congenital spondylo-​epiphyseal dysplasia (Lee
et al., 1989). At the time, exon deletions were easier to iden-
tify by southern blotting, while single nucleotide variations
necessitated extensive cloning and sequencing. In 1986, a
heterozygous single nucleotide substitution in COL1A1
was identified as the cause of lethal osteogenesis imperfecta
(Cohn et al., 1986); rapidly, glycine substitutions in the
triple helical domain of collagen type 1 were established as
the main cause of severe osteogenesis imperfecta. In 1988,
a homozygous point mutation in the TNSALP gene was
identified as the cause of lethal hypophosphatasia (Weiss
et al., 1988). The 1990s surprised us with the notion that
the genes at the basis of skeletal diseases were not only struc-
tural proteins or enzymes but frequently genes involved in
signaling pathways and in transcription regulation, such
as FGFR3 or CBFA1/​RUNX2 (Hermanns et al., 2001).
A first molecular-​pathogenetic classification was drafted
(Superti-​Furga et al., 2001). Ever since, there has been a
constant flow of new gene-​phenotype identification; while
a small number of genes may account for a large propor-
tion of individuals with genetic skeletal conditions, rarer
associations are still being found on a monthly basis. As an
example, the majority of cases of osteogenesis imperfecta
are determined by mutations in COL1A1 and COL1A2
but no less than 20 other genes can produce a brittle bone
phenotype, although the number of cases is much smaller.
In general, molecular data have determined some degree of
“lumping,” that is, the regrouping of conditions sharing a
similar pathogenesis; but, on the other hand, the data con-
tinue to reveal extensive heterogeneity and to identify novel
conditions, leading to “splitting” and thus to a steady in-
crease in the number of conditions listed in the Nosology.
xvii
 Genetic disorders of bone and their contributions to ge-
netics and medicine: In many ways, the skeletal field has had
a pioneering role in medical genetics by contributing fun-
damental concepts. Among these are the observation that a
single nucleotide substitution at the heterozygous state may
result in a lethal phenotype (lethal osteogenesis imperfecta,
lethal collagen 2 dysplasias) (Cohn et al., 1986); the con-
cept of “protein suicide,” precursor to the concept of “dom-
inant negative” (Prockop 1984); the concept of functional
topology of a molecule (different mutations in COL1A1
giving different phenotypes because they affect different
functional domains); the formulation of the concept of
disease families with mild to severe manifestation arising
from the same gene (collagen 1, collagen 2, COMP, and
FGFR3) (Spranger, 1988); the observation of gonadal mo-
saicism as the explanation of affected siblings born to clini-
cally unaffected parents (again COL1A1 mutations) (Cohn
et al., 1990); the discovery of highly recurrent mutations
such as the “achondroplasia mutation” G380R in FGFR3
that occurs at the nucleotide with the highest mutation
rate known in the human genome (Rousseau et al., 1994;
Shiang et al., 1994); and the demonstration that they occur
almost exclusively of paternally derived alleles, highlighting
the paternal age effect (Wilkin et al., 1998). These concepts
that are firmly accepted today were pioneered by the “bone
dysplasia” field.
The changing diagnostic scenario: The approach to di-
agnosis does in part reflect the history of the delineation
of disorders. Thus the diagnosis of constitutional skeletal
disorders still relies mainly on the meticulous analysis of
skeletal radiographs. Correlation with the clinical data
(growth curve, clinical findings, history of fractures or
pain, other specific features) is essential. Biochemical evi-
dence may be diagnostic (e.g., calcium or phosphate imbal-
ance, or reduced activity of a specific enzyme). Molecular
genetic confirmation has long been the last step in the
process. The power of massive parallel sequencing and its
increasing affordability has changed this scenario drasti-
cally. The analysis of gene panels (e.g., a “dysplasia panel,”
“bone fragility panel,” or “chondrodysplasia punctata
panel”) has already replaced single-​gene analysis in most
instances. Even broader approaches, such as that of exome
sequencing, are already being used as first-​line tests. With
further reduction in sequencing costs, a “genotype first,
phenotype later” approach may be implemented soon.
Is the time of careful analysis of clinical features and
radiographs lost forever? Probably not, but the approach
will be changed. The so-​called reverse phenotyping (i.e., to
verify whether the patient’s features [clinical, radiographic,
or biochemical] do fit with a genotype identified by unbi-
ased sequencing) needs as strong an expertise as the a priori
generation of a diagnostic hypothesis. The findings from
massive sequencing will confront the genetic physician with
“common” genetic disorders but also with rare, ultra-​rare,
or even private conditions; no literature will be available (at
xviii
least not for some time) for guidance. Sensitive and accu-
rate sequencing, large databases, and precise bioinformatics
prediction tools will be needed as much as clinical observa-
tion skills and acumen.
Old and novel therapeutic approaches: Whereas the ex-
ploration of the pathogenetic bases of skeletal dysplasias
has been fascinating, the therapeutic fallout has followed at
a much slower pace. Well-​structured observational studies,
providing much needed information on the natural history
of each disorder and its complications, are available only for
the more common conditions. Because surgery is so diffi-
cult to standardize, there is no high-​level evidence on the
risk and benefit of most surgical interventions in individuals
with skeletal dysplasias. For some conditions, knowledge of
the molecular pathogenesis has resulted in the development
of specific medical interventions. Several of the lysosomal
storage diseases are now amenable to enzyme replacement,
substrate reduction, or both (although the skeletal system
is less likely to benefit from these treatments than other
organs). Enzyme replacement therapy in hypophosphatasia
is highly effective and beneficial (Scott, 2016). Several dis-
tinct approaches are being studied to counteract increased
FGFR3 signaling in achondroplasia and related conditions
(e.g., guanyl cyclase activation by a long-​lived C-​Natriuretic
Peptide analog [Lorget, 2012, #63]), modulation of FGF
signaling with a soluble “decoy” FGFR3 receptor (Garcia
et al., 2013), and specific inhibitors to inhibit the tyrosine
kinase activity of FGFR3 (Komla-​Ebri et al., 2016)). In oste-
ogenesis imperfecta and other conditions with fragile bones,
the use of bisphosphonates, which is moderately effective,
should soon be accompanied, or replaced, by approaches
that target the overall bone architecture (such as sclerostin
antibodies; Simsek Kiper et al., 2016; Jacobsen, 2017).
Our evolution in understanding the pathogenesis of
the skeletal dysplasias has undergone rapid changes in
the past few decades. These studies have unearthed key
concepts in genetics. They have also demonstrated the im-
portance of properly naming a condition in order for it to
be recognized by scientists, doctors, and patient advocacy
groups. We are cautiously optimistic that these steps along
a long and winding road will lead to therapeutic advances
for our patients.
U NDE R S TANDING DYS PLAS IAS
AND DYS OS T OS E S T H ROU GH
T H E C OMB INAT ION OF C LINIC AL,
PAT H OGE NE T IC , AND MOLE C U LAR
C R IT E R IA
The conditions included in the Nosology (many of which
are described in this book) are clinically and molecu-
larly heterogeneous. They include dysplasias, dysostoses,
osteolyses, and a few disruptions. Their distinction is essen-
tial, both from a biological and a practical viewpoint. The
I ntroduction
original version of the Paris Nomenclature for Constitutional
Disorders of Bone published in 1970 defined dysostoses as
“malformations of individual bone, singly or in combina-
tion” and osteochondrodysplasias as “abnormalities of carti-
lage and/​or bone growth and development.” This essentially
clinical definition predated the more general distinction,
drawn by an international working group on concepts and
terms of errors of morphogenesis, between malformations
and dysplasias (Spranger et al., 1982). Here, a malformation
was defined as a “morphologic defect of an organ, part of an
organ, or larger region of the body resulting from an intrin-
sically abnormal developmental process.” Thus, the terms
dysostosis and skeletal malformation name the same aberrant
developmental category. It was also noted that a malforma-
tion could result from the extrinsic disturbance of normal
development. Such a “secondary” malformation resulting
from “the extrinsic breakdown of, or an interference with, an
originally normal developmental process” was called a disrup-
tion. A dysplasia was defined as the “abnormal organization
of cells into tissue(s) and its morphologic result(s).” Applying
these broader concepts to the skeletal system, the constitu-
tional errors of bone development can be defined as follows:
• Dysostoses are malformations of single skeletal elements,
alone or in combination.
• Disruptions are malformations of bones secondary to
nonskeletal causes.
• Skeletal dysplasias are developmental disorders of
chondroosseous tissue.
• Osteolyses are regressive disorders which permanently
reabsorb and dissolve preexisting bone.
Advances in developmental genetics now provide the bio-
logic bases for this distinction.
FORMATION OF SKELETAL ELEMENTS
Bone formation starts with the patterning of cells.
Transcription factors are produced that regulate the ex-
pression of genes. Families of genes cooperate to provide
programs that govern the patterning process. Signaling
proteins and other substances, such as retinoic acid, are
produced that diffuse from cell to cell and form gradients
that convey positional information through receptors. Thus
embryonic cells are instructed about their relative position
and influenced to differentiate with regard to that position.
Together, these orchestrated signal loops involving tran-
scription factors and signaling molecules regulate the prolif-
eration, migration (including mesenchymal condensation),
differentiation, in some cases the apoptosis, and, finally, the
function of individual cells. During organogenesis—​that
is, during the first eight weeks of human gestation when
cells segregate into cell groups and tissues into primordia
I ntroduction
that will form future organs—​transcription factors and
signaling pathways are instrumental in the formation of
single organs and specific tissues. Examples are WNT7a
and TBX15, deficiency of which leads to severe dysostosis
of the extremities or of the shoulder and pelvis, respectively.
These genes are responsible for the “blueprint” of the skel-
eton: proper formation, size, and position of one or more
skeletal elements. Other signaling factors, like the fibroblast
growth factor receptors, are activated at subsequent stages
of embryogenesis and continue to be expressed in post-
natal life. A third group of signaling factors is active from
the period of organogenesis to adult life. To this group of
factors belong the runt transcription factor, RUNX2, and
the cartilage-​derived morphogenic protein I, CDMP1 (also
called GDF5). Finally, many genes are not essential for the
patterning and development of the blueprint of skeletal
elements but are crucial to the differentiation and function
of cartilage cells or bone cells, or to the growth and develop-
ment of cartilage and bone as tissues. From these differences
in the time and duration of expression, several axioms can
be deduced and applied to skeletal development.
DYSOSTOSES
Many transcription factors are expressed only for a limited
period of time during embryogenesis. Genes are turned on
and off. In limb development, for instance, 3’ HOX genes
are expressed early in development controlling anterior re-
gions of the limb. 5’ HOX genes are expressed later and
control more posterior regions. A series of genes are respon-
sible for embryonic segmentation and for the development
of vertebrae and ribs. Defects of transcription factors or of
signaling factors, which are only transiently expressed during
early embryogenesis, result in finite organ defects (i.e., in
malformations). Dysostoses are malformations or, in other
words, manifestations of defective skeletal organogenesis
(Figure 1.1). They are finite, because of the transient nature
of the defective process. They may occur singly, in combi-
nation, or as part of pleiotropic disorders if the controlling
gene is expressed in many organ systems. Examples of known
signaling defects leading to dysostoses are summarized in
Table 1.1. Clinically, dysostotic lesions may be asymmetrically
distributed, notably in the disruptive forms (see later discus-
sion). The chondroosseous histology is normal. Dwarfism is
not a primary manifestation unless bones of the vertical body
axis or bones of the limbs are defective or missing.
DISRUPTIONS
Similarly to transiently expressed transcription factors or
signaling genes, toxic substances or infectious agents may
act on the embryo for limited periods of time. They produce
secondary malformations, not dysplasias. Thalidomide and
rubella embryopathies are prime examples. Mechanical
factors may also result in disruptions, the most prominent
xix
Another random document with
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 “Sorry I can’t let you out in the sunshine,” said Tate. “But if you
behave yourselves to-day maybe we’ll let you out to-morrow.”
“Is Davenport in command here?” questioned Jack.
“He’s our leader, yes.”
“Tell him I want to talk to him.”
“He’s gone off and he won’t be back until this afternoon.”
After that the hours dragged by more slowly than ever. The boys
chafed under the restraint but could not think of a single thing to do
to better their condition.
“I wonder if we can’t push some of those logs apart and squeeze
through the opening somehow,” whispered Fred after the breakfast
had been disposed of. “Maybe some of the chains are not as tight as
they look.”
With the coming of day the light in the cave had grown brighter.
With this, and also the lantern to aid them, the four lads set to work
and examined the logs and the chains minutely. As they did this they
watched the opening to the cave so that no one might notice what
they were doing. But none of the gang that had made them captives
appeared.
At first the case looked hopeless and the boys were filled with
despair. But then Andy noticed where one of the chains seemed to
have slipped down over a notch in one of the logs. This was pried up
and by their united efforts the boys were finally able to move the top
of one of the logs a distance of six or eight inches.
“There! I’m sure that opening is wide enough to let a fellow out,”
declared Fred. “Anyhow, I am sure I could get through it.”
“We could all get through if we could get up there,” returned Jack.
The widened opening between the logs was a foot or two above his
head.
It was here that their gymnastic exercises stood the boys in good
stead. Jack quickly managed to place himself on Randy’s shoulders
and then squeezed his way through the opening between the logs.
Fred and Andy followed, and then those outside gave Randy a hand
up, and presently all four of the lads stood outside of what had been
their prison.
“Now what shall we do—make a rush for it?” whispered Fred.
“Wait a minute. I’ll see how the land lies,” announced the young
major, and while the others waited he crawled cautiously to the
entrance of the cave and peered out between the bushes.
The others waited with bated breath wondering what would
happen next. Half a minute passed and then Jack tiptoed his way
back to his cousins.
“Tate and Jackson are out there, smoking their pipes and resting
on the ground,” he announced. “Each has a gun handy. They are
about fifty feet from the entrance to the cave.”
“Are they looking this way?” asked Randy.
“Yes, both are facing the entrance to the cave.”
“Have they got their guns in their hands?” questioned Fred.
“No, their guns are resting against a tree near by.”
“Then why can’t we make a dash for it?” asked Andy recklessly.
“I don’t think we’ll have to do that,” answered the young major.
“I’ve got another plan.”
 CHAPTER XXVIII
TRYING TO ESCAPE

In a whisper so that the two men outside of the cave might not
hear him, Jack outlined his plan for escape.
“The bushes on the left of the entrance are very thick and extend
outside for ten or fifteen feet. There are also several bushes just in
front of the entrance that are a foot or more high. If we can crawl out
in snake fashion maybe we can get into those bushes and work our
way along until we reach some spot where we shall be out of line of
their vision. Then, as soon as we get that far, we can leg it for all we
are worth.”
“Gosh, Jack, I hope we can do it!” returned Randy. “Come on, let’s
try at once. Those fellows may take it into their heads to come into
the cave any time.”
All were more than willing to make the attempt to escape, even
though they realized that the men watching them were desperate
characters and would not hesitate to use their firearms if they
thought it necessary.
The four boys approached the entrance of the cave with caution,
dropping flat on their stomachs as they did so. Then, led by Jack,
one after another wormed his way along until the bushes screening
the opening were reached.
“Now be careful,” warned Jack. “Don’t shake the bushes too much
or those men will get suspicious. It may pay to go slow. And don’t
make any noise.”
As silently as Indians on a hunt the four boys began to worm their
way through the bushes at the side of the cave opening. This was no
easy task, for there was always danger of cracking some dry twig or
of shaking the tops of the bushes unduly. They could hear the men
talking earnestly and even heard Jackson knock out his pipe against
a tree.
“As soon as I get my hands on the dough I’m going to light out for
Mexico,” they heard Jackson tell Tate. “That’s the safest place to
hide.”
“Maybe it is,” they heard Tate answer. “But I don’t like to live
among those Greasers. I’ll try my luck up in the Northwest. I don’t
think anybody will try to follow me to where I’m going.”
“Do you think the Rovers will come across, Tate?”
“Sure, they will! They’ll pay up to the last dollar! Davenport will
make ’em do it!”
“But suppose they balk?”
“Then Davenport will send ’em a finger or an ear. That will surely
bring ’em to terms mighty quick.”
“Would he go as far as that?”
“Davenport? You don’t know the man! He’d go a great deal further
if he thought it would bring him in any money. That fellow is about as
cold-blooded as they make ’em.”
Every one of the boys heard this talk, and it made them feel
anything but comfortable. Evidently the scoundrels who had made
them captives would stop at nothing to accomplish their ends.
Presently Jack found himself confronted by a big rock that stuck
up almost to the top of the bushes. As silently as a cat after a bird,
he crawled over this rock, and one after another the others followed.
Then came a series of rocks and more brushwood, and at last the
four lads found themselves out of sight of Tate and Jackson.
“Which way are you going to head?” questioned Randy when he
thought it was safe to speak.
“I don’t know,” was the whispered reply. “The main thing is to get
out of reach of those fellows. Come on—don’t lose any time. If they
discover our escape they’ll do their best to round us up again.”
 Without knowing where they were going, the four boys plunged on
through the bushes and over the rough rocks until they came to a
narrow trail running along the mountainside.
“I think we’re heading for Sunset Trail,” announced Fred. “And if
we are, so much the better.”
“If we see or hear anybody coming jump behind the trees or
bushes,” ordered Jack. “We might run into Davenport. They said he
had gone off on some sort of an errand.”
The boys pushed on for several hundred feet, and there found that
the trail came to an end at a spring of water which gushed forth from
between several rocks. Beyond this point was a heavy mass of
practically impenetrable forest.
“Doesn’t look as if we could go any farther in this direction,”
remarked Andy, his face falling as he gazed around.
“No. I guess we’ve got to go back,” answered the young major.
“Wait a second. I’m going to have a drink,” cried Fred, and bent
down to partake of the clear, cool water of the spring.
All were thirsty, and they spent a full minute in refreshing
themselves. They were just turning away from the spring when they
heard a shout followed presently by three gunshots in rapid
succession.
“They’ve discovered our escape and that’s a signal to warn the
others!” ejaculated Jack. “Now we’ve got to be careful or they’ll catch
us sure.”
How to turn the boys did not know. They could not go ahead, and
they did not want to backtrack on the trail for fear of running into
some of their enemies. To climb the mountainside was practically
impossible, and it looked almost as dangerous to attempt to descend
between the uncertain rocks and dense brushwood.
“Well, it’s suicide to stay where we are,” was the way Andy
expressed himself.
“Can’t do it,” added his twin.
 “Unless I’m mistaken, I can see some sort of a trail below us,”
announced Jack. “Look there and tell me if I am right.”
All gazed in the direction indicated and came to the conclusion
that there was another and better trail about a hundred yards below
them. Then one after another they began the perilous descent
between the rocks and bushes.
All went well for a distance of sixty yards. Then Randy slipped and
his twin almost immediately followed. Jack was ahead of them, and
in a twinkling they took the young major off his feet. Fred made a
wild clutch to stop Andy, and as a consequence he, too, began to
slide. All of the boys went down with a rush, carrying several small
bushes with them. They slid over the rocks and a number of loose
stones, and finally brought up in a hollow, some small stones rattling
all around them as they did so.
“Wow! Talk about your toboggans!” gasped Randy, when he could
speak. “I guess I came down at the rate of half a mile a minute.”
“Anybody hurt?” sang out Jack. He himself had scratched his
elbow, his ear and one of his knees.
All of them were scratched and bumped, but not seriously, and
they stood up quickly, brushing themselves off and gazing around to
find out where they had landed.
“Look!” cried Jack, pointing. “If that isn’t Sunset Trail over there
then I miss my guess! What do you say?”
“It sure is! And yonder is Longnose’s cabin,” answered Fred.
“Out of sight! All of you!” came quickly from Randy. “There is
Davenport and a couple of others with him!”
One after another the Rover boys tried to hide behind such rocks
and bushes as were available. But their movements came to little.
They were discovered by one of the men with Davenport, and that
individual immediately set up a cry of alarm. Then the men, led by
Davenport, came riding toward the spot as rapidly as the condition of
the trail permitted.
 “Stop where you are!” yelled the man from the oil fields. “Hands up
and stop, or it will be the worse for you!”
The boys heard the rascal but paid no attention to his threat. They
did their best to lose themselves in some bushes below the spot
where they had landed. But the way was rough and uncertain and
one after another they took another tumble, to find themselves at last
hopelessly tangled up in a mass of brushwood.
“You can’t get away from us, so you might as well give up,” yelled
Davenport as he rode as close as the brushwood and rocks would
permit. “Come out of there one by one. If you don’t, we’ll use our
guns.”
Seeing that all of the men were armed, the boys knew it would be
useless to attempt to go farther, and so one by one they came out of
the tangle of rocks and brushwood, their clothing torn and their
hands bleeding from their rough experience. Fred was the first to
emerge, and, telling his companions to “keep all of the rats covered,”
Davenport dismounted and caught the youngest Rover by the arm.
“Thought you’d get away, eh?” snorted the oil man, an ugly look
crossing his face. “I reckon we let you have too much liberty. After
this I’ll see to it that you won’t get a yard from where we place you.”
All of the boys did their best to argue with Davenport, but the oil
man would not listen to them, and in the end they were compelled to
march along the trail as it wound in and out along the mountainside,
at last reaching a camp close to where the cave in which they had
been prisoners was located. At the camp they fell in with Tate and
Jackson, who had been looking everywhere for the lads.
“How did they get away?” stormed Davenport.
“Don’t know,” answered Tate. “We haven’t made an inspection of
the cave yet. They must have crawled through some kind of a hole.”
The cave was entered, and soon the rascals discovered how two
of the logs had been pried apart at the top.
“After this we’ll have to guard ’em! That’s all there is to it!” declared
Davenport. “Why, if we hadn’t been lucky enough to spot ’em, they’d
have gotten away sure.”
“See here, Davenport! what’s the meaning of this, anyway?”
questioned Jack, putting on as bold a front as he could.
“Hasn’t your father already told you what I intend to do?”
demanded the oil man.
“He told me you demanded a lot of money of him.”
“So I did, Jack Rover. And I intend to get it—a whole lot of money.”
“And I suppose you want some money out of my father too,” put in
Fred.
“That’s right!” answered Tate. “If you want to know some of the
particulars I’ll tell you. We’re asking fifty thousand dollars for the
release of Jack Rover, fifty thousand dollars for the release of Fred
Rover and fifty thousand dollars for the release of Andy Rover and
Randy Rover. That’s a hundred and fifty thousand dollars for the
bunch.”
“Huh! Then you think my two cousins are worth twice as much as
my brother and I, eh?” asked the irrepressible Andy, with a faint grin.
“Pah, Andy Rover! Don’t make fun of it!” snarled Davenport. “It’s
nothing to laugh at. If you don’t like the price we’ve put on you and
your brother we can easily raise it to fifty thousand apiece.”
“That’s the talk!” cried Tate. “Then we’d have fifty thousand dollars
more to divide between us,” and he smiled wickedly.
“This high-handed proceeding may get you in hot water,
Davenport,” said Jack.
“I’m willing to take the risk. Now that we’ve got you again I’ll see to
it personally that you’ll never get back to your folks again until that
money is paid.”
“Suppose our folks can’t raise the money?” questioned Fred.
“I happen to know that they can raise it,” answered the oil man.
“Your folks are rich. They have made barrels of money out of their
transactions in Wall Street and in the West and down in the oil fields.
They can pay that hundred and fifty thousand dollars easily enough,
and they are going to do it.”
“Have you already made a demand for the money?” asked Randy.
“We have.”
“Well, if they won’t pay it, what then?” questioned Andy.
“Then we’ll put the screws on you boys until you send word to your
folks that they’ve got to pay.”
“And if we won’t send word, what then?”
“Oh, you’ll send word all right enough before we get through with
you,” replied Davenport suggestively.
Then the boys were hustled back into their prison and additional
chains were placed upon the logs. After that a regular guard was
stationed at the entrance to the cave, so that another escape would
be impossible.
 CHAPTER XXIX
ANOTHER DEMAND

A week dragged wearily by and the four Rover boys still found
themselves prisoners of Carson Davenport and his gang.
During that time they had been given no chance to escape. For
two days they were kept in the close confinement of the cave and
after that they were taken out each day for several hours so that they
might enjoy the fresh air and the sunshine. But when this was done
each had his hands tied behind him and was fastened by a rope to
one of the trees while not less than two of the men sat near by, guns
handy, to guard them.
“Gee, we couldn’t be any worse off if we were in a regular prison,”
was the way Randy expressed himself.
“If we were in a regular prison I think the food would be better,”
answered Fred.
For the first three days the food supplied to them had been fairly
good. But now it was becoming worse every day. That morning they
had had the vilest of coffee and bread that was musty and old, and
the previous evening the stew offered to them had made the twins
sick.
They were satisfied that Davenport and his crowd were negotiating
with not only the twins’ father but with the fathers of Jack and Fred.
But they were given only a slight inkling of how matters were
progressing. Then they heard the oil man tell Jackson and Tate that
he expected Booster to arrive soon.
“And as soon as he comes we’ll put the screws on the boys. That
will bring their folks to terms,” said Davenport.
The next day the fellow called Booster put in an appearance, and
despite the wig he was wearing the boys to their surprise recognized
the young man who had introduced himself as Joe Brooks. The
confidence man smiled grimly when Jack spoke to him.
“I fooled you kids pretty neatly, didn’t I, in New York and in
Chicago?” said Joe Booster, for that was his real name. “You never
suspected that I was in with Davenport, did you?”
“Then you don’t know Fatty Hendry at all, do you?” put in Andy.
“Oh, I met him once,” answered the confidence man carelessly. “I
palmed myself off as a friend of one of his cousins and got him to
lend me ten dollars. That was when I was pretty well down on my
uppers.”
Davenport, Tate, Jackson and Booster had a long conversation
and then the four rascals came again to the boys.
“Well, how are you making out?” asked Booster pleasantly. “They
give you pretty good grub, don’t they?”
“No, it’s getting worse every day,” answered Fred bluntly.
“Why, I thought they were giving you genuine mocha coffee,” went
on the confidence man.
“Giving us dishwater!” retorted Andy.
“And fine stew, too!”
“It made me sick yesterday,” came from Randy.
“Well, you listen to us,” put in Davenport. “Unless you’re willing to
do what we want you to, the grub is going to be a good deal worse
instead of better. More than that, we’ll keep you in the cave all the
time.”
“What is it you want us to do?” questioned Jack, although he
already had an idea on that subject.
“We want all of you boys to write a letter to your fathers, stating
that they had better pay the money that we have demanded of them
and that otherwise you are afraid of what may happen to you. You
can tell them that so far you have had the best of food and the best
of treatment generally, but that you have been threatened with
starvation if the money isn’t forthcoming. We want all of you to make
that letter just as strong as you can. You write the letter,” he went on,
pointing to Jack, “and all of you sign it with your full names, so that
your folks will know it’s a genuine communication.”
“Excuse me, Davenport, but I’m not writing any such letter,”
declared Jack flatly.
“Neither am I,” put in Fred.
“Nor I,” added the twins in concert.
“You will write it!” bellowed Davenport, his anger rising swiftly. “If
you don’t write it I’ll give each of you a horsewhipping.”
“That’s the talk!” cried Tate.
“Give ’em a licking and no supper,” added Jackson.
“I don’t think you’ll have to whip ’em,” came from Joe Booster, who
did not believe in violence of any sort. “Just let ’em go without their
supper, and their breakfast to-morrow morning. Maybe then they’ll
sing a different tune.”
“I owe ’em a licking for all the things they’ve done against me,”
growled Davenport.
“Never mind. It will be enough after we get hold of that money,”
returned Booster. “Just cut ’em off from the eats. That’s the way you
can bring anybody to terms. I’ve tried it before, and I know.”
“All right then,” said the oil man shortly. And then he and his
cronies left the cave.
“Well, they’re a nice bunch, I don’t think!” came from Andy, when
the four boys found themselves alone.
“Going to starve us, eh?” muttered Fred. “Do you think they’ll dare
do it?”
“It looks to me as if they’d dare to do anything,” came from Jack.
“Gee, it’s too bad we didn’t make our escape when we had the
chance.”
 Randy looked toward the entrance of the cave to make certain that
all of the men had departed.
“Let’s try to get away again to-night,” he whispered. “It’s our one
hope.”
“I hope our dads don’t turn over that money to them,” went on
Jack, his eyes flashing angrily. “That bunch oughtn’t to have a
hundred and fifty cents, much less a hundred and fifty thousand
dollars. Such a demand is the worst kind of a hold-up.”
“Well, such demands have been made before, and the money has
been paid, too,” answered Fred. “Don’t you remember that case of
the fellow that was held by the bandits in Algeria, and the case of the
two girls who were held by the Mexican bandits? Their folks had to
come across. Otherwise those people would have been put out of
the way.”
Supper time came, but no food was brought to the boys. They,
however, were given a bucket of drinking water by Ocker.
“Davenport didn’t want you to have this,” whispered the man, as
he handed the water in. “But I told him I wouldn’t stand for letting you
kids go thirsty. It’s bad enough to make you go without the eats.”
“Thank you for so much sympathy anyhow, Ocker,” returned Jack,
and then went on quickly: “Why does a nice fellow like you stand in
with such a bunch as Davenport’s crowd? Why don’t you cut them
and help us to get away? We can make it well worth your while.”
“I wouldn’t dare do it, Rover,” muttered the man. “They’d never
forgive me, and they’d be sure to get me sooner or later. I’m kind of
sorry that I stood in with ’em, just the same,” and then, as Tate
appeared at the entrance of the cave, Ocker walked away hastily.
“Gee, maybe we can work on that fellow’s sympathies and get him
to help us,” was Randy’s comment.
“Maybe if we make him a worth-while offer he’ll help us to escape,”
put in his twin. “Even if they got the money from our folks it isn’t likely
that Davenport, Tate and Jackson, along with that Booster, would let
Ocker or Digby have any great amount of it.”
 The boys wondered what their folks were doing. Of course, they
knew nothing about Dick Rover and Sam joining Tom in Maporah.
Davenport, through Booster, had kept a close watch and reported
the arrival at Maporah of the fathers of Jack and Fred. Thereupon a
demand had been made upon the three older Rovers for the money,
which was to be paid in cash. It was to be placed in a package under
a tree along Sunset Trail, and the Rovers were to take care that no
one was to be in that vicinity during the night or early morning under
penalty of an attack from ambush. As soon as the package was
safely received by the Davenport crowd the four boys were to be
released and set on their way toward Gold Hill.
“Those fellows certainly know what they want,” said Sam Rover to
his two brothers. “What are we to do about it?” All efforts to locate
the boys had failed and their fathers were frantic, not knowing how to
turn or what to do next.
In the meantime Mr. Renton and Mr. Parkhurst, the heavy
stockholders in the Rolling Thunder mine, had reached Maporah and
there had a short but effective interview with Tom Rover.
“I’ll take charge of things here,” declared Mr. Renton, when he had
heard about the boys being held for ransom. “I think I know exactly
how to handle Garrish. You go ahead and look for those kids.
Garrish won’t get away from me, and neither will the Rolling Thunder
mine.” And thereupon Tom turned matters over to the other
stockholders who had agreed to act with him.
The water brought to them by Ocker satisfied the boys’ thirst but it
did not allay their hunger, and as hour after hour passed and none of
their captors presented himself, the lads began to grow desperate.
“I wish I had an ax! I’d try to smash down those logs,” declared
Andy. “We might be able to make a rush for it in the dark.”
“I’ve got an idea! I wonder we didn’t think of it before,” said Jack in
a low tone. “Here, Randy and Andy, stand back to back and give me
a chance to climb up on your shoulders. When I’m up there, Fred,
you hand me the lantern. I’m going to inspect those cracks overhead
and see if I can’t find some sort of an opening up there.”
 The young major, having removed his shoes, was soon standing
upright on the shoulders of the twins. Fred passed up the lantern,
and Jack had the twins move slowly from one part of the rocky
cavern to another.
For a long while Jack found nothing that looked promising, but
presently he discovered a stone that seemed to be loose. He told
those below to be on the watch and pulled and tugged at the bowlder
with all his might. It came down with a crash and a number of loose
stones and some dirt followed. Jack immediately leaped down and
threw himself on the ground, the others following his example.
“Hi there! What are you fellows doing?” came from the entrance to
the cave in Jackson’s voice.
“A loose stone came down! It nearly smashed us!” cried Jack.
“I don’t want to stay here if the roof is coming down on us,” wailed
Fred.
“Do as we told you to and you won’t have to stay there,” answered
Jackson, and then, after waiting a few minutes more, the man
disappeared from the entrance.
Once more Jack mounted to the shoulders of the twins and with
caution he poked at the hole which had been started.
“Take off your jacket, Fred, and catch the loose stones so that they
don’t make any noise,” he whispered. And this the youngest Rover
did.
It was a long, tedious task, and several times the young major was
on the point of giving up. But just when he felt that his labors were of
no avail he broke through an opening overhead. Immediately the
cool night wind struck him and he realized that he had reached the
outer air.
Again their gymnastic training stood the lads in good stead. Jack
hauled Fred up and then held him still higher, and soon the youngest
Rover had crawled through the opening above.
“I’m right here among a lot of bushes,” he whispered, looking
down. “It’s a side hole, so there isn’t much danger of its caving in.”
 Fred leaned down and assisted Jack up, and then the two cut a
long heavy stick and with this assisted the twins to get out of the
cave, bringing Jack’s shoes with them. They were but a short
distance away from the camp of the men and could hear them
talking quite plainly.
Hardly daring to breathe, the four boys crawled through the
brushwood until they reached something of a trail. They could see
little, owing to the darkness, but managed to make fair progress.
“Thank fortune, we’re out of that!” exclaimed Jack presently. “Now
we’ve got to see to it that they don’t catch us again.”
“Right-o!” answered Randy. Then, looking up at the sky, he
continued: “See how dark it is—not a star showing. I think it’s going
to rain.”
He was right, and in a few minutes more the first of the drops
began to come down. Then came a dim flash of lightning, followed
presently by a vivid streak across the heavens.
“We’re in for a regular thunder storm,” said Fred. “Gee, I hope the
lightning doesn’t strike us.”
On and on went the boys, bumping into more than one tree and
sometimes going headlong over the rocks. They had but one
purpose in mind—to put as much space as possible between
themselves and the Davenport gang.
At last, having moved along for over an hour and being soaked to
the skin, they came to rest under the shelter of a rocky precipice.
The storm continued, vivid flashes of lightning being followed by
claps of thunder that echoed and re-echoed through the mountains.
“We’ve got to go on,” said Jack, at last. “As soon as daylight
comes those fellows will be searching for us, and they’ll have a big
advantage for they’ll be on horseback while we’ll be on foot.”
Forward they went again, although in what direction they did not
know. They were hoping that they were getting farther and farther
away from the cave where they had been held captive.
 They were passing along the sloping side of the mountain when
another flash of lightning followed by a loud clap of thunder startled
them and brought them again to a halt. Then came another crash as
a tree toppled down not far away.
“Gee, that was close enough!” exclaimed Jack.
He had scarcely spoken when the four boys were startled by a yell
of fright. A few seconds later came a man’s voice crying piteously:
“Help! Help! For the love of heaven, help! I’m caught fast under the
tree and I’ll be crushed to death! Help!”
 CHAPTER XXX
THE ROUND-UP—CONCLUSION

“Somebody’s in trouble! We’ll have to see if we can’t help him!”

“Beware! It may be one of the Davenport crowd.”
“That may be true, but we can’t let him die. Come on.”
Another flash of lightning lit up the scene, and by this the Rover
boys saw where a tall tree of the mountainside had been broken off.
The top hung down over some sharp rocks and under several limbs
rested the form of a man, held down so that he could do little but kick
frantically with one leg.
“It’s Ocker!” exclaimed Fred, as they drew closer.
“Help! Help!” came faintly from the man as he saw the dim forms
of the boys in the darkness. “Help! I’m being crushed to death!”
Fully realizing that they might be playing into the hands of their
enemies and yet not willing to see Ocker crushed to death, the four
lads sprang forward and began to tug at the tree branches which
held the fellow a prisoner. They could see that any instant the top of
the tree might break away entirely from the trunk and then Ocker
would be crushed to a pulp.
It was strenuous work, but the military experiences of the former
cadets stood them in good stead, and now, as the twins and Jack
raised one limb after another, Fred propped them up with such
stones as were handy so that they could not slip back. Then, while
the twins continued to exert pressure on the treetop, Jack hauled
Ocker away.
The man was bruised and bleeding and for the moment so winded
he could scarcely speak. At first he had not recognized his rescuers
and he stared in astonishment when another flash of lightning
revealed their faces.
“You!” he gasped hoarsely. “You! And I was helping to keep you
prisoners!”
“Ocker, we have saved your life, and you know it,” answered Jack
quickly. “Now then, it is up to you to help us escape. Will you do it?”
“I sure will!” panted the man. “I’m done with that crowd, anyhow. I
told Davenport I wasn’t brought up to do such dirty work as he has
planned.” Ocker paused to regain his breath. “Why, Davenport is as
bad a skunk as Pete Garrish!”
“Pete Garrish!” exclaimed Randy. “Do you know anything about
that man?”
“I know everything about him,” muttered Ocker. “He and his crowd
are trying to swindle your father and some other men out of their
interest in the Rolling Thunder mine.”
“You come with us, Ocker, and you won’t regret it,” put in Jack
hurriedly. “Show us the way to Cal Corning’s house.”
For an instant the man hesitated.
“If I take you back where you belong, you won’t have me arrested,
will you?” he pleaded. “I don’t want to hurt you fellows, and I’d just as
lief tell Mr. Rover what I know about Garrish.”
“You won’t be arrested,” answered Jack. “I’ll give you my word on
it. Come—hurry up! We not only want to get back, but we want to
have a chance to round those other fellows up.”
“But don’t do it before I’ve a chance to get away!” And the man’s
face showed his sudden terror.
“All right, we’ll give you your chance, and we’ll make it worth your
while, too,” answered Jack.
Ocker had been on foot, not daring to take his horse when he had
stolen away from the Davenport crowd. He led the way to a broader
and better trail, and less than half an hour later found the whole
crowd on Sunset Trail. By this time the storm was passing and only a
few scattering raindrops were coming down.
That tramp was one the Rover boys never forgot. Soaked to the
skin, and so footsore they could scarcely walk, they reached Cal
Corning’s place at about five o’clock in the morning. Their knock on
the door brought Corning to that portal, gun in hand.
“Why—why, it’s the Rover boys!” called out the man, in
amazement. “Hurrah! Mr. Rover! Mr. Rover! The boys are here, safe
and sound!” he yelled.
It was then that pandemonium seemed to break loose. From a
couple of the bedrooms rushed Tom Rover followed quickly by Sam
and Dick. The men were partly dressed, having removed only their
coats and shoes.
“My boys! My boys!” cried Tom Rover, and there was almost a sob
in his throat as he rushed to embrace the twins. Then Dick ran to
Jack and Sam to Fred, and there was a genuine hugging match all
around.
“Gee, but it’s good to be back!” was the way Andy expressed
himself, and each of the other lads endorsed that sentiment.
“We were out looking for you until the storm came up,” said Dick
Rover. “We were going out again as soon as it was daylight.”
“Where have you been and what did those rascals do to you?”
questioned Sam Rover.
“It’s a long story, Dad,” answered Fred, and then he added quickly:
“Here’s a man you’ll like to see, Uncle Tom. His name is Ocker, and
he knows all about Peter Garrish.”
“Did he find you?” questioned Tom quickly.
“No. We found him—under a tree that was struck by lightning,” put
in Jack quickly. “We’ll give you the particulars in a little while. Just
now we want to know if you don’t want to get a crowd together to go
after Davenport and his bunch. Those men ought to be rounded up
and put back in prison.”