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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
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by publishing worldwide. Oxford is a registered trade mark of Oxford University
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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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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.
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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 10.3 CHILD (Congenital Hemidysplasia with
Ichthyosiform Erythroderma and Limb
7.21 NANS Deficiency (MIM 610442) 236 Defects) Syndrome (MIM 308050) 357
7.22 Spondylo-​Epi-​Metaphyseal Dysplasia 10.4 Chondrodysplasia Punctata, Rhizomelic Type
with Immune Deficiency and Developmental (MIM 215100, 222765, 600121) 360
Disability, EXTL3-​Deficient Type
(MIM 617425) 240 10.5 Chondrodysplasia Punctata,
Brachytelephalangic Type (MIM 302950,
8. DIASTROPHIC DYSPLASIA AND RELATED CONDITIONS, 602497) 363
AND DYSPLASIAS WITH JOINT DISLOCATIONS 245 10.6 Chondrodysplasia Punctata, Autosomal
8.1 Achondrogenesis, Type IB (MIM 600972) 245 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 chemistry led to a gradual improvement of nosology and a
North American medical genetics, encyclopedist, cardiolo- deeper understanding of pathogenesis.
gist, and expert at the human disorders of connective tissue While some (Müller-​ Hill, 1984) have expressed
(especially the Marfan syndrome) wrote the preface for the concerns about the provenance of some of Grebe’s material,
second edition of the magisterial Spranger et al. Atlas on others have, unwittingly, profited from collaboration with
Bone Dysplasias. Grebe (Grebe and Wiedemann 1953). Wiedemann was a
It was McKusick who in 1968 initiated the annual pediatrician with a strong interest in skeletal dysplasias and
Conferences on the Clinical Delineation of Birth Defects, other human constitutional anomalies. Wiedemann’s small
the first five at John Hopkins Hospital. In 1968, two days text on the great constitutional anomalies of the skeleton
were devoted to the skeletal dysplasias with input and discus- (1960) appeared while Jürgen Spranger was house officer in
sion by Maurice Lamy, Jürgen W. Spranger, David Rimoin, Wiedemann’s department in Kiel (1961–​1974).
Judith G. Hall, John Dorst, Leonard O. Langer, and Hans At a meeting of the European Society of Radiology in
Zellweger, among others. Centers of excellence were flour- Paris in 1968, a group of experts considered nosology in
ishing or being established in Los Angeles, Seattle—​later the skeletal dysplasias with Spranger making the funda-
Vancouver, Baltimore, Kiel, Paris, and Madison (briefly with mental biological distinction between skeletal dysplasia
Jürgen Spranger, Len Langer, Enid F. Gilbert, and myself and dysostoses. The first edition of the Langer, Spranger,
“under one roof ”). Extremely active working relationships and Wiedemann book was a milestone in this field com-
were established between these and other European experts bining clinical, radiologic, genetic, and histologic advances
including Maurice Lamy, Pierre Maroteaux (Paris), Andres on the eve of a major molecular reshaping of our under-
Giedion (Zürich), K. Kozlowski (Australia), G. Camera standing based, in part, on Spranger’s important concept of
(Italy), Jiri Kučera (Prague), and many others. After the the families of skeletal dysplasias identified on the basis of
thalidomide disaster, Widukind Lenz (Münster) became roentgenological and pathogenetic criteria (think: type II
an outstanding authority on the limb dysostoses. collagenopathies, i.e., COL2A1 disorders: achondrogenesis
Sadly, Dr. McKusick did not live to write a revision of type 2, platyspondylic lethal dysplasia [Torrance] in humans
his preface for this edition. and mice, hypochondrogenesis, spondyloepiphyseal dys-
Early efforts in this field were primarily nosological with plasia, spondyloepimetaphyseal dysplasia [SEMD], SEMD
delineation of an ever-​increasing number of entities, subse- Strudwick type, Kniest dysplasia, spondyloperipheral dys-
quently lumped with or split from others, few remaining as plasia, Stickler syndrome type 1, vitreoretinopathy and
originally set out (achondroplasia!). Definition of skeletal phalangeal epiphyseal dysplasia, and so on.)
dysplasias as causal entities was then, and to some extent still The present group of collaborators on this edition of
is, based on family structure (e.g., the spectacular pedigree Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal
of the first family segregating for the Nievergelt syndrome), Development, all have decades of experience in this field.
presence or absence of parental consanguinity, clinical Besides Jürgen Spranger (pediatrician, geneticist, and skel-
manifestations, and paternal age (Penrose, achondroplasia). etal radiologist), there is Paula W. Brill (New York), whose
As noted by McKusick, these efforts culminated in interest in the field was inspired by Leonard O. Langer
several early monographs, for example, by Mørch (1941) and John Dorst, and who collaborated on the second and
and A. Birch-​Jensen (1949) on defects of upper limbs third editions. Dr. Brill is currently Professor Emerita of
in Copenhagen, Hobaek (Norway, 1961), Lamy and Radiology at Weill Cornell Medical College, where she
Maroteaux (Paris), Rubin (United States, 1964), and Grebe previously served as chief of Pediatric Radiology. Gen
(1964); other earlier contributors were members of the Nishimura (Tokyo) claims he was drawn to the field by an
Galton Laboratory, also R.R. Gates in London (1946), and earlier version of this book; he is widely regarded as one
Hanhart in Switzerland. Refinements of radiologic tech- of the world’s finest diagnosticians of skeletal dysplasias;
nique, bone histology, and histochemistry and collagen as head of Pediatric Imaging at Tokyo’s Metropolitan

xi
Children’s Medical Center he contributed substantially to more or less closely related species. But the greatest clin-
this revision, particularly the dysostoses. ical skill is required to perform phenotype analysis in such
Sheila Unger, who trained with the late David Rimoin, a child so astutely as to infer prognosis and required care.
and Andrea Superti-​ Furga, who learned from Andres And, toward that end, this revision of the Langer, Spranger,
Giedion and Jürgen Spranger, are well-​known to all readers and Wiedemann classic will be enormously useful.
of the American Journal of Medical Genetics as compilers
John M. Opitz
of the Nomenclature of Skeletal Dysplasias, now incor-
University of Utah, Salt Lake City
porated into this revision, complementing each other as
April 2012
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 B IB LIOGR APH Y
talents to this field.
Palaeontologists working with an organism’s best pre- Birch-​Jensen A (1949) Congenital deformities of the upper
extremities. Copenhagen: Ejnar Munksgaard.
served tissues, bone and teeth, are to an ever-​increasing Cocchi U (1964) Krankheiten des skeletsystem. In: Humangenetik,
measure able to infer age, growth, and function from di- vol. 2, ed. Becker PE. Stuttgart: Thieme: 113–​178.
rect and indirect evidence, even from material that may be Grebe H, Wiedemann HR (1953) Intrafamiliarität einiger typischer
as old as the Devonian, some 360 million years ago. Form, Missbildungen. Acta Genet Med Gemellol 2:203–​224.
Grebe H (1955) Chondrodysplasie. Rome: Analecta Genetica/​Istituto
growth, and function are more easily inferred in a recently Gregorio Mendel.
stillborn fetus (e.g., with campomelic “dysplasia”) on the Grebe H (1964) Missbildungen der Gliedmaßen. In: Humangenetik,
basis of prenatal ultrasonography, physical and radiological vol. 2, ed. Becker PE. Stuttgart: Thieme: 179–​343.
examination, histological studies of gonads, examination Hobaek A (1961) Problems of hereditary chondrodysplasias.
Oslo: Oslo University Press.
of growth plate and brain, as well as structure of the domi- Lamy M, Maroteaux P (1961) Les chondrodystrophies génotypiques.
nantly inherited SOX9 gene mutations in fetus and parents. Paris: Expansion Scientifique Française.
If neither parent has the infant’s mutation, is the recurrence Mørch ET (1941) Chondrodystrophic dwarfes [sic] in Denmark.
risk as low as the mutation rate at the gene? No, because Opera ex domo Biologiae Hereditariae Humanae Universitatis
Hafniensis. Munksgaard, Kopenhagen.
of germinal mosaicism. Thus, dear reader, please note the Müller-​Hill B (1984) Tödliche Wissenschaft. Die Aussonderung
word “genetic” in the title of this book. von Juden, Zigeunern und Geisteskranken 1933–​ 1955.
But the greatest challenges are presented to the clinician Reinbeck: Reinbeck-​Verlag.
caring for a child with a previously apparently undescribed Rubin P (1964) Dynamic classification of bone dysplasias. Chicago: Year
Book Publishers.
skeletal dysplasia (there are still many, but check Spranger Spranger JW, Winterpacht A, Zabel B (1994) Type II
et al., 2012 first!), but nowadays perhaps exome sequencing collagenopathies. Europ J Pediatr 153:56–​65.
may uncover a phylogenetically ancient gene that must have Warman ML, Cormier-​Daire V, Hall C, et al. (2011) Nosology
been present in LUCA (i.e., the last universal common and classification of genetic skeletal disorders: 2010 revision. Am J
Med Genet 155A:943–​968.
ancestor of the archaea, bacteria, and eukaryotes) and may Wiedemann HR (1960) Die grossen konstitutionskrankheiten des
provide a homologous condition (“animal model”) in a skeletts. Stuttgart: G. Fischer Verlag.

xii F oreword
 ACKNOWLEDGMENTS

Friends and physicians who helped to write the first edi- R. Faqueih, Rihyadh; S. Fellingham, Tiervlei; B. Frame,
tion of this atlas have been acknowledged in it. Much of Detroit; S. Garn, Ann Arbor; A. Geiberger, Stockholm;
its material was used in the second and third editions, and A. Giedion, Zürich; R. Gorlin, Minneapolis; G. Greenway,
we continue to express our thanks to them. The second and Dallas; K. H. Gustavson, Uppsala; N. Haga, Tokyo;
third edition could not have been completed without the J. Hall, Vancouver; C. Hall, London; E. Harms, Münster;
continued encouragement, help, and advice from Roger A. Hatamochi, Tochigi; R. Hernandez, Ann Arbor;
Stevenson and his staff at the Greenwood Genetics Center, J. J. Ho, Syracuse; J. Hoeffel, Nancy; D. Horn, Berlin;
which became a second academic home to JS. A. Jabra, Baltimore; B. Kammer, Urbana; A. E. Kan, Sidney;
The Children’s Hospital of the University of Freiburg, O. H. Kim, Suwon; H. Kitoh, Nagoya; A. Kovanlikaya,
Germany, now houses the Mainz Bone Dysplasia Registry New York; K. Kozlowski, Sidney; K. Kretschmar,
containing much of the material used in this book. Bernhard Marshfield; K. Kuo, Chicago; G. Laborte, Bayonne;
Zabel, Ekkehard Lausch, and their staff in Freiburg pro- R. Lachman, Los Angeles; D. Lassrich, Hamburg; J. Lauzon,
vided the support and friendship needed to gather the ex- Calgary; S. W. Lee, Seoul; M. LeMerrer, Paris; M. Levine,
perience and compose a new edition. The authors are part Torrance; S. Loh, Bandung; R. Markowitz, Philadelphia;
of an international skeletal dysplasia network (ESDN) P. Maroteaux, Versailles; W. McAlister, St. Louis;
that assists colleagues in need of a diagnosis. Part of the P. Meinecke, Hamburg; M. Millar, Chicago; G. Mortier,
new material stems from ESDN and is used with permis- Antwerp; S. Nampothiri, Cochin; Dr. Nayanar, Sidney;
sion of the submitting colleagues. Other cases were shown H. Ohashi, Saitama; I. Ohyama, Tokyo; J. M. Opitz,
to the authors on a personal basis and are part of extensive Salt Lake City; H. Pagan-Saez, San Juan; A. Parson,
electronic databases created by GN in Tokyo and ASF in New Zealand; J. Pina-Neto, Reibeirao Preto; H. Refior,
Lausanne. München; M. Reither, Kassel; A. Richards, Cambridge;
Physicians whom we approached to contribute films O. Ritting, Salzburg; S. P. Robertson, Dunedin; M. Robinow,
from published cases are acknowledged in the legends. Yellow Springs; S. Sane, Minneapolis; J. Sauvegrain, Paris;
Colleagues who shared with us their personal experience R. Savarirayan, Melbourne; A. Schlesinger, Houston;
and allowed us to use material from their unpublished cases D. Sillence, Parramatta; A. Stern, Ann Arbor; C. Stoll,
are gratefully acknowledged in the following list of names: Strassburg; J. Stolte-Dijkstra, Groningen; L. Swishuk,
Y. Alanay, Ankara; B. Albrecht, Essen; G. Alzen, Giessen; Galveston; B. ter Haar, Nijmegen; P. Toering, Odense;
D. Amor, Melbourne; D. Babbit, Milwaukee; P. Beighton, H Toshiyuki Kagawa; M. Uhl, Freiburg; F. Unger, Dayton;
Cape Town; D. Binstadt, Springfield; M. Blick; O. Caglayan, F. van Buchem, Utrecht; H. Vega; P. Verloes, Liege;
Izmir; Dr. Cavalcanti, Campinas; J. Charrow, Chicago; R. Winchester, New York; S. Yoo, Seoul; I. W. Young,
D. Chitayat, Toronto; R. Cohen, Oakland; M. Crone, Loma Linda.
Belfast; Dr. Diaz-Bonnet, San Juan; V. Cormier-Daire,
Paris; A. Crosby, London: J. Dorst, Baltimore; S. Dunbar, J.W. Spranger, P.W. Brill, C. Hall, G. Nishimura,
Cincinnati; O. Eklöf, Stockholm; A. Fabretto, Trieste; 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 that were given new names, such as diastrophic dysplasia
and short trunk (Morquio, 1929); the report was followed (Lamy et al., 1960), familial metaphyseal dysostosis (Spahr
by a large number of related observations, and “Morquio et al., 1961), cartilage-​hair hypoplasia (McKusick et al.,
disease” (now mucopolysaccharidosis type IV) became 1965), spondylo-​epiphyseal dysplasia congenita (Spranger
the prototypic form of short-​trunk dwarfism. Two distinct & Wiedemann, 1966), tricho-​ rhino-​phalangeal syn-
forms of “multiple epiphyseal dysplasia” were described in drome (Giedion, 1966), metatropic dysplasia (Maroteaux
1937 (Ribbing, 1937) and in 1947 (Fairbanks, 1947); we et al., 1966), spondylometaphyseal dysplasia (Kozlowski,
know today that at least six different genetic forms exist. Maroteaux, & Spranger, 1967), and more (the list is ar-
Identification and delineation of new conditions based on bitrary and not exhaustive). This freedom to recognize
specific radiographic signs, often in combination with spe- genetic disorders in the 1960s culminated in the Birth
cific clinical findings, flourished throughout the twentieth Defects Conferences, a first series of which was organized
century and still today constitutes the basis for the identifi- between 1969 and 1971 at the Johns Hopkins Hospital;
cation of the pathogenic gene(s). 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
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 presentations and discussions.
The years following World War II saw a rapid advancement
of biochemistry and genetics. Following the implementation
ATLASES AND CLASSIFICATIONS
of rickets prophylaxis with vitamin D, hypophosphatasia
was recognized as a “genetic form of rickets” associated with In 1951, the British orthopedic surgeon Thomas Fairbank
low alkaline phosphatase activity (Rathbun, 1948). In the published an Atlas of Generalized Affections of the Skeleton
1950s, a new cellular organelle was identified, the lysosome, (Fairbank, 1951). Sir Fairbank was interested in genetic
that contained a number of different hydrolytic enzymes (de bone disorders; in 1947, he had described a form of “dys-
Duve, 1959; de Duve et al., 1955). This led to the discovery plasia epiphysealis multiplex” (Fairbank, 1947). Although
that some of the previously identified clinical syndromes rudimentary by today’s standards, this work was a milestone
were caused by genetic deficiencies of individual enzymes. in the development of the field of constitutional disorders
In 1952, Brante reported evidence of mucopolysaccharide of bone. In 1961, Pierre Maroteaux and his mentor
material in “gargoylism,” and by 1957, experimental evi- Maurice Lamy published a monography on “genotypic
dence established that Hurler disease was characterized chondrodystrophies” (Maroteaux & Lamy, 1961). Unlike
by impaired degradation of mucopolysaccharides (Brante, the Fairbank atlas, this work did not discuss all genetic skel-
1952; Dorfman & Lorincz, 1957). Biochemistry had etal conditions but was focused on the “chondrodysplasias.”
joined the field of genetic skeletal diseases for good. In the The Maroteaux and Lamy classification included eight dif-
late 1950s, the correct number of chromosomes in humans ferent groups of bone dysplasias. The literature index of
was finally determined; this triggered the recognition of the monograph lists an impressive number of case reports
the aneuploidies (trisomies 21, 13, and 18, monosomy X, from the nineteenth century to the 1950s, demonstrating
and others) in rapid sequence. With chromosomes and the abundance of case reports but also the lack of a system-
enzymes, laboratory tests could help medical geneticists atic approach. In 1964, the radiologist Philip Rubin from
and pediatricians confirm a diagnosis and explore the phe- Rochester University published his Dynamic Classification
notypic variability of the individual disorders. Thanks to of Bone Dysplasias (Rubin, 1964). Although some of the
these advancements, the field of medical genetics gained at- diagnoses have changed (e.g., rhizomelic chondrodysplasia
tention and importance. punctata was called “congenital multiple epiphyseal dys-
plasia”), the book was remarkable because it classified
disorders based on the “dynamic pathogenesis” with
THE GOLDEN 1960S speculations on what physiologic process on bone growth
The discovery of chromosomal and biochemical bases for and remodeling was affected. Extensive correlations were
their clinical observations must have reassured pediatricians made to what was known at the time about bone modeling.
and geneticists that what they were observing was real, Rubin modestly wrote that the success of his book would be
and this freed their minds. It was no longer necessary measured paradoxically by the rapidity in which its content
to be conservative by forcing different observations into would become outdated. In 1974, Jürgen Spranger, Len
one category; whereas the 1950s were still hesitant and Langer, and Hans-​Rudolph Wiedemann published their
saw new entities such as “recessive achondroplasia” and Bone Dysplasias: Atlas of Constitutional Disorders of Skeletal
“pseudoachondroplasia,” the 1960s saw the full delinea- Development, an extensive atlas that was based on the corre-
tion of achondroplasia (Maroteaux & Lamy, 1964; Langer lation of radiographic, clinical, and genetic data to delineate
et al., 1967) and flourished with newly recognized entities conditions (Spranger et al., 1974); in 1975, the radiologists

xvi I ntroduction
Hooshang Taybi and Ralph Lachman published their conditions. Morphogenesis, development, growth, and ho-
Radiology of Syndromes and Skeletal Dysplasias (Taybi meostasis of the skeleton and its over 200 distinct elements
and Lachman, 1975). Both the Spranger and the Taybi-​ is a complex mechanism with many levels of integration
Lachman books have been revised periodically and are in and control, and because of our ability to recognize mor-
their fourth and fifth editions, respectively. 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
NOMENCLATURE AND NOSOLOGY the many forms of genetic rickets or the lysosomal storage
Contemporary to the description of well-​defined disorders disorders) were identified in the 1960s, the 1970s and early
in the late 1950s and 1960s, it became clear that much confu- 1980s saw the first evidence of “molecular pathology” with
sion had been caused by the inhomogeneous denomination the collagens (collagen 1 and osteogenesis imperfecta, col-
of entities. Clinically different disorders had been reported lagen 3 and the Ehlers-​Danlos syndrome type IV, and col-
under the same name (e.g., “chondrodystrophy”), and indi- lagen 2 and chondrodysplasias), and the late 1980s (thanks
vidual disorders had been reported under different names. to the possibility of molecular cloning and then, particu-
In 1969, in the wake of the Birth Defects Conference on larly, the polymerase chain reaction technique) saw the
Skeletal Dysplasias, a group of experts (mainly radiologists) underlying gene mutations unravel. In 1983, a multi-​exon
convened in Paris in 1970 to prepare an “International deletion in COL1A1 was identified in lethal osteogenesis
Nomenclature of Constitutional Diseases of Bones,” a list imperfecta (Chu et al., 1983); in 1988, a multi-​exon dele-
of conditions grouped by their main radiographic or clin- tion in COL3A1 was identified in Ehlers-Danlos syndrome
ical features. This “Paris nomenclature,” compiled by one of type IV (Superti-​Furga et al., 1988) (not a skeletal condi-
us ( JS), was so welcome that it was published, with minor tion, but the “collagen field” was united at that time); and
variations and comments, in at least five different journals in 1989, a single-​exon deletion was identified in a family
(e.g., Kozlowski et al., 1969). The 1970 nomenclature un- segregating congenital spondylo-​epiphyseal dysplasia (Lee
derwent revisions in 1977, 1983, 1992, 1997, 2001, 2005, et al., 1989). At the time, exon deletions were easier to iden-
2010, and 2015 (see Bonafe et al., 2015; Superti-​Furga tify by southern blotting, while single nucleotide variations
et al., 2007; Warman et al., 2011). Following the founda- necessitated extensive cloning and sequencing. In 1986, a
tion of the International Society for Skeletal Dysplasias heterozygous single nucleotide substitution in COL1A1
(ISDS) in 1999, the revisions were prepared by an ad hoc was identified as the cause of lethal osteogenesis imperfecta
group within the ISDS; the term nomenclature has been (Cohn et al., 1986); rapidly, glycine substitutions in the
replaced with nosology. The 2015 revision contains over 450 triple helical domain of collagen type 1 were established as
distinct entities. Notably, recent revisions of the Nosology the main cause of severe osteogenesis imperfecta. In 1988,
have included more dysostoses to reflect the fact that there a homozygous point mutation in the TNSALP gene was
is often a common genetic basis, that elements of dysostosis identified as the cause of lethal hypophosphatasia (Weiss
and dysplasia may occur in the same condition, and that et al., 1988). The 1990s surprised us with the notion that
patients with dysplasias or dysostoses are often seen in the the genes at the basis of skeletal diseases were not only struc-
same clinic. The Nosology should help in the delineation tural proteins or enzymes but frequently genes involved in
of new conditions by providing a list of those conditions signaling pathways and in transcription regulation, such
that have been recognized as distinct entities on clinical, as FGFR3 or CBFA1/​RUNX2 (Hermanns et al., 2001).
radiographic, and genetic grounds. Notwithstanding the A first molecular-​pathogenetic classification was drafted
many ties of friendship between the Nosology experts and (Superti-​Furga et al., 2001). Ever since, there has been a
the late Victor A. McKusick and the subsequent curators constant flow of new gene-​phenotype identification; while
of the MIM catalogue, there are inconsistencies between a small number of genes may account for a large propor-
the Nosology and OMIM due to the fact that while OMIM tion of individuals with genetic skeletal conditions, rarer
grows rather appositionally, the Nosology committee does associations are still being found on a monthly basis. As an
more pruning of obsolete entities. example, the majority of cases of osteogenesis imperfecta
Molecular data and the clinical-​ radiographic are determined by mutations in COL1A1 and COL1A2
classifications: There have been times when skeletal dys- but no less than 20 other genes can produce a brittle bone
plasia experts suffered from a dubious reputation. For many phenotype, although the number of cases is much smaller.
colleagues, it seemed hard to believe that there was a ra- In general, molecular data have determined some degree of
tionale for preparing long lists of very rare conditions with “lumping,” that is, the regrouping of conditions sharing a
Greek-​derived names. Yet, cell biology, biochemistry, and similar pathogenesis; but, on the other hand, the data con-
molecular genetics have confirmed the work of the clinical tinue to reveal extensive heterogeneity and to identify novel
and radiographic “stamp collectors”: there is an extraordi- conditions, leading to “splitting” and thus to a steady in-
nary variety of molecular mechanisms at the basis of skeletal crease in the number of conditions listed in the Nosology.

I ntroduction xvii
 Genetic disorders of bone and their contributions to ge- least not for some time) for guidance. Sensitive and accu-
netics and medicine: In many ways, the skeletal field has had rate sequencing, large databases, and precise bioinformatics
a pioneering role in medical genetics by contributing fun- prediction tools will be needed as much as clinical observa-
damental concepts. Among these are the observation that a tion skills and acumen.
single nucleotide substitution at the heterozygous state may Old and novel therapeutic approaches: Whereas the ex-
result in a lethal phenotype (lethal osteogenesis imperfecta, ploration of the pathogenetic bases of skeletal dysplasias
lethal collagen 2 dysplasias) (Cohn et al., 1986); the con- has been fascinating, the therapeutic fallout has followed at
cept of “protein suicide,” precursor to the concept of “dom- a much slower pace. Well-​structured observational studies,
inant negative” (Prockop 1984); the concept of functional providing much needed information on the natural history
topology of a molecule (different mutations in COL1A1 of each disorder and its complications, are available only for
giving different phenotypes because they affect different the more common conditions. Because surgery is so diffi-
functional domains); the formulation of the concept of cult to standardize, there is no high-​level evidence on the
disease families with mild to severe manifestation arising risk and benefit of most surgical interventions in individuals
from the same gene (collagen 1, collagen 2, COMP, and with skeletal dysplasias. For some conditions, knowledge of
FGFR3) (Spranger, 1988); the observation of gonadal mo- the molecular pathogenesis has resulted in the development
saicism as the explanation of affected siblings born to clini- of specific medical interventions. Several of the lysosomal
cally unaffected parents (again COL1A1 mutations) (Cohn storage diseases are now amenable to enzyme replacement,
et al., 1990); the discovery of highly recurrent mutations substrate reduction, or both (although the skeletal system
such as the “achondroplasia mutation” G380R in FGFR3 is less likely to benefit from these treatments than other
that occurs at the nucleotide with the highest mutation organs). Enzyme replacement therapy in hypophosphatasia
rate known in the human genome (Rousseau et al., 1994; is highly effective and beneficial (Scott, 2016). Several dis-
Shiang et al., 1994); and the demonstration that they occur tinct approaches are being studied to counteract increased
almost exclusively of paternally derived alleles, highlighting FGFR3 signaling in achondroplasia and related conditions
the paternal age effect (Wilkin et al., 1998). These concepts (e.g., guanyl cyclase activation by a long-​lived C-​Natriuretic
that are firmly accepted today were pioneered by the “bone Peptide analog [Lorget, 2012, #63]), modulation of FGF
dysplasia” field. signaling with a soluble “decoy” FGFR3 receptor (Garcia
The changing diagnostic scenario: The approach to di- et al., 2013), and specific inhibitors to inhibit the tyrosine
agnosis does in part reflect the history of the delineation kinase activity of FGFR3 (Komla-​Ebri et al., 2016)). In oste-
of disorders. Thus the diagnosis of constitutional skeletal ogenesis imperfecta and other conditions with fragile bones,
disorders still relies mainly on the meticulous analysis of the use of bisphosphonates, which is moderately effective,
skeletal radiographs. Correlation with the clinical data should soon be accompanied, or replaced, by approaches
(growth curve, clinical findings, history of fractures or that target the overall bone architecture (such as sclerostin
pain, other specific features) is essential. Biochemical evi- antibodies; Simsek Kiper et al., 2016; Jacobsen, 2017).
dence may be diagnostic (e.g., calcium or phosphate imbal- Our evolution in understanding the pathogenesis of
ance, or reduced activity of a specific enzyme). Molecular the skeletal dysplasias has undergone rapid changes in
genetic confirmation has long been the last step in the the past few decades. These studies have unearthed key
process. The power of massive parallel sequencing and its concepts in genetics. They have also demonstrated the im-
increasing affordability has changed this scenario drasti- portance of properly naming a condition in order for it to
cally. The analysis of gene panels (e.g., a “dysplasia panel,” be recognized by scientists, doctors, and patient advocacy
“bone fragility panel,” or “chondrodysplasia punctata groups. We are cautiously optimistic that these steps along
panel”) has already replaced single-​gene analysis in most a long and winding road will lead to therapeutic advances
instances. Even broader approaches, such as that of exome for our patients.
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. U NDE R S TANDING DYS PLAS IAS
Is the time of careful analysis of clinical features and AND DYS OS T OS E S T H ROU GH
radiographs lost forever? Probably not, but the approach T H E C OMB INAT ION OF C LINIC AL,
will be changed. The so-​called reverse phenotyping (i.e., to PAT H OGE NE T IC , AND MOLE C U LAR
verify whether the patient’s features [clinical, radiographic, C R IT E R IA
or biochemical] do fit with a genotype identified by unbi-
ased sequencing) needs as strong an expertise as the a priori The conditions included in the Nosology (many of which
generation of a diagnostic hypothesis. The findings from are described in this book) are clinically and molecu-
massive sequencing will confront the genetic physician with larly heterogeneous. They include dysplasias, dysostoses,
“common” genetic disorders but also with rare, ultra-​rare, osteolyses, and a few disruptions. Their distinction is essen-
or even private conditions; no literature will be available (at tial, both from a biological and a practical viewpoint. The

xviii I ntroduction
original version of the Paris Nomenclature for Constitutional that will form future organs—​transcription factors and
Disorders of Bone published in 1970 defined dysostoses as signaling pathways are instrumental in the formation of
“malformations of individual bone, singly or in combina- single organs and specific tissues. Examples are WNT7a
tion” and osteochondrodysplasias as “abnormalities of carti- and TBX15, deficiency of which leads to severe dysostosis
lage and/​or bone growth and development.” This essentially of the extremities or of the shoulder and pelvis, respectively.
clinical definition predated the more general distinction, These genes are responsible for the “blueprint” of the skel-
drawn by an international working group on concepts and eton: proper formation, size, and position of one or more
terms of errors of morphogenesis, between malformations skeletal elements. Other signaling factors, like the fibroblast
and dysplasias (Spranger et al., 1982). Here, a malformation growth factor receptors, are activated at subsequent stages
was defined as a “morphologic defect of an organ, part of an of embryogenesis and continue to be expressed in post-
organ, or larger region of the body resulting from an intrin- natal life. A third group of signaling factors is active from
sically abnormal developmental process.” Thus, the terms the period of organogenesis to adult life. To this group of
dysostosis and skeletal malformation name the same aberrant factors belong the runt transcription factor, RUNX2, and
developmental category. It was also noted that a malforma- the cartilage-​derived morphogenic protein I, CDMP1 (also
tion could result from the extrinsic disturbance of normal called GDF5). Finally, many genes are not essential for the
development. Such a “secondary” malformation resulting patterning and development of the blueprint of skeletal
from “the extrinsic breakdown of, or an interference with, an elements but are crucial to the differentiation and function
originally normal developmental process” was called a disrup- of cartilage cells or bone cells, or to the growth and develop-
tion. A dysplasia was defined as the “abnormal organization ment of cartilage and bone as tissues. From these differences
of cells into tissue(s) and its morphologic result(s).” Applying in the time and duration of expression, several axioms can
these broader concepts to the skeletal system, the constitu- be deduced and applied to skeletal development.
tional errors of bone development can be defined as follows:
DYSOSTOSES
• Dysostoses are malformations of single skeletal elements,
alone or in combination. Many transcription factors are expressed only for a limited
period of time during embryogenesis. Genes are turned on
• Disruptions are malformations of bones secondary to
and off. In limb development, for instance, 3’ HOX genes
nonskeletal causes.
are expressed early in development controlling anterior re-
• Skeletal dysplasias are developmental disorders of gions of the limb. 5’ HOX genes are expressed later and
chondroosseous tissue. control more posterior regions. A series of genes are respon-
sible for embryonic segmentation and for the development
• Osteolyses are regressive disorders which permanently
of vertebrae and ribs. Defects of transcription factors or of
reabsorb and dissolve preexisting bone.
signaling factors, which are only transiently expressed during
early embryogenesis, result in finite organ defects (i.e., in
Advances in developmental genetics now provide the bio- malformations). Dysostoses are malformations or, in other
logic bases for this distinction. words, manifestations of defective skeletal organogenesis
(Figure 1.1). They are finite, because of the transient nature
FORMATION OF SKELETAL ELEMENTS of the defective process. They may occur singly, in combi-
nation, or as part of pleiotropic disorders if the controlling
Bone formation starts with the patterning of cells. gene is expressed in many organ systems. Examples of known
Transcription factors are produced that regulate the ex- signaling defects leading to dysostoses are summarized in
pression of genes. Families of genes cooperate to provide Table 1.1. Clinically, dysostotic lesions may be asymmetrically
programs that govern the patterning process. Signaling distributed, notably in the disruptive forms (see later discus-
proteins and other substances, such as retinoic acid, are sion). The chondroosseous histology is normal. Dwarfism is
produced that diffuse from cell to cell and form gradients not a primary manifestation unless bones of the vertical body
that convey positional information through receptors. Thus axis or bones of the limbs are defective or missing.
embryonic cells are instructed about their relative position
and influenced to differentiate with regard to that position.
DISRUPTIONS
Together, these orchestrated signal loops involving tran-
scription factors and signaling molecules regulate the prolif- Similarly to transiently expressed transcription factors or
eration, migration (including mesenchymal condensation), signaling genes, toxic substances or infectious agents may
differentiation, in some cases the apoptosis, and, finally, the act on the embryo for limited periods of time. They produce
function of individual cells. During organogenesis—​that secondary malformations, not dysplasias. Thalidomide and
is, during the first eight weeks of human gestation when rubella embryopathies are prime examples. Mechanical
cells segregate into cell groups and tissues into primordia factors may also result in disruptions, the most prominent

I ntroduction xix
 Defect Examples

TRANSIENT SIGNALING DEFECT

Dysostosis Holt-Oram Syndrome
Isolated Polydactyly

PERMANENT SIGNALING DEFECT

– early intrauterine expression Cleidocranial dysplasia
Dysostosis – Dysplasia Fibrodysplasia ossificans
–

– late intrauterine expression Achondroplasia

Dysplasia Jansen metaphyseal dysplasia
–

DEFECTIVE CELLULAR FUNCTION SED congenita

– Dysplasia, prenatal Diastrophic dysplasia
–

– Dysplasia, postnatal Multiple epiphyseal dysplasia

–
- Osteolysis Winchester-Torg syndrome

Embry og enesis B irt h

Figure 1.1 Scheme illustrating the concept of time-​dependent gene expression and resulting defects.

example being the amniotic band disruption sequence. In accumulation of abnormal sterol products caused by the
cases with symmetric involvement of the fingers, differen- defective activity of 3-​beta-​hydroxysteroid dehydrogenase
tiation between amniotic band disruption and a geneti- (emopamil binding protein) transiently disrupts normal
cally determined primary dysostosis (e.g., brachydactyly skeletal development and that warfarin acts by a similar
type B) can be difficult. In some cases, a genetic defect mechanism. At any rate, the skeletal lesions in both appear
may be regarded as producing a disruption. In X-​linked to be disruptions (i.e., secondary dysostoses rather than
chondrodysplasia punctata, calcifications originate during dysplasias).
embryogenesis and disappear after birth, leaving scar-​like
areas of defective bone formation. Histology shows no DYSPLASIAS
signs of an ongoing dysplasia. The embryopathy caused
by warfarin consumption during pregnancy is very sim- Defects of genes that are expressed continuously, from in-
ilar to chondrodysplasia punctata. It is possible that the trauterine to extrauterine life, lead to dysplasias (Figure 1.1).

EXAM PLE S O F DY S O S TO S E S C AUS E D B Y D EFEC TS I N TR A N S C R I P TI O N FAC TO R S O R S I GN A L TR A N S D UCTION

TA B L E 1 . 1
P ROTEI N S

Name Inheritance Gene Protein

Al-​Awadi/​Raas-​Rothschild syndrome AR WNT7a Wingless-​type MMTV integration site family, member 7A (transcription
factor)

Ulnar-​mammary syndrome AD TBX3 T-​box 3 transcription factor

Holt-​Oram syndrome AD TBX5 T-​box 5 transcription factor

Cousin syndrome AR TBX15 T-​box 15 transcription factor

Hand-​foot-​genital syndrome AD HOXA13 Homeobox-​containing A13 transcription factor

Greig polysyndactyly, Pallister-​Hall AD Gli3 GLI-​Kruppel family member 3 transcription factor

syndrome, Postaxial polydactyly A

Brachydactyly A AD IHH Indian hedgehog (diffusible signal protein)

Brachydactyly B AD ROR2 Receptor tyrosine kinase-​like orphan receptor 2

Brachydactyly C AD GDF5 (CDMP1) Growth and differentiation factor 5 (Cartilage-​derived morphogenic protein 1)

Cenani-​Lenz syndactyly AR LRP4 Low density lipoprotein-​receptor related protein 4

Note. AD = autosomal dominant; AR = autosomal recessive; MMTV = mouse mammary tumor virus.

xx I ntroduction
 EXA MPLES O F DY SPLASI AS ASS OC IATED WITH M UTATIONS IN TR A NS C R IP TION FAC TO R S
TA B L E 1 . 2
OR S IGNA L T RAN SD UCI N G MO LECULES
Name Inheritance Gene Protein

Campomelic dysplasia AD SOX9 SOX9 transcription factor

Tricho-​rhino-​phalangeal syndrome AD TRPS1 TRPS1 transcription factor

Dyschondrosteosis XD SHOX SHOX transcription factor

Achondroplasia family (thanatophoric dysplasia, AD FGFR3 Fibroblast growth factor receptor 3

achondroplasia, hypochondroplasia, others)

Craniosynostosis (various types) AD FGFR1,2,3 Various fibroblast growth factor receptors

Metaphyseal dysplasia type Jansen, Blomstrand dysplasia AD PTHR PTH/​PTHrP receptor

Robinow syndrome (COVESDEM) AR ROR2 Receptor tyrosine kinase-​like orphan receptor 2

Note. AD = autosomal dominant; AR = autosomal recessive.

In contrast to dysostoses, dysplasias do not result from a the differentiation of proliferating chondrocytes into hy-
disturbance of the skeletal blueprint but from perturbation pertrophic cells and inhibits mineralization wherever
of growth and homeostasis of cartilage and bone as tissues. the PTH/​PTHrP receptor is expressed. Some transcrip-
“Primary” skeletal dysplasias result from mutated genes that tion factors also play a pivotal role in signal transduction;
are expressed in chondroosseous tissue (e.g., collagen 1 in hence, their mutations are responsible for dysplasias.
bone and collagen 2 in cartilage). “Secondary” dysplasias Dysplasias due to mutations of genes that regulate cell
are caused by abnormalities of extraosseous factors with structure and/​or function: A second group of bone dysplasias
secondary effects on the skeletal system. Examples are is caused by mutations in genes regulating cellular structure
skeletal abnormalities caused by metabolic errors, such as and function. With differentiation, cells assume special
hypophosphatemic rickets, or endocrine disease, such as functions—​notably the production or removal of matrix
hypothyroidism. Since skeletal dysplasias are disorders of components. Thus a skeletal dysplasia might originate from
cartilage and bone as tissues, mutations of dysplasia genes a mutated gene that encodes a faulty cell product such as
affect those tissues at all anatomic sites. Homologous sites collagens. Other skeletal dysplasias result from defective in-
are affected, and the resulting disorders are mostly sym- tracellular transport or degradation systems. In diastrophic
metric. Short stature is common. The expression may be re- dysplasia, for instance, the transport of sulfate, crucial for
stricted to, or vary quantitatively in, body segments leading the synthesis of sulfated proteoglycans, is impaired, and in
to disproportionate forms of short stature, for example, pycnodysostosis, the extracellular matrix cannot be prop-
spinal, rhizomelic, mesomelic, and acromelic dysplasias. erly degraded because of cathepsin K deficiency. A defec-
Asymmetric lesions, such as in enchondromatosis, mul- tive vacuolar proton pump interferes with bone resorption,
tiple cartilaginous exostoses, or fibrous dysplasia, develop leading to an infantile form of osteopetrosis. Cellular func-
under the influence of local mechanical factors or somatic tion may also be more generally impaired as in cartilage-​
mutations. Primary dysplasias may result from mutated hair hypoplasia, where RNA processing is impaired, or in
signaling genes or from genes affecting cell structure and/​ Schimke immunoosseous dysplasia, in which DNA repair
or function. mechanisms are defective. Mutations of the genes control-
Dysplasias due to mutated transcription factors and ling these functions may be expressed during fetal life, as in
signal-​transducing genes: In contrast to the genes respon- severe cases of osteogenesis imperfecta or diastrophic dys-
sible for dysostoses, dysplasia-​causing signaling genes are plasia. Other mutations of the same gene become apparent
expressed after early embryogenesis and remain active after only during later life, as exemplified by mild cases of oste-
birth. Accordingly, mutations lead to postnatally ongoing ogenesis imperfecta or diastrophic dysplasia. However, as
errors of cell proliferation, differentiation, and degener- in late-​manifesting signaling defects, most genes disrupting
ation and thus to defective skeletal growth and develop- cellular structure and/​or function are not involved in early
ment. Examples are achondroplasia, the Jansen type of embryogenesis. Examples are listed in Table 1.3.
metaphyseal dysplasia, and others (Table 1.2). Both achon-
droplasia and Jansen metaphyseal dysplasia are disorders
O S T E O LY S E S
of the growth plate: in achondroplasia, chondrocyte
proliferation is reduced because of a mutated fibroblast Osteolyses are disorders in which the primary development
growth factor receptor, FGFR3. In Jansen metaphyseal of skeletal elements and the first phases of growth are normal
dysplasia the mutant PTH/​PTHrP receptor suppresses but are followed by a phase of gradual bone resorption

I ntroduction xxi
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muyta humil. fagraçáo fe vicraõ a Cantuaria , dade ; fahidos eíles ao
amanhecer crendo que nifto faziaô lerviço a cntravaõ outros doze
pobres, a clRey,&compriaô côa obrigarão quem hum Religiofo lavava
os pés^ devida ao amor , que tinhaõ ao & lacs dava de comer- A
horas de fanto Arccbifpo. PaíTados alguns Terça mãdava dar de
comer a cem dias depois de fuafagraçaô, raan- pobres
merceeyros,queencomen. dou Santo Thomàs dar o bcdien- davaó a
Deos as couías de feu Ar« cia ao Summo Poncifice Alexan-
ccbiípado. Coftumava dormir hú dreTerceyro, que cnta5 eftava cm
pouco depois de rezar , & fervir Mompilhcr por caufa do fcifma, aos
Religioíos, 6c acordando fere. que ha via na Igreja de Dcos, &pe-
colhia a leu eftudo, onde gaitava dirlhc com muyta humildade o
algumas horas na liçaõdaEfcritura Pallio,& a principal peífoa, que hia
Divina , & outras em meditação a efta embayxada , era.o venera»
das coufas da Bcmaventuraça éter* vcl Abbade do Moíkyro Vieftani-
na , & naô queria cftudar fem ter cnfechamado Adam,aqucoSan.
comfigo hum homem douto, com 10 Arcebirpo , fendo CanceUario,
quem conferia os íentidos daEfcri* dera aquella Abbadia. E quando
tura fagrada por naõ errar cmaU tornarão comoPailio íahio Santo
gumdelíes , tanta era fua humilda. Thomàs ao receber em prociíTaõ
de, & o pouco que prefumia de feu com os pés d ef calços, & grande
entendimento. Vifitava cada dia íubiTiilTaó , como quem conhecia
osRcIígiofos enfermos, confolan. os myílerios daquella fagrada in. do
os em tudo com obras, & palaíignia,de que jà falíamos ncftahif- vras,
&aliviando-lhes a grandeza toria. VcQdo-fe o Santo naquella de feu
mal c5 fantas exhortações. grande dignidade, fe pos a confor
Pregava ao povo com grande promar a vida com a obrigação dcUa,
vey to , & além da elegância, & f ervelando, defpachando, dando or-
mofura da pratica tinha conceytos dem à reformação do Clero, 6c fa-
fingularidimos , & trazia admira, zendo outras coufas tocantes ao
veisexpoliçõesda Efcritura áiyi' cíTicio de Primas de mancyra , na*
Ct^lebrava MiiFa alguns dias Ppp ij com
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714 L[F%0 SEXTO com gwíide vcneiaçaó da^elíc fo pí^^â

rqjutaçáo ó& ái gnidade , ícm beíiinôiftyálencÔcpormai» rci^c terem
ícuanimo fombra deaUiTctGKÍi tiâé cckbravâ cada du j ^ sm j
Sccpiniaó Êobcrba. Ccmia píj mSacriíiia ikcc^cíccuò blu:*mcntc em
humsi íaLa acompa. as ínfigmits Saccrdotâcíi para h rc« irfiaéo de
homens doutos , &. Rdiveílir^as^ccytava com miiytas^U» gioíos, &
nourra meia apartada co» gfimasjkmbrando-yic a íignifíc^ miaôos
fccularcs, aquém aparra* çaõ de Gâdâ hiiíi^a delias* E fK> dif . va
de fi, |>cíias naôachar aííey çoa . curfo da Mríia derramava tangas
dos a oat ir a lição íagrada, que á \i lagrimas , como tiC¥Ítar os
penfamcntos , & «cnta- nha ordenado , ícm íer necefíaria çôet j ^úc
alli Iht podáaõ vir para o haver pratica , nem r cbo ; i ço^ que
diftraliireiTi , ^ o próprio UzU ao inquiccaíFe o íilencio da mefa/a :t3
coiOàlutígat* £jfa muj^ contrario a q^iando o Santo per honrar
algum dsdms j ài, naéconícnsia que íeus o cba msva para j unto de
fu Eri deípachadores tomaffem peytadc muyfobrío, Ôí temperado no
coagem, pos fenaô dobrarem com mer tanto ^ que nunca íc íhc co»
eUâj ^ttOTQZtem à jtííliça , & affim nhcceo demafia neílc pariícular,
^ aconrcdco vir humceno Abbaíkà poílo que pelos nobres
eonvidaCcíttddo Arccbifpocomhuma de- dos , qfcmpre tinha, foíTeíiia
mcfi fflaadâ > & querendo abreviar nc abundante de iguarias
cxcellcntcíís gocios com peytaraos Juizes^iiunt» nunca o Santo
cornava delias fe naã caachoii qucfú lhe aceytaffc coufa omenos 5 &
de menor sppetitc. E a!gia , gc te côtogu para fu a cafa cô como h u
m d ia t i vcíí c di a nt e d e fi © negocio defpachado , & com ím
hum fay íaô para ccmer^ lhe lançea dinheyro na bolfa. Csda dia
dava cerco Frade muy prefumido de novas €rmoIâs aos pobres, 3c f
en. abítinenre hum remoque , dandodo ofanto Arcebifpo Theobaldo
lhe a entender que na5 convinha dobrado o eílipendio,qiie íeus ían-
r^nío mimx) para mas de tudo uíava no exterior di^áoa muytos
dclkscom Uu^a 
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'DA CH%03\(iICA DE CISTE% fi% recer. Para haver de

ordenar algu que cntravaõ jà nas cafas onde cfSacerdote , uíava
eftranho rigor tava appofentado , o fahio a rccecxaminando fua
geração, vida , & bcr à pnmeyra fala com tâtas mofcoftumcs , & a
fuíiiciencia da dou - trás de conrcntamento , que bem trina , cm
modo , que aquclle que fe deyxava ver nelle o amor que tio Santo
approvava ^ era peíToa de nhaao fanto Arccbifpo , ôc naõ íe partes
lufficicnte para fe lhe enco- cançando de o ver , & fallar cõ cllc
mcdar (jualquer negocio importa- cm publico , & fecrcramente , deu
tc.Contra hereges era grade pcrfe tal defengano aos que tinhaó
agguidor,& zelava as couía de Deos, gravo de lhe o Santo tirar as
terras ô: da Religião Catholica com hum que tinhaõ ufurpadas à fua
Igreja, animo vcrdadeyrdmente Apoftoli- que nuca mais fe atreverão
a fallar CO. EraoArcebifpodeCantuaria aciUcy cm femelhante
matéria, fenhor de muy tas terras, algumas vendo o pouco fruto que
daqui das quats andavaò alienadas , & lhe havia derefultar. E como
aili ufurpadas de pcíToas feculares ha- cftiveífc alguns dias com
elRey , fc via muyto tempo, as quaes Santo tornou para Cantuaria
levando cõ« Thomàs tornou a reltituir breve* figo o Principc, 5c
ficando mais mente à íua Igreja , humas por de- confirmado na
graça , & amor dei» manda, cutras por outras vias di« Rcy do que
antes citava. Succedeo vcrfas . naõ fem queyxume das pcf- ncfte
meyo tempo que o Papa Alc/oas que as tinhaõ ufurpadas , que
xandre Terccyro, convocou hum íc hiaó aeiRey fazendolhe quey
Concilio geral na Cidade de Tu« xume do Arcebifpo , mas como ron ,
para dar remédio à fcifma que ainda cftava em fua graçí naõ ad-
fuftcntava na Igreja de Deos o An« mittia coufa algúa contra elle ,
an- tip; pa Viíítor, chamado primeyro tcs reípondia que em indo para
o Odaviano , com favor do EmpcraReyno os ouviria junto com a rc«
dor Frederico, & como íc ajuntafpoíla doAr^cbifpo , cntaô deter- fem
muy tos Prelados de naçoens minaria íua cauía. diverlas , quiz
tambcmb Arccbif po de Cantuaria acharfe prcíentc , & depois de ter
havido licença dciCAPITULO IV- Rcy, & de lhe ter levado a Londres o
Príncipe feu filho , que ate entaõ Como elRey fe veyo para Inglaterra
» cftivera cm feu poder íe embarcou £>• ovijitou Santo Thomàs ^ ó'
para França , amda que porcaufa como je come ^h ao as dtfcerdias
dotempofoy tomar porto cm Fiade entre an.hos , à* ^ perfegnição
des na Cidade dcGraviiinga.ondc do Santo por defender a Uberda*
foy muy feílejado , & dahi paíTan» dedalgreja» do por Normandia, &
outras Pro« vinciasquecraõdc Inglaterra naTEndo elRey compoítas
fuás quclle tempo, fe foy a Turon,don. diícordias na melhor forma de
o íahiraõ a receber quantos Pre* polfivcl, retornou para o Rcy no,
lados alli eíiavaô juntos para o & tomou porto em hum lugar cha .
Concilio, & o que foy mais,todos mado Suthantom onde Sãto Tho*
os Cardeacs, fem ficarem mais que màs o veyo a vifit ar juntamente
c5 douspara companhia do Padre Sãií feu filho o Príncipe
Hcnrique,que to , que o recebeo tm huma grande ainda tinha a feu
cargo naCidadc fala , com tantas dcmonílraçoers de Cantuaria , &
fabendo clRey de favor, & contentamento, que Pppiij foy
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Vi€ Lir%0 SEXTO »íby coufâ muy notada de todos , & T

lícologia , & homem digno de tofliuy invejada de alguns. Durando da
a veneração por íuas heróicas oConciíioremoftrGUO Arccbiípo
virtudes. Feytas eftas cUyçocns taó folicito nas coutas da Igreja, &
taõ acertadas , foy Santo Thomàs taô douto cm tratar os pontos ar-
confagrar a Igreja do Mofícyro de tiuosqucíclcvâtava6?qucem pu»
ladinos, onde jazia cl Rey Hcnriblico,éc fecretamentc era louvado,
que o Primeyro ^ avô deílc feguru & admirado de todos , impetrou -
do, para o que mandou vir todos do Papa confirmação de todos os
osBiípos íeusiíuífraganeos, & o Pnvilcgios,& liberdades de íiia próprio
Rcy fequiz achar prefenIgreja,& com outros muytos favo- te , por
honra dos oflos , & memores, fc tornou para íngíatcrra^onde
riadcfcusantfpaíTados , & profeosnaô achou menores em cl Rey A
g&indoncíiebomirxcntopcdioao feu filho : porq ainda durava aquel*»
íanto Arccbiípo, que villas as pr5« le antigo amor que fc tivcraõ , &
dcs maravilhas que o Senhor cbradurou cm quanto náo houve de va
pelos merecimentos do Santo çcrmey o matéria de intereíTepndc Rey
Eduardo, oquizcííe levantar ©íanto Arcebifpo moílrafTe querer a
mayor rcfpeyto , & pcllo cm feantes agradar a Deosque aclRey:
pultura mais eminente do que até tnascomo cfta fc levantou cefláraò
cntaõ eftivera. Vendo o Sãto quaó «s privanças,& começarão as per.
juílaeraa petição dcl Rcy, oquiz fcguiçoens. Efíavaó em Inglaterra
fatisfazer nefíc particular,& indovagos os Bifpados de Erfordia , & fe
ao Convento de Uvettmonaíí^dc Uvigornia , & como el Rey na rium,
que efià perto de Lf íidres , vagante de cada hum delles, lhe collocou
feu corpo entre o deoucomia os rendimentos, dcyxava. tros Santos,
& deu ordem como os cílar fcm paílor havia muy to felhenãodiceíTe
mais Miíla de Retempo, com grande detrimento do quicm pela alma ,
nem fc lhe reíafEftadoEcclcíiaílico, & das almas femRefponl»os'de
defuntos, ccmo daquellas Diccefis: pelo que lhe até eniaõíe fizera, &
fcyras eftas çtàio Santo Thomis híia , & muy- coufas fc tornou à fua
Igre ja^fican» ias vezes, que dcíTe Sua Alteza do naquclla antiga
benevolência, iugar aos Eleytores para cfcolhc- que tivera coro clRey,
a qual lhe t'cm Prelados que osgovernaíTem: durou muy pouco
tempo , como mas por mais inftancia que nifto coftumaô todas as
coufas fundadas fezj&pordefenganos que deu a cmprivança. Porque
dando o poclRcy o naô pode acabar , fem ai- vo a elRey para ajuda
dos gaftos da gCías admocftaçocns , mais afperas guerra húa certa
quantidade de di« do coftujiíado, com que fe veyo a nhcyroem irodo
de fubíidio , ellc concluir o negocio, & íe começou o mandava dey tar
no thcfouro das a rcfabiar o animo dcIRcy , pofto mais rendas da
Coroa , & lançallo que cntaô o naô dèíTc a entender, cm caderno ,
como coufa devida Foy cleyto na Igreja de Uvigornía por obrigação ,
ao que fe oppoz o hum homem de muytas letras, &
fantoArcebifpomcílrandolheccvirtude , chamado Henriquc^filho
moem confciencia não podia fazer de Roberto Conde Glonorienfe, tal
couía. Algum tempo depois primeyro filho na conlagraçâo de vendo
Santo Thcmàs que cíRey bantoThomàs. NoBIÍpadodeEr» naô provia
o officio de Canccllalordia, foy provido Roberto de rio,& lhe remetia
ainda os rego» Molcduno, graviílimo Doutor cm cios como no tempo
que o era , a V^ ;• C que
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T)A CH%p!h(iICA T>E CISTE% n? cjuc naõ [podia dar

expediente pc« grave, podcrlhe dar caíiigo com los muyios que tinha
cm Tua Pre- forme as leyjs do Reyno pelas juftila(ia^ lhe pedio que
o deíaliviailb ças Reaes^aâãrmando que cõ ello daqudlc trabalho ,
dando aquclla temor íerefteariaõ dcaggravar as honra aquém a
mcreceíTe , éc pu- juítiçasdclRey,ôcdeQõnicíterou» deíTe fervir como
convinha. Da troscxceíTos, quccômetiaõeílriqual petição elRey fc
refentio algú bados em lhe naõ haverem de cuftanto , mas ainda
como amigo: & tar fangue. Parecco cila propoíl» provendo a
ferventia não lhe k^míz çãodclRey muy dura de fotrcr> tirar a
fuperioridadc , & fuperin- ícndo ( como era) contra os Cano»
tendência dos negócios. Pouco nes (agrados, & contra a liberdade
•depois acontccco no Bifpado de da Igreja, pelo que fe levantou o
Salisbcria ,acuíarcmhum Clérigo fanto Arccbirpo,&ein nome de topor
morte de hum homem , a qual dos fez hua cloquentifííma pratica íe
iheinaô pede nunca provar cm 0 clRey, onde lhe moftrou a pouca
forma juridica , & íendo remetido xazaô que tinha cm fua cauía , & a
a fcu Prc lado, & acufado pelos p». -impoflibilidadc que havia noClcc
rentes do morto , & pelas juftiças %.o para lha conceder ,
accrefcentâí que com iftomitigaíTe a indinaçáo nigo chamado Filippc
de Lidroes delRey , pelo que foy rcprchendiaflrontou hum A!cayde ,
& juftiça do de bantoThomàs,& aífrontado fecular,pofto que o fanto
Arccbif» do próprio Rey com palavras folpo o caftigâíTe com msis
rigor do tas,& defcortefes. Quando clRcy que a culpa merecia , clRey
íc naõ vio a conftancia do Arccbifpo , & deu por iatisf ey to , defc
jando dar* dos outros Prelados ^ 5c que naó lhe a pena conforme
aos Leygos, queriaó íimplezmente confirmar wdizcndo que naõ
haveria peííoa cõ fua ley , mandou ao Arccbifpo que aa vida fcgura
de Clérigos, feos deyxaíTe as liberdades, & preroga■ crimes que
elles cõmetiaõ naõ ti> civas^que ainda tinha por razaõ do iVCÍTem
pena que os magoaífe: & oíficiodeCancellario, o que cllc •para tomar
niíio hum aílento a fcu fez com muy ta vontade, & fcm re» gofto ,
mandou convocar todos os pugnancia algúa , como quem naó
Prelados do Reyno, aquém pedio deíejava outra coufa* E ao
diafe^quc confentilTem quando algum guintc ante manhaa fcm fali
ar aos iClcrigo foffe achado cm delidlo Prelados ^ íe partio para
Londres, mof
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7x% L1V%0 SEXTO moftrando a indinação , & cólera clle,

pcdindolhc fc compadcccflc que levava , por medo da qual o ÍCm da
Clcrcíia , que cftava cm nfco de guiraõ logo para a Cidade j onde o
Termal tratada por fua conAancia^ B:ípo de Londres que havia dias
que houve de jurar as leys ncfta cftavafóradagraça dclRcy, aquiz
forma. Que clle guardaria os Eíalcançar com artrahir alguns Bif.
tatutos, & novas leys de Sua Aipos àíuaoptniaó,d( fazer quedei-
tcza|em boa fc caliando aquellas aroparaíTem o íantoj Arcebiípo nas
p-lavras ( falva minha ordem ) acDiãosde fcus contrários, como cm
crclccntandomais, que aílim procftcytofizcraõ; mas como allinaõ
mettia fazellas comprirem ley de ciurava icu voto , naò acabava el«
verdade. H«vido cite cautelofo juRev de fc aquietar, nem de fazer
ramcnto,mandouclReycícrevcras officios,boracon. brandurasjhora
Icysemvanos cadernos, & dallos com ameaças, para que juraíTe as a
peíloas principaes do Rcyno, a leys, ícm aqucila ciauíuia (" falva
quem competia íazellas comprir^ nanha ordem) que fempre dizia, &
pedio ao Arcebtfpo que com os 1-1 ( u e muy tos Prelados Ecclcíiaf-
outros Bifpos que alh fc acha vaô as ticos, & Príncipes
feculares,quaes íellaífem có ícus íclos,oqueo Artoraõ Hylario Biípo
Ciceftrcnfc, ccbifporecufou de fazer, dizendo Roberto Bifpo de
Erfordja, o Có- que por fcrjà tarde, &naóhavcr de de Vendonia , o
Abbadc de Ele» commodo para fc fazer feria bom mrfína , que com
rogos , & lagri» díííirillo para o dia íeguintc:& co* mas lhe pedirão^
condecendeííe no mo naqueila noyte viíTc o caderno juramento que
elRcy pedia , & naõ das Leys,& a contradicçáo q havia quizeife
peronudar húa palavra na ncllas contra os Cânones fagrados
proncíTa, ir ctcr em tribulação to- compungido em feu coração do
dooReynode Inglaterra,8c tanto n^al que tinha feyto em jurar ícm
iníiítiraó , & lhe aleviàraô o nego - íaber o que , fc foy para Cantuaria
cio, que elle fc foy a Oxofordia, fcmporofelonasleys,efcufandoonde
citava clRey , & lhe premer, fc com palavras equivocas,, de moteo
que mudaria aqutlla palavra , ào que elRcy ficou íatisfcyto. que tanto
o efcandaíizava, coufa E indo ro caminho com o roílo quecllemuyto
eflimou , & agra» melencolico, &triftc peloquetidcceocô palavras de
muyto amor, nhafeyto,ouvio murmurares fcus poílo que jà diíferentcs
das anti. ^^ inconiíancia quemolirara,cm gas , & fahidas de animo
reconci» particular oCapellaô quelhclevaíiado. QuizclRcy que
ojurameni vaaCruzdiante,qucfallandopara to fefí^eííe em publico, &
as leys outro Ihediííe. Eu naófey que virfoílcm confirmadas cem
appiaufo tudcficou àquellcquejuntocoma univerfai, para o que
convocou fama perdeu a confcicncia própria? Cortes cm Clarendonia,
onde cm E perguntando-lhe o Santo por prciença da nobreza do
Rcyno quem dizia aquellas palavras, o quizqueoArccbiípo, &maisPrc-
Capellaô rcfpondeu. Por vós o lados juraíTem de compnr as leys digo
Senhor , que hoje junto com a que elle ordenaííe acerca da Clcre-
fama arrifcaílcs a coníciencia, por fia , & povo, & pofto que houvclTe
naò defgoftar a elRey , & antepon* repugnância no Arccbiípo em ju.
do aphvança, & goíiodo Reyda raro que naõ via,&ftaccendcí?em
terra, aorcípcyto do Senhor do novos efcandalos, ao fim mfiíliraô
Ceo, quifcíks dcyxar de vôs hum cantas pcífoas de authuridade cem
perpetuo exemplo de ínconílancia con«
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DA CH%OU^lCA T>E CISTE% 719 contrario a toda

avirtude , pois ^ naõ acho ciicoufa,quc dcfculps o " ' ~ " juraméto,
que cíTas mãos fagradas CAPÍTULO V« fizeraô contra a liberdade da
Igrc* ja, Dâsleys que elReyfez y é^tManiott denaçaò. Callou-fc o
Sãto Arcebií» ao jírcekfpOy para qne as felUjJe, po a eítas palavras ,
naõ dcyxando ó' das grandes per (egui coes ^ que dcasícntir no
intimo deícucora- pa(fúu nas Cortes de Anlonapor çaò ) &
convertidos íeus olhos cm defender a íiberdaas da Igreja, duas
fontes de lagrimas> foy fai'ã» docomDeos, & pedindo-lhepcr- TTliido
à noticia delRcy o daõ de fua culpa com tanta defcon- V
arrependimento do Arceíolaçaô , q os íeus chegarão ao con- bifpo,&
a penitencia, que faziapor folar com muytas palavras , ali vi- caufa
do'}uramento, lhe mandou ando-lhe odefcyto cõ as cccafiões hum
caderno tô as leys feguintcs , que houvera para o cómetter: mas,
fque eraõ as próprias de Claren-. como nada lhe dèííe quietação,
dona} para que lhe pufcírc feu mandou hum corrcyo ao Santo Pa-
fello , & as confirmaífe , íabendo a drc , pedindo-lhe abíolviçaô da
occafíaódcdircordiajqucniílolhp culpa que cómettera, & contando-
mandava, lhe por txtenfo quanto com elR ey Efia Ibefofreo a Cttria
Romana, paflàra,pedio que IhcdèíTe pcni- i Que as Igrejas das terras
tencia do erro cõmettido,porquc a feudatanas à Coroa naó podcíTera
qualquer ficava a parclhado , ainda fem licença delRey fer providas
ia qic íoíTs renunciar a dignidade perpetuum cm peííoa alguma, nem
que tinha, pois caõ mal íabia dcten- por fua Santidade , nem por
outro der as prehcirinencias delia. Em Prelado algum, quanto efte
correyo foy, &: veyoa h(tas condenou,
Sans,ondeeftavaoPapa,feabftcvc 2 Que, fe a Juftiça Real citar, o
Santo Arcebifpo do Altar , & accuíar»ouadmoeftaralgúClengo, mais
exercício de Ordens ,perma- venha ref poder na audiência Real,
necendo em cilícios, &dicipiinas & fcja nclla julgado conforme as
continuas, fem ceifar de íuas lagri- jeys do Reyno fem a Igreja o
pomaSjatèquelhc chegou hum Breve der izentar da pena: com tanto
de exhortaçaó, ôc côfolaçôes eípi» que o Juiz faça íabcr a fcus Prcla.
rituaes, coque tornou cm fi,&co. dosacaufa,porqueojulga. brou novo
animo para refift^r às j Que,íefobrcainftituiçaó,& preteníóes delRey ,
a quem foy di. apprefentaçaó de BeneScios hou« toque jao
Arcebifpo eftavamuda- ver duvida entre Clérigos, &leydo, & naó tin
ba animo de comprir gos, ou entre leygos, & Clérigos, o
jurámento,que fizera cni Cortes, fempre a conrrovcrfia fc julgue pe*
pelo que começou ao vexar com IcsJuizcsdclRey. modos novos de
tribulação , buf» 4 Que os excomungados na5 cando de induftria
coufas, com que daraõ fiança , nem juramento para o inquictaíre,&
lhe pcrturbaíT: o comprirem aquillo, qucficàraõdc. animO' veiKio de
fuás obrigações, mas fí.' cando em fuás palavras , & limplcs promeíla
, os abíoiveraõ. f Oà Prelados Ecclefiafticos nag fahiràõ
fóradoRcynoícm li*ccnçn
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accurate

7J0 LlF%0 SEXTO ccnça dclRey , & indo faraó pro- terra ,
que o conílranjaõ a fatisfamc& de naó procurar coufa aigu» zcr: &
lendo a juíliça ncgligetits roa contra ciR£y,&fuâ Coroa.
nifto,ficaraocaftigoàvôtadedel« Eftamiíentto. Rcy, & o Bifpo
procederá coarra 6 Qaecmcaíoquc os levgos o culpado acè íatisfazer.
fcjaô accuíados perante o A rccbi í- Efla confentiraó. po . fe faça a tal
accufaçaô por ceí- i o Os Arccbifpos,& Bifpos, q temunhas^oo
legítimos accufado- dclRey tiverem rendas, terras, ofres,& naó
doutro modo,& todavia ficios , & titules, como Baroados, o
Arcediago, diante de quem a cm razaó dos quacs lhe hajaô de
accuíaçaóle fizer jíempre haverá o rcfpondcr, ou a luasjuftiças, &
dircyto,que dahi Te lhe dever j & fc Miniftros , fera 3 obrigados a
fcos culpados forem tacs , que por g^^ir , & guardar as Leys,
Ordemfuas valias naõ haja quem íe atreva çoens^òc coftumes
Rcaes, & pagaraos accufar,oJuiz fará vir ameo lhe qaaeíquer
direycos, que por Biípo doze homens bons do lugar, razaó das ditas
rendas , & terras , que conforme fuasconfcicnciasju- &c. lhe devem.
E aifim como to» remoque íoubercm,& julgará peio djs os outros
Barões haõ decftar, que lhes ouvir. & refpondcr no Juizo fccular
deiEftareprovott, Rcy , ôi guardar fuás fentenças 7 As
AppcllaçõesdoArccdia^ atè morte, &cortamento de mcmgo iraô ao
Biípo , dalli ao Ar ccbif . bro. po, & delie c m falta de Jultiça a cl •
Eftâ condenott, Rey , para que cllc mande ao Arcc- 1 1 Quando
vagar algum Ar . biípo que faça juftiça naquelleca. ccbifpado,
Biípado, ou Abbadia fo ; & dahi cm diante naõproccderà das terras
delRey , poderá levar os na tal demanda ícm ordcm,êi licen- frutos ,
& rendas dos tacs Bencfi • ça dclRcy* cios no tempo de fua vacante
, coEííás condenou. mo le foraô rendas Reaes. E quan8 Se por
raantinjento^ou fala- do fe houver de fazer clcyção, fera rio de
ordens recrecer duvida en. na Capclla dclRcy , aíliítindo com trc
Clérigo , &: Icygo , gffirniando os clcy torcs as pcfToasque eMe or •
cada qual que pertence a leu foro, denar , .$£ o que for eJey toantes
de fe determinara por doze homens lua fagragâo, prometterà fiel
vafbons fera fufpeyca diante de Juiz fa lagcm a eIRey como legitimo
fccular , & no Juízo que eílesdc- fcnhor, & que naô fera contra fcu
terminarem íc tratará a duvida , íerviço , vidi , peíloa , Eílado
temfalvo feas partes ambas fe louva- poral, íalva fua ordem. rem no
Bifpo. Porèm quando os Eftas lhe çonientirao. doze louvados
dcterminareo) o 12 Se algum dos grandes do foro,a que compete,
nem por ííTj Rcyno aggravar para os Prelados fcrà nenhum
esbulhado de tua pof- Eccleíiaííicos>& lhes ufurpar íeus fcaté
afcntençafinal. bens, aelRcy convém o juizo deite 5> Se algum
morador em terras cafo. E havendo quem ufurpe bens ão património
da Coroa for citado da Coroa , os taes Prelados ficcleperancc algum
Bi fpo,& naó qjizer íiaílicos conftrangeraó os culpaacoiir,podcra j p
jrlhe interdidlo : dos a meter elRcy na poíTc do que mas antes de
procederem com Iheufurpàraò. excomunhões , fera requerido o ij
Do> contratos de dividas Juíliça n òr dclRcy , & o daqudia que fe
fizerem , hora íirmadois com 3 jura.
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accurate

T>A CH%0:NÍ1CA 'DE CISTE% 731 juramento , hora

fcmelle,fc toma* que acbdio o Capcllaõ , & vendo rà conhecimento
na Cúria Real. feu Pafíor daqucllc modo , íe lan1+ Os filhps de
lavradores , & çou a feus pés cuberto de lagrimas, gente de aldeã
naô fcraô admitti- nacidas de triíteza, & compayxaô dos a Ordens
facias íem confcnti» de ver taõ grande peííoa cercada mento do
fenhor daqucllas terras, de tantos trabalhes, & pedindoihc donde íaõ
naturacs. íc recolheíTe para dentro , lhe prc. Quando o fanto
Arccbifpo leu parouo agazalho na melhor forma as injuftas leys , que
contra a de poffivcl , & paíTando a noyte com Deos jurara nas Cortes
de Claren- alguns Religiofos que fez chamar, dona, culpando-fc
novamente pelo lhe eucve contando como as ondas erro commettido
, & animando fc do mar contraftàraõ a fua navegapara a íatisfaçáo ,
repugnou à pre- ção taô furiofamcntc , que íem
dutcnfaòdelReVj&naõquiz em mO' vida moílràraófervirnaquelle pardo
algum lellar o caderno que lhe licular de inítrumentos da juftiça
mandara, antes determmou paf- Divina. Ao dia feguinte chcgàraÕ
far a F rança , & praticar com o Sú- cercos officiaes delRey para
lançamo Pontifice neftas matérias, para r>em maõ dos móbeis do
fanto Aro que fe preparou íecretamente , & cebifpo , que diziaõ íer
devolutos metendo-fc em hum navio fretado ao Fifco Real por íua
fugida do à fua conta , fez vela em tal conjun» Reyno , ôc quando o
acharão nos çáo, que o mcfmo ímpeto do mar Paços , & viraó fua
peíToa, ufando ofez dar algúas vezes em terra, de diílimulação ,
converterão a moftrando fer vontade do Senhor diligencia em v iíití .
E o Santo para que íicaífe no Reyno para com ma- inreyrar a elRey
de íua prcícnça, & yores pcríeguições pagar a fraque- atalhar hnguas
de murmuradores, za paííada, & moítrar hum raro o foy vi fitarão
lugar deUvodfcolc exemplo de conftancia àquclles, q onde ao
preíente eítava , & poíto íc cfcandalizàraô de íua queda. Sa» que o
interior cílivcíTc bem diífe* bendo oscríados do lanto Arce« rente áo
paíTado, nasmoítras cx» bifp 1 de fua ida, & temendo ain- teriofes
foy o Santo recebido dcldinaçáodclRey , fc foraó cada hum Rey com
moftras de muy to favor, a fud parte, (alvo humCapelIaõ, &
benevolência , agradecendolhc que fe foy a Cantuaria , íi de noy fua
vinda , & motejandolhe como te Ic mctco nos Paços do Arccbif- cm
modo de corre a fugida encupo , porque os naô roubaíTem : & berça
, Sr a contrariedade de condicomonaquclla noyte cftiveíTe pra-
çoens.quecraôcaufa de ambos naó ticandocomíigo,&cuydandonos
caberem no Reyno. E como íc o trabalhos do Santo, & na revolta
fanto Arcebifpo tornaíFe poucos que havena no Rcyno,íabendo fua
dias depois a Cantuaria,& moítrafpartida , mandou jà alta noyte a hQ
fc em publico , & íecretamente o moço, que tinha comfigo , que to«
animo contrario às leys novâS,que malTehúa candea,&foíre fecharas
clReyconítituira, dizendo que em portas do Paço,& faindoà fala bem
nenhum modo as confirmaria , eldeícuydado de tal fucceíTo, vio o
Rey o quiz defautorizar com lhe lanto Arccbifpo citar fcntado a tirar o
cargo, que tinha de Legado hum canto íò , triftc, & muy pen»
Apoftolico no Reyno de Inglaterfativo , de que o moço ficou taõ ra,
annexo aos Arcebifpos de Cancfpantado , que cuydando fer fan-
tuaria : & mandando Embayxadotafma, deu dous grandes gritQS, a
tci à Corte do Papa , tanto infiíli. raõ
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accurate

731 LIV%0 SEXTO raó com ellcs, que houve de conce-

emfabendo que elRey da nofio Breve der a eiRey o que pedia ,
rcíalvaii- ao dito Arcebifpo (o que naõcremos fado todavia que
nenliúa pcflba,Cín rà femprimeyro no lo fa;^er a faber ) que a
Lcgacia íe provcíTe , foíTc ou- logo por fiel menjageyro no lo efcre»
íada de entender cm coufa algúa i^aisf para cjue declaremos como
"Z/offa do Arv ebifpado de Cantuaria , né igreja , OpeJJoa , Cí?» a
Cidade deCana peíToa , & bens do Arccbiípo lhe tuaria^que tendes a
carguy faopor an' foíTem fui^eytos em nada. Ficou
thoridade^poftoUca t;^ntasdodirey clRey taóutanocomaquella líccn-
to ^^ júri fdic fio datai jgreju çado Papa, que em publico ,& it* Com
cite Breve do Papa ficou o cretamente mofava de S. Thomàs, fanto
Arccbifpo muy confolado,ôc como de homem que jà tinha Tu» com
hum novo animo para reíiííir geyto a outro Legado , que foy o aos
intentos delRey ,fcm o movcré Arcebifpo Eboraccníc contrario os
temores, & novas ameaças, que cm tudo à opinia6,& conílancia de
cada hora lhe fobrevinhaõj & como Santo Thomas. Diffimulou o Sã •
o Santo perfeveraflc em contrariar to com grande prudência aquelle
asleys,&cÍRey infiíHíTe em asfadisfavor do Summo Pontifíce,por zer
com prir , mâdou chamar Cornaõ dar gofto a feus inimigos , tes dos
Eftados do Reyno para a mas por cartas fe queyxou a cllc , ViIIa de
Antona , & cirar juridica. moftrandolhe quaõ pouca razaó mente a
Santo Thomàs , para que cradefarmar da dignidade de Le- cm certo
dia compareceíTc neilas, gado hu homem , que fe via cm tan- &
refpondcíTe às culpas, que fc lhe tos perigos , por defender a caufa
pufeííem. Naõ deu o Santo muy to de Chriíto , & a honra , & lib rda*
pela citação Real , vendo que na5 de de fua Igreja. E vendo o íanto
era fugcyto a feu juizo: mas por Padre quanta razaõ tinha o Santo,
cortcíiajôc reverencia dei Rey manoconfolou por Breve particular >
dou hum Procurador, que em feu cujo teor he o ícguinrc. ; o r>iíp
nome rcrpondeífe o que convinha ; Alexandre Papa III a Thomàs ^r-
O qual foy taô mal acey to , que fem cebifpo de Cantuaria. Naõ he
ra^aÕ o quererem ouvir ícntenciàraõ o que vojio animo fe confuma
em la^n* Santo a perdimento de feus bens mas ^or caufa da
Legacia,que cones» moveis , & os confíícàraò para a demos a eiRey
de Inglaterra , porque Coroa , h. Camará Real, dey xando antes de
nos movermos ao conceder ^0* a execução da fentença na vontade
darmos a ifto conjentimento os Embaj • dclRey . Sentio o Santo cfte
atrevixadores delRey nos prometterao com mento naó tanto por
ÍÍ,COmopela firme "Verdade ioda a fegurança pojji fraqueza dos
BiTpos , & Prelados, ^el{Ú7* ainda no la queriaÕ ratificar que alli fe
achàraõ^ em que teve com Juramento ) que nunca delRsJ dá' niais
força o rcfpey to dclRey , que ria o Breve da Legada t que lhe man'
ode Jcfu Chrlft& , ôc porque O mal damos ^ ao ^rcebifpo
Eboracenfe fem naô procedcíTc avante damaneyra noija
licençaf&^fem primeyro no íofa» ^ue começara , fe vcyo o SantO
Ar:^erafaberf &" crede [em duvida que cebifpO à Viila de Antona , &
na inuncafoy no[]a tenção ( n em fera me» fegunda Scífaõ das
Cortes lhe pe« diante o favor Divino^ que vcffa igre^ dio clRey
quinhentas libras de praja^ &* peffoafejaÕJugeytas , nem obe» ta ,
de que aigum tempo antes lhe deção no foro Ecclefiaflico a outra
pef- fizera mercê para ajuda de cufta, foa fora do Romano Pontífice,
Peloque &poftoqueoSantoallegaíreomo-^w admoefiamos^ C^
mandamos que do, porque lhe foraõ dadas , ôc fe conhc 
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V A C B%0 :J\(Í1 C A Ti E C1STE% 733 conheccíTc o mao

termo delRcy Ao Domingo, & ícgunda fcyra cf • nclic particular ,
todavia lhe con- teve o Santo muy atormentado de veyo dar alli
fiadores, que fícàraó cólica , como o era algumas vezes, pela
rcftituiçaô da quantia. Na ter- poílo que cl Rcy cuy dou fcr o mal cey
ra fcíTaõ das Cortcs,quc foy cm fingido para naó ir ao Paço. Na
mahum Sabbado , mandou clRcy fe- nháa da terça feyra fe foraõ os
Bifchar em hum retrete a Santo Tho- pos viíitar o Santo antes de ir
ante màs , Ôc aos mais Biípos , & lhes clRcy , dizendo-lhe que
eftavaõ as mandou notificar que concluiíTcra coufas em cftado , que
íe naó obena obediência de íuasley sem todo decia, quando
cfcapaíTe da morte, cafo, porque íe naó procederia nas o mandariaõ
prender cm ferros, & Cortes até ifto íe concluir , & por o julgaria5
por traidor, & perjuro afíligir o Santo lhe mandou que fe à Coroa Real
: & conhecendo o aparelhaíTe para dar conta dos red« Santo como
aquclles confelhos naf* ditos de muy tos Bifpados , & ciaõ de animo
inclinado adarqualAbbadias, em cujas vacantes os
querfentcnçaqueclRcymandaíTe, cllc arrecadara , fendo graõ Can-
lhe éíiranhou a que tinhaõ dado ccllario do Reyno , fcm até entaó
contra clle,& com cenfuras Eccicíi • ter dadodefcarga. Aiílo reípon-
aílicas (de que logo appellou o deo o Santo por confclho de Hen»
Bifpo de Londres) Ihesmãdou que rique Bifpo de Vintonia, que favo-
mais fe naõ intromctteílem em juU recia fuás partes, que ao tempo
gar caufa fua, pois era abufo , & que fora cleyto em Arcebifpo de
monftruofidade , fer o pay julgado Cantuaria , o dera Sua Alteza por
dos filhos, o Prelado dos lubditos, livre, & quite de todos os encar-
&o Paftor das ovelhas. Idos elles gos daquclle officio , & por fatis.
foy o Santo celebrar, & diíle a MiíTa feytas as dividas , ôc contas que
de Santo Eílevaó , cujo Intróito nellc havia , por onde naõ havia lu-
começa : Etenim feder ut Príncipes^ gar aquella notificação dclRey ,
e^ adverfâm me loquehantur, que nem elle tinha obrigação de lhe
rei- quer dizer. Aílim que fe fentàraõ pondcr de outro modo. Quanto
à os Principes , & faziaó coníultas deliberação de refponder às pre»
contra mim jO qual facrífício ceie* maticas delRey com cíFeyto de
brou comPallio, coufa queíó fe obediência, diife que em tudo o
coíluma nas feílas, dando naquclla que naõ prejudicaíle aos Cânones
novidade a entender outra,quc ha . fagrados,&à liberdade EcclefiaíU-
via derefultar de fua conílancia. ca, obedeceria a clRcy como a íeu
Acabada a MiíTa , fcm tirar as vcf* fcnhor natural ; mas que havendo
tcs Sacerdotaes, mais que o Pallio, de permcyo o refpcyto da Igreja,
vcftio cm fíma huma loba preta, cílava prompro a derramar feu com
que as encobria, 6í com fua fangue primeyro que obedecerlhe Cruz
diante fefoy ao Paço corrocontra íuaconfcienciai& por mais
boradocom a graça Divina, & com qucoBifpodcLondreSj&oCiccf- o
Sanciíli mo Sacramento da Eu* trenfe o incitarão ao contrario , &
cariília , que recebera havia taõ hum dcllcs indo com recado a cl-
pouco, & ainda dizem alguns que Reyjhedeu aentenderqueo Ar- o
levava fecrctamente comíigo. ccbifpQconlcntiria cm tudo, clleo
Quando havia de entrar no apo* fez ficar confufo, & permanecendo
fcnio dcl Rey , tomou a Cruz das cm fua conftancia , fe deu por
mãos de Alexandre feu Capellaó, aquclle dia fim a citas coiKcndas. &
a levou por fi mefmo, fcm a queQqq rcr
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