Bone dysplasias : an atlas of genetic

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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
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 CONTENTS

Foreword xi 4.3 Spondyloepiphyseal Dysplasia Congenita

John M. Opitz (MIM 183900) 72

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

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

2.2 Multiple Epiphyseal Dysplasias, Autosomal 5.1 Dysostosis Multiplex 109

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

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

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

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

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

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

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

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

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

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

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

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

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

14.6 Osteogenesis Imperfecta, Type IV 17.3 Dysplastic Cortical Hyperostosis Type

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

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

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

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

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

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

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

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

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

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

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 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
Campomelic dysplasia AD
Tricho-​rhino-​phalangeal syndrome AD
Dyschondrosteosis XD
Achondroplasia family (thanatophoric dysplasia, AD
achondroplasia, hypochondroplasia, others)
Craniosynostosis (various types) AD
Metaphyseal dysplasia type Jansen, Blomstrand dysplasia AD
Robinow syndrome (COVESDEM) AR
Note. AD = autosomal dominant; AR = autosomal recessive.
In contrast to dysostoses, dysplasias do not result from a
disturbance of the skeletal blueprint but from perturbation
of growth and homeostasis of cartilage and bone as tissues.
“Primary” skeletal dysplasias result from mutated genes that
are expressed in chondroosseous tissue (e.g., collagen 1 in
bone and collagen 2 in cartilage). “Secondary” dysplasias
are caused by abnormalities of extraosseous factors with
secondary effects on the skeletal system. Examples are
skeletal abnormalities caused by metabolic errors, such as
hypophosphatemic rickets, or endocrine disease, such as
hypothyroidism. Since skeletal dysplasias are disorders of
cartilage and bone as tissues, mutations of dysplasia genes
affect those tissues at all anatomic sites. Homologous sites
are affected, and the resulting disorders are mostly sym-
metric. Short stature is common. The expression may be re-
stricted to, or vary quantitatively in, body segments leading
to disproportionate forms of short stature, for example,
spinal, rhizomelic, mesomelic, and acromelic dysplasias.
Asymmetric lesions, such as in enchondromatosis, mul-
tiple cartilaginous exostoses, or fibrous dysplasia, develop
under the influence of local mechanical factors or somatic
mutations. Primary dysplasias may result from mutated
signaling genes or from genes affecting cell structure and/​
or function.
Dysplasias due to mutated transcription factors and
signal-​transducing genes: In contrast to the genes respon-
sible for dysostoses, dysplasia-​causing signaling genes are
expressed after early embryogenesis and remain active after
birth. Accordingly, mutations lead to postnatally ongoing
errors of cell proliferation, differentiation, and degener-
ation and thus to defective skeletal growth and develop-
ment. Examples are achondroplasia, the Jansen type of
metaphyseal dysplasia, and others (Table 1.2). Both achon-
droplasia and Jansen metaphyseal dysplasia are disorders
of the growth plate: in achondroplasia, chondrocyte
proliferation is reduced because of a mutated fibroblast
growth factor receptor, FGFR3. In Jansen metaphyseal
dysplasia the mutant PTH/​PTHrP receptor suppresses
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Gene Protein
SOX9 SOX9 transcription factor
TRPS1 TRPS1 transcription factor
SHOX SHOX transcription factor
FGFR3 Fibroblast growth factor receptor 3
FGFR1,2,3 Various fibroblast growth factor receptors
PTHR PTH/​PTHrP receptor
ROR2 Receptor tyrosine kinase-​like orphan receptor 2
the differentiation of proliferating chondrocytes into hy-
pertrophic cells and inhibits mineralization wherever
the PTH/​PTHrP receptor is expressed. Some transcrip-
tion factors also play a pivotal role in signal transduction;
hence, their mutations are responsible for dysplasias.
Dysplasias due to mutations of genes that regulate cell
structure and/​or function: A second group of bone dysplasias
is caused by mutations in genes regulating cellular structure
and function. With differentiation, cells assume special
functions—​notably the production or removal of matrix
components. Thus a skeletal dysplasia might originate from
a mutated gene that encodes a faulty cell product such as
collagens. Other skeletal dysplasias result from defective in-
tracellular transport or degradation systems. In diastrophic
dysplasia, for instance, the transport of sulfate, crucial for
the synthesis of sulfated proteoglycans, is impaired, and in
pycnodysostosis, the extracellular matrix cannot be prop-
erly degraded because of cathepsin K deficiency. A defec-
tive vacuolar proton pump interferes with bone resorption,
leading to an infantile form of osteopetrosis. Cellular func-
tion may also be more generally impaired as in cartilage-​
hair hypoplasia, where RNA processing is impaired, or in
Schimke immunoosseous dysplasia, in which DNA repair
mechanisms are defective. Mutations of the genes control-
ling these functions may be expressed during fetal life, as in
severe cases of osteogenesis imperfecta or diastrophic dys-
plasia. Other mutations of the same gene become apparent
only during later life, as exemplified by mild cases of oste-
ogenesis imperfecta or diastrophic dysplasia. However, as
in late-​manifesting signaling defects, most genes disrupting
cellular structure and/​or function are not involved in early
embryogenesis. Examples are listed in Table 1.3.
O S T E O LY S E S
Osteolyses are disorders in which the primary development
of skeletal elements and the first phases of growth are normal
but are followed by a phase of gradual bone resorption
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 EXA MPLES O F DY SPLASI AS AN D OS TEOLY S ES C AUS ED BY DEF EC TS IN C EL L UL A R
TA B L E 1 . 3
FUNCT ION A ND/​O R STRUCTURE
Name Inheritance Gene Protein

Osteogenesis imperfecta, dominant forms AD COL1A1, COL1A2 Collagen 1 protein

Osteogenesis imperfecta, recessive forms AR Various Various

SED congenita family (achondrogenesis type 2, AD COL2A1 Collagen 2

hypochondrogenesis, Kniest dysplasia, SEDC, Stickler
arthroophthalmopathy, premature arthrosis, etc.)

Metaphyseal dysplasia, Schmid type AD COL10A1 Collagen 10

Pseudoachondroplasia and Dominant multiple epiphyseal AD COMP Cartilage oligomeric matrix protein
dysplasia (one form)

SED tarda, X-​linked XLR TRAPPC2 Sedlin

Achondrogenesis 1B, Diastrophic dysplasia, Recessive AR SLC26A2 Cell membrane sulfate transporter DTDST
multiple epiphyseal dysplasia

Dyssegmental dysplasia, Schwartz-​Jampel syndrome AR HSPG2 Perlecan

Hypophosphatasia AR TNSALP Tissue nonspecific alkaline phosphatase

Mucopolysaccharidoses, Oligosaccharidoses (multiple types) AR, XLR Various Several lysosomal hydrolases

Osteopetrosis, infantile AR TCIRG1 Proton pump subunit

Osteopetrosis and renal tubular acidosis AR CA2 Carboanhydrase2

Pycnodysostosis AR CTSK Cathepsin K

Multicentric osteolysis Winchester-​Torg AR MMP2 Matrix metalloproteinase 2

Metaphyseal anadysplasia AD, AR MMP9, MMP13 Matrix Metalloproteinases 9 and 13

Note. AD = autosomal dominant; AR = autosomal recessive; SED = spondyloepiphyseal dysplasia; SEDC = spondyloepiphyseal dysplasia congenital type; XLR = X-linked recessive;
DTDST = diastrophic dysplasia sulfate transporter.

that may eventually lead to the disappearance of skeletal
elements. Some forms of osteolysis are generalized, while
some are more or less restricted to a group of bones (e.g., the
carpal-​tarsal osteolyses). The pathogenesis must reside in a
defect of homeostasis; bone is formed and can grow, but a
defect in its “trophism” leads to gradual reabsorption and
lysis. In one of the most dramatic osteolyses, the Winchester-​
Torg syndrome, the genetic defect in the metalloproteinase
2 (MMP2) is believed to result in defective activation of
TGFβ, but the pathogenesis is not yet entirely understood.
MIXED DISORDERS
osteoblast-​specific genes encoding osteocalcin, osteopontin,
and type I collagen. In heterozygous mice, the CBFal defect
leads to osteoporosis, and in humans it is probably respon-
sible for the postnatal changes seen in cleidocranial dysostosis,
such as metaphyseal changes and stunted growth. In the re-
lated condition, spondylo-​megaepiphyseal-​metaphyseal dys-
plasia, there is a severe dysostosis affecting clavicles, pubis, and
vertebrae but the continuing action of the gene in childhood
is reflected by the appearance of numerous pseudoepiphyses
and metaphyseal dysplasia. Other “dysosto-​dysplasias” re-
flecting the disruption of both early patterning and of later
cell structure and/​or function are listed in Table 1.4.1

Mutations of genes that are expressed during early embryo-

genesis and remain active during later prenatal and postnatal
life result in disorders combining single bone defects, or
dysostoses, and ongoing tissue defects, or dysplasias (Figure
1.1). An example of such “dysosto-​dysplasia” is cleidocranial
dysostosis. It is caused by mutations of the RUNX2 gene
encoding the transcription factor CBFal. CBFa1 acts as an
activator of osteoblast differentiation during embryogen-
esis and its mutation has early “dysostotic” effects, for ex-
ample on the development of the clavicles. However, the
gene is also active postnatally, regulating the expression of
RECOGNITION AND PRACTICAL IMPLICATIONS
OF DEVELOPMENTAL CATEGORIES
Differential criteria of dysostoses, disruptions, and
dysplasias are summarized in Table 1.5. Although
1
The original names of cleidocranial dysostosis and metaphyseal dysostosis (Jansen,
1934) have been replaced by the names of cleidocranial dysplasia and metaphyseal
dysplasia in the 1970 Nomenclature. On the other hand, the old term dysostosis
multiplex, used to defi ne the pattern of bone changes in the mucopolysaccharidoses,
has remained in use although the bone disease is clearly a dysplasia.

xxii I ntroduction
TA B L E 1 . 4 EXA MPLES O F D E F ECTS LEAD I N G TO C OM BINED DIS OR DER S ( DY S OS TO- D
Name Inheritance
Cleidocranial dysostosis AD
Campomelic dysplasia AD
Spondylo-​megaepiphyseal-​metaphyseal dysplasia AR
Grebe/​Hunter-​Thompson dysplasia AR
Nail-​patella syndrome AD
Note. AD = autosomal dominant; AR = autosomal recessive.
occasionally it may be difficult to classify a given disorder,
closer analysis of its development may help in the assign-
ment to one of the different etiopathogenetic groups. If
the disorder dates back to early embryogenesis and affects
the skeletal patterning blueprint, it has the elements of
a skeletal malformation (i.e., a dysostosis). When a dis-
order manifests after organogenesis and when it impairs
cellular development, structure, or function and tissue
homeostasis, it is a dysplasia. Crouzon syndrome appears
to be a dysplasia, although it has been named craniofa-
cial “dysostosis.” Allelic mutations may have generalized
or localized effects. The G380R mutation of the FGFR3
gene leads to achondroplasia and the P250R mutation to
coronal craniosynostosis. Knowing that the FGFR3 gene
is postnatally expressed, one has to conclude that both
are dysplasias, one generalized and the other localized,
even though one is tempted to call the isolated skull de-
fect a “dysostosis.” Analysis of a given condition may
help predict the stages and principal function of an un-
known gene. Thus it can be predicted (a) that the gene
causing chondroectodermal dysplasia is a signaling gene
expressed in the acral skeleton, heart, teeth, and other
organs and (b) that it is expressed during organogenesis
and remains expressed throughout postnatal life. Dosage
may influence the time of gene expression. Heterozygous
CDMP1 (GDF5) mutations result in brachydactyly C—​
an embryogenetic defect. Brachydactyly C is a dysostosis.
Homozygosity for CDMP1 mutations leads to Grebe
dysplasia. From this we must conclude that a full dose of
the CDMP1 effect is needed to ensure normal early limb
TA B L E 1 . 5 DIFFE RE N TI AL CRI TERI A O F DYS OS TOS ES A ND DY S P L A S IA S
Dysostoses
Primary Secondary
Affected structure Skeletal element as organ
Distribution Mostly symmetric, often mildly asymmetric, in some cases even unilateral
Determination period Organogenesis Growth period
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​ YSPLASIAS)
Gene Protein
RUNX2 Runt transcription factor
SOX9 SOX9 transcription factor
NKX3–​2 NKX3–​2 homeobox transcription factor
GDF5 (CDMP1) Growth and differentiation factor 5 (Cartilage-​derived
morphogenic protein 1)
LMX1B Lmx1b homeodomain protein
development but that half the dose suffices to allow for
normal skeletal development after the eighth week of
embryogenesis.
The distinction of dysostoses, disruptions, and
dysplasias has practical implications. For example, the
search for detrimental environmental influences should
focus on dysostoses rather than on skeletal dysplasias.
On the other hand, metabolic studies should focus
on dysplasias, as inborn errors of metabolism produce
dysplasias, not dysostoses. A third practical considera-
tion concerns malignant degeneration. Since dysostoses
are finite disorders caused by a past, closed process,
there is no danger of malignant degeneration. An extra
finger will not become malignant. This is not always true
for dysplasias. Dysplasias, by definition, are caused by
mutations of postnatally expressed genes. Some mutated
genes involved in cell proliferation or apoptosis may pre-
dispose to malignant degeneration. Examples for this are
multiple exostoses, enchondromata, notably in combina-
tion with hemangiomata (i.e., the Maffucci syndrome),
and fibrous dysplasia. Thus examining a child with a
dysostosis and dysplasia, looking at radiographs, using
morphology to pinpoint a specific diagnosis, and asking
for a diagnostic test is challenging and rewarding. Trying
to address the pathogenesis—​by asking when this dis-
order originated and whether it affects cartilage, bone,
or the growth plate, or the body biochemistry—​adds an-
other fascinating dimension to the diagnostic process and
brings us much closer to understanding the patient and
his or her disorder.
Skeletal Dysplasias
Primary Secondary
Bone and/​or cartilage as tissues
Mostly symmetric
Growth period
xxiii
 BIBL IOGRA PHY Jansen M (1912) Achondroplasia—​ its nature and its cause.
Leiden: Brill.
Albers-​Schönberg H (1904) Röntgenbilder einer seltenen Jansen M (1934) Über atypische Chondrodystrophie (Achondroplasie)
Knochenerkrankung. Münch Med Wochenschr 51:365. und über eine noch nicht beschriebene angeborene Wachstums-​
Bergsma D, McKusick VA, Dorst JP (eds.) (1969) The First Störung des Knochensystems: Metaphysäre Dysostosis. Z Orthop
Conference on the Clinical Delineation of Birth Defects—​Part IV: Chir 61:255–​286.
Skeletal Dysplasias. Birth Defects: Orig. Articles Series, Vol V, no. 4. Kaufmann E (1892) Untersuchungen über die sogenannte foetale
Bergsma D, McKusick VA, Hall JG et al. (eds.) (1969) The First Rachitis (chondrodystrophia foetalis). Berlin: Verlag von Georg
Conference on the Clinical Delineation of Birth Defects—​Part III. Reimer.
Limb Malformations. Birth Defects: Orig. Articles Series, Vol V, no. 3. Komla-​ Ebri D, Dambroise E, Kramer I, et al. (2016) Tyrosine ki-
Bloch A. (1909). Observations sur les nains du jardin d'acclimatation. nase inhibitor NVP-​B GJ398 functionally improves FGFR3-​related
Comparaison avec d'autres nains déjà décrits, et avec les pygmées. dwarfism in mouse model. J Clin Invest 126:1871–​1884.
Bull Mém Soc Anthropol (Paris) V° Série, 10:533–​574. Kozlowski K, Maroteaux P, Silverman F, Kaufmann H,
Bonafe LV, Cormier-​Daire V, Hall C, et al. (2015) Nosology and Spranger J (1969) Classification des dysplasies osseuses. Ann
classification of genetic skeletal disorders: 2015 revision. Am J Med Radiol 12:965–​1007.
Genet A 167. Kozlowski K, Maroteaux P, Spranger J (1967) La dysostose
Brante G (1952) Gargoylism: a mucopolysaccharidosis. Scand J Clin spondylo-​métaphysaire. Presse Méd 75:2769–​2774.
Lab Invest 4:43. Lamy M, Maroteaux P (1960) Le nanisme diastrophique. Presse
Caffey J (1946) Infantile cortical hyperostoses. J Pediat 29:541. Méd 68:1976–​1983.
Camurati M (1922) Di un raro caso di osteite simmetrica ereditaria Lamy M, Maroteaux P, Frézal J (1958) Les chondrodystrophies
degli arti inferiori. Chir Organi Mov 6:662. génotypiques. Définition et limites. Sem Hôp Paris 34:1675–​1679.
Chu ML, Williams CJ, Pepe G, et al. (1983) Internal deletion in a Langer LO, Baumann PA, Gorlin JJ (1967) Achondroplasia. Am J
collagen gene in a perinatal lethal form of osteogenesis imperfecta. Roentgenol 100:12–​16.
Nature 304:78–​80. Ledoux-Lebard R, Chabanei D, Dessane M L’ostéopoecilie forme
Cohn DH, Byers PH, Steinmann B, et al. (1986) Lethal osteo- nouvelle d’ostéite condensante généralisée sans symptomes clinique.
genesis imperfecta resulting from a single nucleotide change in J Radiol Electrol Med Nucl, 1916-1917, 2, 1.
one human pro alpha 1(i) collagen allele. Proc Natl Acad Sci U S Lee B, Vissing H, Ramirez F, et al. (1989) Identification of the mo-
A 83:6045–​6047. lecular defect in a family with spondyloepiphyseal dysplasia. Science
Cohn DH Starman BJ, Blumberg B, et al. (1990) Recurrence of le- 244:978–​980.
thal osteogenesis imperfecta due to parental mosaicism for a dom- Léri A, Joanni J (1922) Une affection non décrite des os: hyperostose
inant mutation in a human type I collagen gene (COL1a1). Am J “en coulée” sur toute la longueur d’un membre ou mélorhéostose.
Hum Genet 46:591–​601. Bull Soc Méd Hôp Paris 46:1141.
Cohn M (1933) Konstitutionelle Hyperspongiosierung des Skeletts Léri A, Weill J (1929) Une affection congénitale et symétrique du
mit partiellem Riesenwuchs. Fortschr Roentgenstr 47:293–​298. développement osseux: la dyschondrostéose. Bull Soc Méd Hôp Paris
De Duve C. (1959) Lysosomes, a new group of cytoplasmic particles. 53:1491–​1494.
In: Subcellular particles. T. Hayashi. New York: Ronald Press. Maroteaux P, Lamy M (1959) Les formes pseudo-​achondroplasiques
De Duve C, Pressman BC, Gianetto R, et al. (1955) Tissue frac- des dysplasies spondylo-​épiphysaires. Presse Méd 67:383–​386.
tionation studies. 6. Intracellular distribution patterns of enzymes in Maroteaux P, Lamy M. (1961) Les chondrodystrophies génotypiques.
rat-​liver tissue. Biochem J 60:604–​617. Paris : L’Expansion Scientifique Française.
Dorfman A, Lorincz AE (1957) Occurrence of urinary acid muco-​ Maroteaux P, Lamy M (1964) Achondroplasia in man and animals.
polysaccharides in the Hurler syndrome. Proc Nat Acad Sci USA 43:443. Clin Orthop Relat Res 33:91–​103.
Enderle A, Meyerhofer M, Unverfehrt G (eds.) (1994) Small Maroteaux P, Lamy M, Bernard J (1957) La dysplasie spondylo-​
people—​great art. Hamm: Artcolor Verlag. épiphysaire tardive. Description clinique et radiologique. Presse Méd
Engelmann G (1929) Ein Fall von Osteopathia Hyperostica 65:1205–​1208.
(sclerotisans) Multiplex Infantalis. Fortschr Roentgenstr 39:1101. Maroteaux P, Spranger J, Wiedemann HR (1966) Der
Fairbank HAT (1947) Dysplasia epiphysialis multiplex. Brit J Surg metatropische Zwergwuchs. Archiv für Kinderheilkunde
34:225–​232. 173 :211–​226.
Fairbank, HAT (1951) An atlas of general affections of the skeleton. Maroteaux P, Wiedemann R, Spranger J, Kozlowski K, Lenzi
Edinburgh: Livingstone. L (1968) Essai de classification des dysplasies spondylo-​epiphysaires.
Faure C, Kaufmann HJ, Kozlowski K, et al. (1970) International Lyon, France : SIMEP Editions.
nomenclature of constitutional diseases of bones. Ann Radiol Mckusick VA, Eldridge R, Hostetler JA, et al. (1965) Dwarfism
13(7):455–​464. in the Amish. II. Cartilage-​hair hypoplasia. Bull Johns Hopkins
Garcia S, Dirat B Tognacci T, et al. (2013) Postnatal soluble Hosp 116:285–​326.
FGFR3 therapy rescues achondroplasia symptoms and restores bone Morquio L (1929) Sur une forme de dystrophie osseuse familiale. Bull
growth in mice. Sci Transl Med 5:203ra124. Soc Pédiat Paris 27:145–​152.
Giedion A. (1966) [Tricho-​rhino-​phalangeal syndrome]. Helv Paediatr Parrot J (1878) Sur la malformation achondroplasique et le Dieu Ptah
Acta 21:475–​485. Bull S Anthr, 3ème série, 1:296–​308.
Hermanns P, Lee B (2001). Transcriptional dysregulation in skeletal Parrot J (1886) Maladies des enfants—​la syphilis hereditaire et le ra-
malformation syndromes. Am J Med Genet 106:258–​271. chitis. Paris : Librairie de l’Academie de Medecine.
Hunter C (1917) A rare disease in two brothers. Proc Roy Soc Med Pyle E (1931) A case of unusual bone development. J Bone Joint Surg
10:104. Am 13:874-​876.
Hurler G (1919) Über einen Typ multipler Abartungen, vorwiegend Rathbun JC (1948) Hypophosphatasia, a new developmental anomaly.
am Skelettsystem. Z Kinderheilk 24:220. Am J Dis Child 75:822.
Jacobsen CM (2017) Application of anti-​sclerostin therapy in non-​ Ribbing S (1937) Studien über hereditäre multiple Epiphysenstörungen.
osteoporosis disease models. Bone 96:18–​23. Acta Radiol suppl. 34.

xxiv I ntroduction
Rousseau F, Bonaventure J, Legeai-​Mallet L, et al. (1994)
Mutations in the gene encoding fibroblast growth factor receptor-​3
in achondroplasia. Nature 371:252–​254.
Rubin P (1964) Dynamic classification of bone dysplasias. Chicago: Year
Book Medical Publishers.
Scott LJ (2016) Asfotase alfa: a review in paediatric-​ onset
hypophosphatasia. Drugs 76:255–​262.
Shiang R, Thompson LM, Zhu YZ, et al. (1994) Mutations in the
transmembrane domain of FGFR3 cause the most common genetic
form of dwarfism, achondroplasia. Cell 78:335–​342.
Simsek-​Kiper PO, Saito H, Gori F, et al. (2016) Cortical-​bone
fragility—​insights from SFRP4 deficiency in Pyle's disease. N Engl
J Med 374:2553–​2562.
Spahr A, Spahr-​Hartmann I (1961) [Familial metaphysial dysostosis.
Study of 4 cases in siblings]. Helv Paediatr Acta 16:836–​849.
I ntroduction
Spranger J (1988) Bone dysplasia “families.” Pathol Immunopathol
Res 7:76–​80.
Spranger J, Benirschke K, Hall JG, et al. (1982) Errors of mor-
phogenesis: concepts and terms. Recommendations of an interna-
tional working group. J Pediatr 100(1):160–​165.
Spranger JW, Wiedemann HR (1966) Dysplasia spondyloepiphysaria
congenita. Helv. Paed Acta 21:598–​611.
Superti-​ Furga A, Bonafé L, Rimoin DL (2001) Molecular-​
pathogenetic classification of genetic disorders of the skeleton. Am J
Med Genet 106:282–​293.
Taybi H, Lachman R (1975) Radiology of syndromes, metabolic
disorders, and skeletal dysplasias. 1st ed. Mosby, St. Louis.
Warman ML, Cormier-​Daire V, Hall C, et al. (2011) Nosology
and classification of genetic skeletal disorders: 2010 revision. Am J
Med Genet A 155A(5):943–​968.
xxv
 1.
ACHONDROPLASIA AND RELATED FGFR3 CONDITIONS
1.1 TH AN AT OP HORI C DYS P LA SIA,
TY PES 1 A ND 2 ( M I M 1 8 7 6 0 0 ,
187601)
Includes: San Diego type of lethal platyspondylic
chondrodysplasia.
M A J OR CL IN I CAL FI N D I N G S
1. Disproportionate dwarfism with very short extremities
and relatively normal trunk length.
2. Narrow thorax.
3. Disproportionately large head with depressed nasal
bridge, prominent forehead, and protruding eyes. Often
secondary skull deformity caused by premature closure
of cranial sutures. Encephaloceles occur in some cases,
notably type 2 thanatophoric dysplasia.
4. Death in early infancy (see “Course and Prognosis”).
Age of manifestation: Birth. The condition is detected in
utero by ultrasound on the basis of short limbs and narrow
thorax. Hydramnios is frequently present.
M A J OR RA DI O G RAPHI C FEATURES
1. Narrow thorax in anterioposterior and lateral views due
to short ribs.
2. Distinct flatness of the ossification centers of the
vertebral bodies, less severe in type 2 than in type 1
thanatophoric dysplasia, with notch-​like ossification
defects of the central portion of the upper and lower
plates.
3. Decreased vertical diameter and horizontal inferior
margins of the iliac bones; narrow sacrosciatic notch;
short and broad pubic and ischial bones.
4. Short and relatively broad long tubular bones. They are
bowed in type 1 and straight in type 2 thanatophoric
dysplasia.
5. Small facial bones, relatively large calvarium; signs of
craniostenosis. Cloverleaf skull deformity more often in
type 2 than in type 1 thanatophoric dysplasia.
GE NE T IC S
MODE OF INHERITANCE
Sporadic occurrence caused by de novo dominant mutations
with paternal age effect.
M O L E C U L A R B A S I S A N D PAT H O G E N E S I S
Both types of thanatophoric dysplasia are caused by
mutations of the gene encoding the fibroblast growth
factor receptor 3 (FGFR3). Type 1 thanatophoric dys-
plasia is caused by FGFR3 mutations leading to the intro-
duction of a new cysteine residue in various locations of
the extramembranous segment of the receptor. Stop codon
mutations have also been described. Type 2 thanatophoric
dysplasia is caused by a specific A to G transition at nucleo-
tide 1948, predicting a Lys650Glu substitution in the tyro-
sine kinase domain of the receptor.
C OU R S E AND PROGNOS IS
Short tubular bones and insufficient vertebral ossification
are detected in utero by ultrasound. After birth, respiratory
insufficiency develops and unassisted infants die within the
first hours or days. With intensive medical intervention,
a few patients have survived for longer periods. They
remained ventilator-​ dependent and mentally deficient.
Language and motor skill remained within the late infantile
range. Seizures and hearing loss occurred. Final height was
estimated to be in the range of 80 to 90 cm.
MAJOR DIF F E R E NT IAL DIAGNOS E S
Achondroplasia: The bone changes in achondroplasia are
qualitatively similar but milder than in thanatophoric dys-
plasia. In particular, the vertebral bodies are rectangular in
1
both projections and not as flat as in thanatophoric dysplasia;
the long bones are not as short and do not have flared ends.
Homozygous achondroplasia may be suspected in the
offspring of two achondroplastic parents. It is radiographi-
cally more severe than heterozygous achondroplasia but less
severe than thanatophoric dysplasia.
Spondyloepiphyseal dysplasia congenita: There are no
cranial changes and the pubic bones are not ossified at
birth. These children survive to adulthood.
Severe achondroplasia with developmental delay and
acanthosis nigricans (SADDAN dysplasia): In addition to
skeletal abnormalities of severe achondroplasia, there is de-
velopmental delay and acanthosis nigricans.
R EM A R K S
Nervous system abnormalities seen in thanatophoric dys-
plasia include polymicrogyria, neuronal heterotopia, tem-
poral hyperplasia, cerebral gyral disorganization due to
premature development of aberrant sulci, hippocampal dys-
plasia, nuclear dysplasia, abnormal axonal bundles, and cere-
bellar hypoplasia. The San Diego type of lethal platyspondylic
chondrodysplasias (Horton et al., 1979) has been shown to
be a particular manifestation of FGFR3 mutations.
BIBL IOGRA PHY
Baker K, Olson DS, Harding CO, Pauli RM (1997) Long-​term
survival in typical thanatophoric dysplasia type 1. Am J Med Genet
70:427–​436.
2 B one D ysplasias
Brodie SG, Kitoh H, Lachman RS, et al. (1999) Platyspondylic
lethal skeletal dysplasia, San Diego type, is caused by FGFR3
mutations. Am J Med Genet 84:476–​480.
Hevner F (2005) The cerebral cortex malformation in thanatophoric
dysplasia: neuropathology and pathogenesis. Acta Neuropathol
110:209–​221.
Horton WA, Rimoin DL, Hollister DW, Lachman LS
(1979) Further heterogeneity within lethal neonatal short-​limbed
dwarfism: The platyspondylic types. J Pediatr 94:736–​742.
Kitoh H, Lachman RS, Brodie SG, et al. (1998) Extra pelvic ossi-
fication centers in thanatophoric dysplasia and platyspondylic lethal
skeletal dysplasia–​San Diego type. Pediatr Radiol 28:759–​763.
Krakow D, Alanay Y, Rimoin DL, et al. (2008) Evaluation of
prenatal/​o nset osteochondrodysplasias by ultrasonography: a
retrospective and prospective analysis. Am J Med Genet
146A:1917–​1 924.
Langer LO, Yang SS, Hall IG, et al. (1987) Thanatophoric dysplasia
and cloverleaf skull. Am J Med Genet Suppl 3:167–​179.
Maroteaux P, Lamy M, Robert IM (1967) Le nanisme
thanatophore. Presse Med 75:2519–​2524.
Martinez-​Frias ML, deFrutos CA, Bermejo E, et al. (2010)
Review of the recently defined molecular mechanisms underlying
thanatophoric dysplasia and their potential therapeutic implications
for achondroplasia. Am J Med Genet 142:2245–​255.
Tavormina PL, Shjian R, Thompson LM, et al. (1995)
Thanatophoric dysplasia (types I and II) caused by distinct mutation
in fibroblast growth factor receptor 3. Nat Genet 9:321–​328.
Van der Harten HI, Brons ITI, Disjkstra PF, et al. (1993) Some
variants of lethal neonatal short-​limbed platyspondylic dysplasia: a
radiological and ultrasonographic, neuropathological and histopath-
ological study of 22 cases. Clin Dysmorphol 2:1–​19.
Wilcox WR, Tavormina PL, Krakow D, et al. (1998) Molecular,
radiologic, and histopathologic correlations in thanatophoric dys-
plasia. Am J Med Genet 78:274–​281.
 (A) (B) (C)

(D) (E)

Figure 1.1.1 Type I thanatophoric dysplasia. Patient 1: A. Clinical appearance after death at 36 hours after birth. The extremities are disproportionally
short, the head is large with depressed nasal bridge but without temporal bulging; the thorax is small and the abdomen protuberant. B. The thorax is
narrow owing to short ribs. The rib ends are wide and cupped and the scapulae small and deformed. The clavicles appear normal. The flat vertebral
bodies and the better mineralized posterior elements of the vertebrae produce an H-​shaped appearance. The interpediculate distance is narrowest
at the L3 to L4 level. The pelvic configuration is short and broad. The long bones are very short and relatively broad with flaring of the cupped
metaphyses. There is marked bowing of the femora. Epiphyseal centers are not ossified in the knee region. Phalanges and metacarpal and metatarsal
bones are particularly short; the phalanges are bullet-​shaped. C. The posterior elements of the vertebrae are well developed, but the vertebral bodies
appear flat with a wide space between them. The posterior half of the bodies is larger than the anterior half and has a bulbous configuration. The
narrowest point is the middle of the body. D, E. The calvarium shows good mineralization, large fontanels, prominence of the forehead, and a depressed
nasal bridge. The facial bones are small in relation to the size of the calvarium.

ACHONDROPLASIA AND RELATED FGFR3 CONDITIONS 3

 (A) (B) (C)

(D)

Figure 1.1.2 Type II thanatophoric dysplasia. A. Patient 2, stillborn. The skull is trilobate with a towering vertical and two lateral craniofacial bulges (so-​
called cloverleaf deformity). Maxilla and mandible are disproportionately small. The thorax is small, the abdomen protuberant, and the extremities
short. B, C. Patient 3, newborn, cloverleaf deformity. The base of the skull is foreshortened with small anterior and posterior cranial fossae, a large and
deepened middle fossa, and trilobate vertical and lateral expansion of the skull. D. Patient 3. Findings are similar to those described in thanatophoric
dysplasia I (Figure 1.1.1 B), except that the thorax is not as narrow and the long tubular bones are straight or only slightly bowed. The vertebral bodies
are clearly abnormal but less severely affected than in thanatophoric dysplasia I.

(A) (B)

Figure 1.1.3 San Diego variant of thanatophoric dysplasia. Patient 4, fetus terminated at 21 weeks’ gestation. The skeleton shows many of the
abnormalities of type 2 thanatophoric dysplasia, but there is no gross cranial abnormality, the vertebral bodies are wafer-​thin, the metaphyseal margins
are cupped, and the characteristic oval-​shaped lucent appearance of the proximal femora is not present.

1.2 ACH ONDROP LA S I A ( M I M 1 0 0 8 0 0 )
Includes: Chondrodystrophia fetalis; Chondrodysplasia
fetalis; Chondrodystrophic dwarfism.
M A J OR CL IN I CAL FI N D I N G S
1. Disproportionate short-​l imb dwarfism; proximal
segment of upper extremity relatively shorter
than middle and distal segments (rhizomelic
micromelia).
2. Head disproportionately large in relation to height or,
less commonly, in relation to age; characteristic face
with depressed nasal bridge, prominent forehead, mild
hypoplasia of midface with narrow nasal passages.
3. Kyphosis at thoracolumbar junction in infancy;
prominent buttocks and abdomen secondary to
increased pelvic tilt in children.
4. So-​called “trident hand” (deviation between third and
fourth fingers) with relatively short fingers; limitation
of elbow extension.
Age of manifestation: Birth. After 24 weeks’ gestation
ultrasound may show short femora. The specificity of this
finding is less than 0.25.
M A J OR RA DI O G RAPHI C FEATURES
1. Large calvarium with prominent frontal, parietal and
occipital regions; decreased size of the base of the skull
and of the foramen magnum.
2. Decrease in the interpediculate distance from
upper to lower lumbar spine; short pedicles on
lateral view.
3. Flat, rounded iliac bones with lack of iliac flaring;
broad, horizontal superior acetabular margins and
narrow sacrosciatic notches.
4. Short tubular bones at all ages. In infancy, square or
oval radiolucent areas in proximal femur and humerus
due to decreased anterio-​posterior diameter of these
regions.
5. In children and adults, massive appearance of
tubular bones due to disproportion between normal
width and reduced length; prominence of muscle
attachments; short femoral necks; mild metaphyseal
irregularities, most notably in the distal femora
and proximal tibiae. Essentially normal epiphyseal
ACHONDROPLASIA AND RELATED FGFR3 CONDITIONS
ossification except in the knee region, where it is
retarded and irregular. Disproportionate shortness of
the humerus and lengthening of the fibula relative to
the tibia.
GE NE T IC S
MODE OF INHERITANCE
Autosomal dominant, with approximately three-​quarters of
cases being caused by de novo mutations. Gonadal mosai-
cism seems to be much rarer than in other dominant bone
disorders (e.g., osteogenesis imperfecta), and the recurrence
risk of achondroplasia in sibs of achondroplastic children
with unaffected parents is low (around 0.02%).
M O L E C U L A R B A S I S A N D PAT H O G E N E S I S
Achondroplasia is mostly caused by a c.1138G>A mutation
of the FGFR3 gene on chromosome 4 (4p 16.3) coding for
the fibroblast growth factor receptor 3. The mutation results
in a p.Gly380Arg substitution in the transmembraneous
segment of the receptor. Rare mutations are c.1043C>G
(for p.Ser348Cys), c.l138G>C (for p.Gly380Arg) and
p.Gly375Cys. The altered FGFR3 is constitutively activated
with unregulated signal transduction through the receptor,
resulting in inappropriate cartilage growth plate differentia-
tion and ultimately deficient endochondral growth.
C OU R S E AND PROGNOS IS
Muscular hypotonia is present in infancy and delays early
motor development. It improves spontaneously with age.
Narrow nasal passage, small thorax, recurrent upper res-
piratory infections with adenoidal hypertrophy, and mus-
cular hypotonia lead to respiratory difficulties in infants.
Severe obstructive sleep apneas may result in cardiorespira-
tory failure and death. The severity of these complications
correlates with the degree of stenosis of the foramen
magnum, jugular, and hypoglossal canals and is reflected
in the degree of muscular hypotonia. Cervicomedullary
compression may also lead to neurological impairment
of the extremities, manifesting with hyperreflexia, clonus,
and eventually paresis. The frequency of neurological
abnormalities is inversely correlated with the diameter of
the foramen magnum seen on CT. With the development
of internal and external hydrocephalus, the occipitofrontal
head circumference increases excessively during the first
3 years of life. Hydrocephalus stabilizes spontaneously in
almost all patients. Intellectual development is normal ex-
cept for delayed speech comprehension in children with
recurrent otitis and untreated hearing loss. There is no
5
correlation between the degree of hydrocephaly and in-
tellectual performance. In middle or old age, compression
of nerve roots or cord may develop due to a narrow spinal
canal further compromised by anterior wedging of verte-
bral bodies, osteophyte formation, and/​or disc herniation.
This usually occurs in the lower thoracic or lumbar region.
Numbness, pain, weakness, hyperreflexia, and bladder dys-
function are early symptoms and signs. Thoracic kyphosis is
common in early childhood but in most patients disappears
spontaneously with improving muscle tone. Lumbar lor-
dosis develops and with it back pain, the most common
complaint in older children and adults. Significant tibial
bowing is present in up to 40% of older children. Dental
malocclusion caused by maxillary hypoplasia is seen in ap-
proximately 50% of children after the age of 10 years. Being
overweight is common in adults.
Due to various complications, the overall life expec-
tancy is decreased by approximately 10 years in the present
adult achondroplasia population. Mean adult height in
males is 131 cm ± 5.6 and in females 124 cm ± 5.9.
TR EATM ENT
Symptomatic. In infants, polysomnography and neuro-
imaging procedures are recommended. Neurosurgical
occipitocervical decompression may be necessary in
infants and young children, but guidelines are still con-
troversial. Clinical indications are unusually severe mus-
cular hypotonia and/​or life-​threatening apneas. Abnormal
polysomnography, abnormal subcortical somatosensory
evoked potentials, and abnormal MR findings (foramen
magnum diameter below the normal range for achon-
droplasia, significant spinal cord compression, and/​ or
blockade of CF flow in functional flexion/​hyperextension
studies, syringomyelia) establish firm intervention criteria.
Appropriate treatment of middle ear infections is required
in children with recurrent ear infections. Repeated au-
diometry should be performed routinely during the first
3 years of life. Orthodontic therapy may be necessary in
older children. Dietary management is required to prevent
obesity. Bilateral leg lengthening is available to improve
adult height. It may be combined with correction of severe
bowlegs and is preferably deferred until adolescence. With
the development of neurogenic claudication, lumbar lami-
nectomy becomes necessary in about 30% of the patients.
Surgical procedures should be performed by surgeons fa-
miliar with achondroplasia. Growth hormone therapy has
no place in the treatment of achondroplasia. New thera-
peutic strategies interfering with FGFR3 signal transduc-
tion are clinically tested.
6 B one D ysplasias
MAJOR DIFFERENTIAL DIAGNOSES
Hypochondroplasia: The condition is allelic to achon-
droplasia, and the skeletal changes are qualitatively similar
but quantitatively much milder.
Thanatophoric dysplasia: Patients exhibit more severe
changes and usually die in early infancy. The vertebral
bodies are underossified and band-​like.
Homozygous achondroplasia has bone changes similar to
those in thanatophoric dysplasia. The patients usually die
of respiratory failure in early infancy. The diagnosis is made
from the parental history.
Pseudoachondroplasia differs from achondroplasia
by the normal skull and severely disturbed epiphyseal
ossification.
B IB LIOGR APH Y
Bellus GA, Hefferon TW, Oritz De Luna RI, et al. (1995)
Achondroplasia is defined by recurrent G380R mutations of FGFR3.
Am J Hum Genet 56:368–​373.
Brinkmann G, Schlitt H, Zorowka P, Spranger J (1993)
Cognitive skills in achondroplasia. Am J Med Genet 47:800–​804.
Brower PA, Lubout CM, Van Kijk KM, et al (2012) Cervical
high-​intensity intramedullary lesions in achondroplasia, Eur Radiol
22:2264–​2272.
Danielpour M, Wilcox WR, Alanay Y, et al. (2007) Dynamic
cervicomedullary cord decompression and alterations in cerebro-
spinal fluid dynamics in children with achondroplasia. J Neurosurg
107 (6 Suppl):504–​507.
Ireland PJ, McGill J, Zankl A, et al. (2011) Functional perfor-
mance in young Australian children with achondroplasia. Developm
Med Child Neurol 53: 944–​950.
Langer LO, Bauman PA, Gorlin RJ (1967) Achondroplasia. Am J
Roentgen l00:12–​26.
Natacci F, Baffico M, Cavallari U, et al. (2008) Germline mosai-
cism in achondroplasia detected in sperm DNA of the father of three
affected sibs. Am J Med Genet 146A:784–​786.
Schkrohowsky JG, Hoernschemeyer DG, Carsons BS, Ain
BC (2007) Early presentation of spinal stenosis in achondroplasia. J
Pediatr Orthop 27:119–​122.
Tenconi R, Khirani S, Amaddeo A, et al. (2017) Sleep-​disordered
breathing and its management in children with achondroplasia. Am
J Med Genet 173:858–​878.
Tofts L, Das S, Collins F, et al. (2017) Growth charts for Australian
children with achondroplasia. Am J Med Genet 173:2189–​2200.
Trotter TL, Hall JC (2005) Health supervision for children with
achondroplasia. Pediatrics 116:771–​783.
White KK, Bompadre V, Goldberg MJ, et al. (2015) Best
practices in the evaluation and treatment of foramen magnum
stenosis in achondroplasia during infancy. Am J Med Genet
170:42–​51.
Wynn J, King TM, Gambello MJ, et al. (2007) Mortality in
achondroplasia study: a 42-​ year follow-​up. Am J Med Genet
143A:2502–​2511.
Xue Y, Sun A, Mekikian PB, et al. (2014) FGFR3 mutation frequency
in 324 cases from the international skeletal dysplasia registry. Mol
Genet Genomic Med 2:497–​503.
 (A) (B) (C)

Figure 1.2.1 A. Newborn. B. Adolescent. C. Adult. Note short extremities and relatively long trunk, abundance of soft tissue in A and C, large calvarium,
typical facies, and rhizomelic shortness of the arms.

(A) (B)

Figure 1.2.2 A. Newborn. The calvarium is large. B. Adolescent. The base of the skull appears foreshortened, the frontal bone is prominent; the bones of
the midface are hypoplastic, and the mandible is prognathic.

ACHONDROPLASIA AND RELATED FGFR3 CONDITIONS 7

 Figure 1.2.3 Newborn. The vertebral bodies appear slightly flat and the height of the intervertebral
spaces is increased. There is dorsal scalloping of the vertebral bodies. The interpediculate distance
decreases from the upper to the lower lumbar spine. The anterior ends of the ribs are cupped.

(A) (B) (C)

Figure 1.2.4 A. Young child. B. Older child. C. Adult. The posterior aspect of the vertebral bodies is concave. The pedicles are squared. There is increased
angulation at the lumbosacral junction.

8 B one D ysplasias
 (A) (B) (C)

Figure 1.2.5 A. Young child. B. Older child. C. Adult. In addition to the changes in Figure 1.2.4, there are different degrees of anterior wedging of
the vertebral bodies, causing gibbus. In the early stages, they are related to the children’s muscular hypotonia and in most instances improve
spontaneously. In the rare case in which they progress, they must be treated in order to avoid spinal compression.

(A) (B) (A) (B) (C)

Figure 1.2.6 A. Young child. B. Older child. Note relative narrowing of the
interpediculate distance in the lower lumbar spine.
Figure 1.2.7 A. 22 months. In the young child the distal femoral metaphyses
are more extensively ossified medially than laterally. The ossified
epiphyses are relatively small. B. 7 years. There is an inverted V
configuration of the growth plate of the distal femur and, to a lesser
degree, of the proximal tibia. C. 14 years. The growth plates are relatively
straighter at this age, and the ossified epiphyseal centers are as broad
as the metaphyses. The articular surface of the distal femur is irregular.

ACHONDROPLASIA AND RELATED FGFR3 CONDITIONS 9

 (A) (B)

(C) (D)

Figure 1.2.8 A. Newborn. B. 22 months. C. 7 years. D. 14 years. The overall pelvic configuration is low and broad. The iliac bones are essentially square
with rounding of the corners and lack of flaring. Their inferior margins are horizontal. The greater sciatic notch is narrow. The sacrum articulates low
in relationship to the crest of the ilia. In A and B the ischial and pubic bones are broad and short, and there is characteristic oval-​shaped lucent
appearance of the proximal femora.
 (A) (B) (C)

Figure 1.2.9 A. Newborn. The tubular bones are short. Note irregular metaphyseal borders. The proximal and middle phalanges are broad and bullet-​
shaped. B. Young adult. C. Middle-​aged adult. Note dorsally angulated proximal humerus and prominence of deltoid muscle attachment.

(A) (B)

(C) (D)

Figure 1.2.10 A. Young child. There is some deformity of the

metacarpals, but the most striking changes are in the proximal
and middle phalanges, which are short, broad, and cone-​
shaped. B. Older child. The changes are similar to those
in the younger child and demonstrate a marked degree of
separation of the fingers. C. 14 years. The tubular bones of
the hands are short and broad. The third and fourth fingers
cannot be completely approximated. D. Adult. There is
moderate shortness of the tubular bones. Note the inability to
completely approximate the fingers in extension. The fingers
in achondroplasia are not as short as in many other short-​limb
dwarf conditions.

1.3 H Y POC HONDROP LA S I A
(MIM 146 0 0 0 )
M A J OR CL IN I CAL FI N D I N G S
1. Small stature with relatively long trunk and short
extremities.
2. Normal or slightly macrocephalic skull.
3. Slightly increased lumbar lordosis and protuberant
abdomen.
4. Limited elbow extension and forearm supination.
5. Bowlegs in childhood.
Age of manifestation: Usually school age. Earlier, even
prenatal (sonographic) diagnosis has been achieved in some
cases, particularly children of affected parents.
M A J OR RA DI O G RAPHI C FEATURES
1. Moderate narrowing of interpediculate distances,
anterioposterior shortening of the pedicles, and
increased dorsal concavity of the vertebral bodies in the
lumbar spine.
2. Short and relative square tubular bones.
3. Slightly small ilia with narrowed sciatic notches.
4. Short, broad femoral neck.
5. Elongated distal end of the fibula in respect to the tibia.
6. Occasionally moderately increased size of neurocranium.
GENETICS
MODE OF INHERITANCE
Autosomal dominant.
M O L E C U L A R B A S I S A N D PAT H O G E N E S I S
Hypochondroplasia is caused by allelic mutations of
FGFR3, the gene causing achondroplasia. About 60% of
patients with clinical and radiographic manifestations
of hypochondroplasia have a C1620A transversion at
nucleotide 1620 of the FGFR3 gene, resulting in an
ASN540Lys substitution (N540K) in the proximal
tyrosine kinase domain of the fibroblast growth factor
receptor 3. Other mutations have also been described (e.g.,
12
AI651G:I538V), and complete screening of the FGFR3
gene is recommended in cases with typical radiographic
signs of hypochondroplasia but failure to demonstrate the
common mutations.
C OU R S E AND PROGNOS IS
Diagnosis of hypochondroplasia is difficult in infancy,
though the average birth length is slightly below normal.
The most reliable radiographic signs are short ilia, short
greater sciatic notch, horizontal acetabula, and short and
broad femora. Bowlegs may appear in early childhood and
tend to straighten out spontaneously. Adult height varies
between 132 cm and 147 cm. Life expectancy is normal.
Mild intellectual disability has repeatedly been described
and found to be associated with structural brain anomalies,
notably temporal lobe dysgenesis. Exercise-​dependent joint
pain is frequently observed in adults. Cesarean section may
be necessary in females.
T R E AT ME NT
Symptomatic. Leg lengthening may be considered. The role
of growth hormone therapy is unsettled.
MAJOR DIF F E R E NT IAL DIAGNOS E S
Achondroplasia: The skeletal changes are qualitatively
similar but quantitatively more pronounced than those of
hypochondroplasia. The differences are best seen in the
skull and pelvis, which are more severely affected.
Idiopathic short stature: Children may have rela-
tively short extremities, but radiographic abnormalities
characterizing hypochondroplasia, notably the vertebral
and pelvic changes, are absent. Heterozygous mutations
in SHOX9, ACG1 or NPR2 may cause this type of
short stature and must be ruled out before naming it
“idiopathic.”
Metaphyseal chondrodysplasia, Schmid type: In most cases
the vertebral bodies are normal; the vertebral pedicles are not
short. Coxa vara characterizes Schmid metaphyseal dysplasia.
R E MAR K S
Hypochondroplasia is difficult to differentiate from “con-
stitutional” (“idiopathic” or “familial normal variant”)
shortness of stature. Some patients with assumed normal
variant short stature may have hypochondroplasia, as,
vice versa, short normal children may be misdiagnosed as
hypochondroplasia. Macrocephaly appears to be a discrim-
inating factor in favor of hypochondroplasia but molecular
analysis is indispensable to be certain.
B one D ysplasias
 BIBL IOGRAPHY
Bellus GA, McIntosh I, Smith EA, et al. (1995) A recurrent mu-
tation in the tyrosine kinase domain of fibroblast growth factor re-
ceptor 3 causes hypochondroplasia. Nat Genet 10:357–​359.
Fano V, Gravina LP, Pino MD, et al. (2005) High specificity of head
circumference to recognize N540K mutation in hypochondroplasia
Ann Hum Biol 32:782–​788.
Hall D, Spranger J (1979) Hypochondroplasia: clinical and radio-
logical aspects in 39 cases. Radiology 133:95–​100.
Heuertz S, LeMerrer M, Zabel B, et al. (2006) Novel FGF3
mutations creating cysteine residues in the extracellular domain of the
receptor cause achondroplasia or severe forms of hypochondroplasia.
Eur J Hum Genet 14:1240–​1247.
Linnankivi T, Mäkitie O, Valanne L, Toiviainen-​Salo S
(2012) Neuroimaging and neurological findings in patients with
hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet
158:3119–​3125.
Ramaswami U, Rumsby G, Hindmarsh PC, Brook CCD
(1998) Genotype and phenotype in hypochondroplasia. J Pediat
133:99–​102.
Ravenna F (1913) Achondroplasie et chondrohypoplasie.
Contribution clinique. Nouvelle Iconographie de la Salpetrière,
Clinique des maladies du systeme nerveux 26:157–​163.
Rousseau F, Bonaventure I, Legeai-​Mallet I, et al. (1996)
Clinical and genetic heterogeneity of hypochondroplasia. J Med
Genet 33:749–​752.
Saito T, Nagasaki K, Nishimura G, et al. (2016) Criteria for ra-
diologic diagnosis of hypochondroplasia in neonates. Pediatr Radiol
46:513–​518.
Song SH, Balce G, Agashe MV, et al. (2012) New proposed clinico-​
radiologic and molecular criteria in hypochondroplasia: FGFR3
gene mutations are not the only cause of hypochondroplasia. Am J
Med Genet 158:2456–​2462.

Figure 1.3.1 11-​year-​old boy with hypochondroplasia. Note relatively long trunk and short extremities.

(A) (B)

Figure 1.3.2 A. Patient 1, 8 years. B. Patient 2, adult (mother of Patient 1). In Patient 1, as in other children with hypochondroplasia, the neurocranium
may be moderately enlarged and the frontal bones protuberant. In other patients of the same age, the skull may be essentially normal, as is the case
in Patient 2 or the patient depicted in Figure 1.3.1.

ACHONDROPLASIA AND RELATED FGFR3 CONDITIONS 13

 (A) (B) (C) (D)

Figure 1.3.3 A. Patient 3, 7 months. There is normal craniocaudal widening of the interpediculate distances in the lumbar spine. B. Patient 1, 8 years. No
major abnormality. C. Patient 4, 6 years. In this patient, the interpediculate distances of the lower lumbar spine are smaller than those of the upper
lumbar spine. D. Patient 5, 15 years. The interpediculate distances remain constant from the upper to the lower lumbar vertebrae. Though in the
normal person there is usually an increase of the interpediculate distance, craniocaudal widening is occasionally absent.

14 B one D ysplasias
 (A) (B) (C) (D)

(E)

Figure 1.3.4 A. Patient 6, 2 months. Except for minimal anterior beaking of L2, there are no abnormalities. B. Patient 4, 6 years old. The laminae are
short; the lumbar vertebral bodies are slightly ovoid and their craniocaudal dimension decreased. C. Patient 1, 8 years. The dorsal borders of the
lumbar vertebral bodies are slightly concave. D. Patient 5, 15 years. The vertebral bodies are squared, their dorsal borders are scalloped, and their
laminae are short. E. Patient 2, adult. Note the short laminae and the accentuated lumbar lordosis.

(A) (B)

Figure 1.3.5 A. Patient 7, newborn. The iliac bones are square with rounded corners, devoid of flaring; horizontal inferior margins and spurs extend
downward from their medial ends. The femora are short and broad. The pelvic changes are similar to, but less pronounced than, those in
achondroplasia. B. Patient 3, 7 months. The leg bones are moderately short and the metaphyses wide.

ACHONDROPLASIA AND RELATED FGFR3 CONDITIONS 15

 (A) (B)

(C) (D)

Figure 1.3.6 A. Patient 6, 2 months old. The iliac bones are slightly squared. The sciatic notches are small. B. Patient 4, 6 years. The lower portions of
the iliac bones are broad and the acetabular roofs horizontal. The femoral necks are short and broad with slightly concave inner margins. C. Patient
1, 8 years. In this patient the pelvic bones appear normal. The capital femoral epiphyses are relatively large, and the femoral necks are in mild valgus
position with mildly concave inner margins. D. Patient 8, adult (father of Patient 5). The pelvis is normal. The femoral necks are short.

16 B one D ysplasias
 (A) (B)

Figure 1.3.7 A. Patient 3, 8 years. B. Patient 2, adult. The fibula is disproportionately long. The tibia appears short and plump. There is mild metaphyseal
widening of the femur and tibia.

ACHONDROPLASIA AND RELATED FGFR3 CONDITIONS 17

 (A) (B)

(C) (D)

Figure 1.3.8 A. Patient 3, 15 months. B. Patient 1, 8 years. C. Patient 5, 15 years. D. Patient 8, adult. At all ages, the phalanges are short and broad,
particularly the proximal and middle phalanges. In C and D the distal ends of the radius and ulna are flared and the ulnar styloid process is prominent.
A comparison of the films of father and daughter (C and D) shows the degree of variability to be expected.

18 B one D ysplasias
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rencontrait pour lui des fêtes magnifiques pompeusement célébrées
au coucher du soleil, quand l’astre versait ses couleurs rouges sur
les flots comme un manteau de pourpre. Pour lui la mer était gaie,
vive, spirituelle au milieu du jour, lorsqu’elle frissonnait en répétant
l’éclat de la lumière par ses mille facettes éblouissantes; elle lui
révélait d’étonnantes mélancolies, elle le faisait pleurer, lorsque,
résignée, calme et triste, elle réfléchissait un ciel gris chargé de
nuages. Il avait saisi les langages muets de cette immense création.
Le flux et reflux était comme une respiration mélodieuse dont
chaque soupir lui peignait un sentiment, il en comprenait le sens
intime. Nul marin, nul savant n’aurait pu prédire mieux que lui la
moindre colère de l’Océan, le plus léger changement de sa face. A
la manière dont le flot venait mourir sur le rivage, il devinait les
houles, les tempêtes, les grains, la force des marées. Quand la nuit
étendait ses voiles sur le ciel, il voyait encore la mer sous les lueurs
crépusculaires, et conversait avec elle; il participait à sa féconde vie,
il éprouvait en son âme une véritable tempête quand elle se
courrouçait; il respirait sa colère dans ses sifflements aigus, il courait
avec les lames énormes qui se brisaient en mille franges liquides sur
les rochers, il se sentait intrépide et terrible comme elle, et comme
elle bondissait par des retours prodigieux; il gardait ses silences
mornes, il imitait ses clémences soudaines. Enfin, il avait épousé la
mer, elle était sa confidente et son amie. Le matin, quand il venait
sur ses rochers, en parcourant les sables fins et brillants de la grève,
il reconnaissait l’esprit de l’Océan par un simple regard; il en voyait
soudain les paysages, et planait ainsi sur la grande face des eaux,
comme un ange venu du ciel. Si de joyeuses, de lutines, de
blanches vapeurs lui jetaient un réseau fin, comme un voile au front
d’une fiancée, il en suivait les ondulations et les caprices avec une
joie d’amant, aussi charmé de la trouver au matin coquette comme
une femme qui se lève encore tout endormie, qu’un mari de revoir sa
jeune épouse dans la beauté que lui a faite le plaisir. Sa pensée,
mariée avec cette grande pensée divine, le consolait dans sa
solitude, et les mille jets de son âme avaient peuplé son étroit désert
de fantaisies sublimes. Enfin, il avait fini par deviner dans tous les
mouvements de la mer sa liaison intime avec les rouages célestes,
et il entrevit la nature dans son harmonieux ensemble, depuis le brin
d’herbe jusqu’aux astres errants qui cherchent, comme des graines
emportées par le vent, à se planter dans l’éther. Pur comme un
ange, vierge des idées qui dégradent les hommes, naïf comme un
enfant, il vivait comme une mouette, comme une fleur, prodigue
seulement des trésors d’une imagination poétique, d’une science
divine de laquelle il contemplait seul la féconde étendue. Incroyable
mélange de deux créations! tantôt il s’élevait jusqu’à Dieu par la
prière, tantôt il redescendait, humble et résigné, jusqu’au bonheur
paisible de la brute. Pour lui, les étoiles étaient les fleurs de la nuit;
le soleil était un père; les oiseaux étaient ses amis. Il plaçait partout
l’âme de sa mère; souvent il la voyait dans les nuages, il lui parlait,
et ils communiquaient réellement par des visions célestes; en
certains jours, il entendait sa voix, il admirait son sourire, enfin il y
avait des jours où il ne l’avait pas perdue! Dieu semblait lui avoir
donné la puissance des anciens solitaires, l’avoir doué de sens
intérieurs perfectionnés qui pénétraient l’esprit des choses. Des
forces morales inouïes lui permettaient d’aller plus avant que les
autres hommes dans les secrets des œuvres immortelles. Ses
regrets et sa douleur étaient comme des liens qui l’unissaient au
monde des esprits; il y allait, armé de son amour, pour y chercher sa
mère, en réalisant ainsi par les sublimes accords de l’extase la
symbolique entreprise d’Orphée. Il s’élançait dans l’avenir ou dans le
ciel, comme de son rocher il volait sur l’Océan d’une ligne à l’autre
de l’horizon. Souvent aussi, quand il était tapi au fond d’un trou
profond, capricieusement arrondi dans un fragment de granit, et dont
l’entrée avait l’étroitesse d’un terrier; quand, doucement éclairé par
les chauds rayons du soleil qui passaient par des fissures et lui
montraient les jolies mousses marines par lesquelles cette retraite
était décorée, véritable nid de quelque oiseau de mer; là, souvent, il
était saisi d’un sommeil involontaire. Le soleil, son souverain, lui
disait seul qu’il avait dormi en lui mesurant le temps pendant lequel
avaient disparu pour lui ses paysages d’eau, ses sables dorés et ses
coquillages. Il admirait à travers une lumière brillante comme celle
des cieux, les villes immenses dont lui parlaient ses livres; il allait
regardant avec étonnement, mais sans envie, les cours, les rois, les
batailles, les hommes, les monuments. Ce rêve en plein jour lui
rendait toujours plus chères ses douces fleurs, ses nuages, son
soleil, ses beaux rochers de granit. Pour le mieux attacher à sa vie
solitaire, un ange semblait lui révéler les abîmes du monde moral, et
les chocs terribles des civilisations. Il sentait que son âme, bientôt
déchirée à travers ces océans d’hommes, périrait brisée comme une
perle qui, à l’entrée royale d’une princesse, tombe de la coiffure
dans la boue d’une rue.

COMMENT MOURUT LE FILS.

En 1617, vingt et quelques années après l’horrible nuit pendant

laquelle Étienne fut mis au monde, le duc d’Hérouville, alors âgé de
soixante-seize ans, vieux, cassé, presque mort, était assis au
coucher du soleil dans un immense fauteuil, devant la fenêtre ogive
de sa chambre à coucher, à la place d’où jadis la comtesse avait si
vainement réclamé, par les sons du cor perdus dans les airs, le
secours des hommes et du ciel. Vous eussiez dit d’un véritable
débris de tombeau. Sa figure énergique, dépouillée de son aspect
sinistre par la souffrance et par l’âge, avait une couleur blafarde en
rapport avec les longues mèches de cheveux blancs qui tombaient
autour de sa tête chauve, dont le crâne jaune semblait débile. La
guerre et le fanatisme brillaient encore dans ces yeux jaunes,
quoique tempérés par un sentiment religieux. La dévotion jetait une
teinte monastique sur ce visage, jadis si dur et marqué maintenant
de teintes qui en adoucissaient l’expression. Les reflets du couchant
coloraient par une douce lueur rouge cette tête encore vigoureuse.
Le corps affaibli, enveloppé de vêtements bruns, achevait, par sa
pose lourde, par la privation de tout mouvement, de peindre
l’existence monotone, le repos terrible de cet homme, autrefois si
entreprenant, si haineux, si actif.
—Assez, dit-il à son chapelain.
Ce vieillard vénérable lisait l’Évangile en se tenant debout devant
le maître dans une attitude respectueuse. Le duc, semblable à ces
vieux lions de ménagerie qui arrivent à une décrépitude encore
pleine de majesté, se tourna vers un autre homme en cheveux
blancs, et lui tendit un bras décharné, couvert de poils rares, encore
nerveux, mais sans vigueur.
—A vous, rebouteur, s’écria-t-il, voyez où j’en suis aujourd’hui.
—Tout va bien, monseigneur, et la fièvre a cessé. Vous vivrez
encore de longues années.
—Je voudrais voir Maximilien ici, reprit le duc en laissant
échapper un sourire d’aise. Ce brave enfant! il commande
maintenant une compagnie d’arquebusiers chez le roi. Le maréchal
d’Ancre a eu soin de mon gars, et notre gracieuse reine Marie pense
à le bien apparenter, maintenant qu’il a été créé duc de Nivron. Mon
nom sera donc dignement continué. Le gars a fait des prodiges de
valeur à l’attaque...
En ce moment Bertrand arriva, tenant une lettre à la main.
—Qu’est ceci? dit vivement le vieux seigneur.
—Une dépêche apportée par un courrier que vous envoie le roi,
répondit l’écuyer.
—Le roi et non la reine-mère! s’écria le duc. Que se passe-t-il
donc? les Huguenots reprendraient-ils les armes, tête-dieu pleine de
reliques! reprit le duc en se dressant et jetant un regard étincelant
sur les trois vieillards. J’armerais encore mes soldats, et, avec
Maximilien à mes côtés, la Normandie...
—Asseyez-vous, mon bon seigneur, dit le rebouteur inquiet de
voir le duc se livrant à une bravade dangereuse chez un
convalescent.
—Lisez, maître Corbineau, dit le vieillard en tendant la dépêche à
son confesseur.
Ces quatre personnages formaient un tableau plein
d’enseignements pour la vie humaine. L’écuyer, le prêtre et le
médecin, blanchis par les années, tous trois debout devant leur
maître assis dans son fauteuil, et ne se jetant l’un à l’autre que de
pâles regards, traduisaient chacun l’une des idées qui finissent par
s’emparer de l’homme au bord de la tombe. Fortement éclairés par
un dernier rayon du soleil couchant, ces hommes silencieux
composaient un tableau sublime de mélancolie et fertile en
contrastes. Cette chambre sombre et solennelle, où rien n’était
changé depuis vingt-cinq années, encadrait bien cette page
poétique, pleine de passions éteintes, attristée par la mort, remplie
par la religion.
—Le maréchal d’Ancre a été tué sur le pont du Louvre par ordre
du roi, puis... Oh! mon Dieu...
—Achevez, cria le seigneur.
—Monseigneur le duc de Nivron...
—Eh! bien.
—Est mort!
Le duc pencha la tête sur sa poitrine, fit un grand soupir, et resta
muet. A ce mot, à ce soupir, les trois vieillards se regardèrent. Il leur
sembla que l’illustre et opulente maison d’Hérouville disparaissait
devant eux comme un navire qui sombre.
—Le maître d’en haut, reprit le duc en lançant un terrible regard
sur le ciel, se montre bien ingrat envers moi. Il ne se souvient pas
des hauts faits que j’ai commis pour sa sainte cause!
—Dieu se venge, dit le prêtre d’une voix grave.
—Mettez cet homme au cachot, s’écria le seigneur.
—Vous pouvez me faire taire plus facilement que vous
n’apaiserez votre conscience.
Le duc d’Hérouville redevint pensif.
—Ma maison périr! mon nom s’éteindre! Je veux me marier, avoir
un fils! dit-il après une longue pause.
Quelque effrayante que fût l’expression du désespoir peint sur la
face du duc d’Hérouville, le rebouteur ne put s’empêcher de sourire.
En ce moment, un chant frais comme l’air du soir, aussi pur que le
ciel, simple autant que la couleur de l’Océan, domina le murmure de
la mer et s’éleva pour charmer la nature. La mélancolie de cette
voix, la mélodie des paroles, répandirent dans l’âme comme un
parfum. L’harmonie montait par nuages, remplissait les airs, versait
du baume sur toutes douleurs, ou plutôt elle les consolait en les
exprimant. La voix s’unissait au bruissement de l’onde avec une si
rare perfection qu’elle semblait sortir du sein des flots. Ce chant fut
plus doux pour ces vieillards que ne l’aurait été la plus tendre parole
d’amour pour une jeune fille, il apportait tant de religieuses
espérances qu’il résonna dans le cœur comme une voix partie du
ciel.
—Qu’est ceci? demanda le duc.
—Le petit rossignol chante, dit Bertrand, tout n’est pas perdu, ni
pour lui, ni pour vous.
—Qu’appelez-vous un rossignol?
—C’est le nom que nous avons donné au fils aîné de
monseigneur, répondit Bertrand.
—Mon fils, s’écria le vieillard. J’ai donc un fils, enfin quelque
chose qui porte mon nom et qui peut le perpétuer.
Il se dressa sur ses pieds, et se mit à marcher dans sa chambre
d’un pas tour à tour lent et précipité; puis il fit un geste de
commandement et renvoya ses gens, à l’exception du prêtre.
Le lendemain matin, le duc appuyé sur son vieil écuyer allait le
long de la grève, à travers les rochers cherchant le fils que jadis il
avait maudit; il l’aperçut de loin, tapi dans une crevasse de granit,
nonchalamment étendu au soleil, la tête posée sur une touffe
d’herbes fines, les pieds gracieusement ramassés sous le corps.
Étienne ressemblait à une hirondelle en repos. Aussitôt que le grand
vieillard se montra sur le bord de la mer, et que le bruit de ses pas
assourdi par le sable résonna faiblement en se mêlant à la voix des
flots, Étienne tourna la tête, jeta un cri d’oiseau surpris, et disparut
dans le granit même, comme une souris qui rentre si lestement dans
son trou que l’on finit par douter de l’avoir aperçue.
—Hé! tête-dieu pleine de reliques, où s’est-il donc fourré? s’écria
le seigneur en arrivant au rocher sur lequel son fils était accroupi.
 —Il est là, dit Bertrand en montrant une fente étroite dont les
bords avaient été polis, usés par l’assaut répété des hautes marées.
—Étienne, mon fils bien-aimé! s’écria le vieillard.
L’enfant maudit ne répondit pas. Pendant une partie de la
matinée, le vieux duc supplia, menaça, gronda, implora tour à tour,
sans pouvoir obtenir de réponse. Parfois il se taisait, appliquait
l’oreille à la crevasse, et tout ce que son ouïe faible lui permettait
d’entendre était le sourd battement du cœur d’Étienne, dont les
pulsations précipitées retentissaient sous la voûte sonore.
—Il vit au moins, celui-là, dit le vieillard d’un son de voix
déchirant.
Au milieu du jour, le père au désespoir eut recours à la prière.
—Étienne, lui disait-il, mon cher Étienne, Dieu m’a puni de t’avoir
méconnu! Il m’a privé de ton frère! Aujourd’hui, tu es mon seul et
unique enfant. Je t’aime plus que je m’aime moi-même. J’ai reconnu
mon erreur, je sais que tu as véritablement dans tes veines mon
sang ou celui de ta mère dont le malheur a été mon ouvrage. Viens,
je tâcherai de te faire oublier mes torts en te chérissant pour tout ce
que j’ai perdu. Étienne, tu es déjà duc de Nivron, et tu seras après
moi duc d’Hérouville, pair de France, chevalier des Ordres et de la
Toison-d’Or, capitaine de cent hommes d’armes, grand-bailli de
Bessin, gouverneur de Normandie pour le roi, seigneur de vingt-sept
domaines où se comptent soixante-neuf clochers, marquis de Saint-
Sever. Tu auras pour femme la fille d’un prince. Tu seras le chef de
la maison d’Hérouville. Veux-tu donc me faire mourir de chagrin?
Viens, viens! ou je reste agenouillé là, devant ta retraite, jusqu’à ce
que je t’aie vu. Ton vieux père te prie, et s’humilie devant son enfant
comme si c’était Dieu lui-même.
L’enfant maudit n’entendit pas ce langage hérissé d’idées
sociales, de vanités qu’il ne comprenait point, et retrouvait dans son
âme des impressions de terreur invincibles. Il resta muet, livré à
d’affreuses angoisses. Sur le soir, le vieux seigneur, après avoir
épuisé toutes les formules de langage, toutes les ressources de la
prière et les accents du repentir, fut frappé d’une sorte de contrition
religieuse. Il s’agenouilla sur le sable, et fit ce vœu:
—Je jure d’élever une chapelle à saint Jean et à saint Étienne,
patrons de ma femme et de mon fils, d’y fonder cent messes en
l’honneur de la Vierge, si Dieu et les saints me rendent l’affection de
monsieur le duc de Nivron, mon fils, ici présent!
Il demeura dans une humilité profonde, agenouillé, les mains
jointes, et pria. Mais ne voyant point paraître son enfant, l’espoir de
son nom, de grosses larmes sortirent de ses yeux si longtemps
secs, et roulèrent le long de ses joues flétries. En ce moment,
Étienne, qui n’entendait plus rien, se coula sur le bord de sa grotte
comme une jeune couleuvre affamée de soleil, il vit les larmes de ce
vieillard abattu, reconnut le langage de la douleur, saisit la main de
son père, et l’embrassa en disant d’une voix d’ange:—O ma mère,
pardonne!
Dans la fièvre du bonheur, le gouverneur de Normandie emporta
dans ses bras son chétif héritier qui tremblait comme une fille
enlevée; et le sentant palpiter, il s’efforça de le rassurer en le baisant
avec les précautions qu’il aurait prises pour manier une fleur, il
trouva pour lui de douces paroles qu’il n’avait jamais su prononcer.
—Vrai Dieu, tu ressembles à ma pauvre Jeanne, cher enfant! lui
disait-il. Instruis-moi de tout ce qui te plaira, je te donnerai tout ce
que tu désireras. Sois bien fort! porte-toi bien! Je t’apprendrai à
monter à cheval sur une jument douce et gentille comme tu es doux
et gentil. Rien ne te contrariera. Tête-dieu pleine de reliques! autour
de toi, tout pliera comme des roseaux sous le vent. Je vais te donner
ici un pouvoir sans bornes. Moi-même je t’obéirai comme au Dieu de
la famille.
Le père entra bientôt avec son fils dans la chambre seigneuriale
où s’était écoulée la triste vie de la mère. Étienne alla soudain
s’appuyer près de cette croisée où il avait commencé de vivre, d’où
sa mère lui faisait des signaux pour lui annoncer le départ de son
persécuteur qui maintenant, sans qu’il sût encore pourquoi, devenait
son esclave et ressemblait à ces gigantesques créatures que le
pouvoir d’une fée mettait aux ordres d’un jeune prince. Cette fée
était la Féodalité. En revoyant la chambre mélancolique où ses yeux
s’étaient habitués à contempler l’Océan, des pleurs vinrent aux yeux
d’Étienne; les souvenirs de son long malheur mêlés aux
mélodieuses souvenances des plaisirs qu’il avait goûtés dans le seul
amour qui lui fût permis, l’amour maternel, tout fondit à la fois sur
son cœur et y développa comme un poëme à la fois délicieux et
terrible. Les émotions de cet enfant habitué à vivre dans les
contemplations de l’extase, comme d’autres se livrent aux agitations
du monde, ne ressemblaient à aucune des émotions habituelles aux
hommes.
—Vivra-t-il? dit le vieillard étonné de la faiblesse de son héritier
sur lequel il se surprit à retenir son souffle.
—Je ne pourrai vivre qu’ici, répondit simplement Étienne qui
l’avait entendu.
—Hé! bien, cette chambre sera la tienne, mon enfant.
—Qu’y a-t-il? dit le jeune d’Hérouville en entendant des
commensaux du château qui arrivaient dans la salle des gardes où
le duc les avait convoqués tous pour leur présenter son fils, en ne
doutant pas du succès.
—Viens, lui répondit son père en le prenant par la main et
l’amenant dans la grande salle.
A cette époque un duc et pair, possessionné comme l’était le duc
d’Hérouville, ayant ses charges et ses gouvernements, menait en
France le train d’un prince; les cadets de famille ne répugnaient pas
à le servir; il avait une maison et des officiers: le premier lieutenant
de sa compagnie d’ordonnance était chez lui ce que sont aujourd’hui
les aides de camp chez un maréchal. Quelques années plus tard, le
cardinal de Richelieu eut des gardes du corps. Plusieurs princes
alliés à la maison royale, les Guise, les Condé, les Nevers, les
Vendôme avaient des pages pris parmi les enfants des meilleures
maisons, dernière coutume de la chevalerie éteinte. Sa fortune et
l’ancienneté de sa race normande indiquée par son nom (herus villa,
maison du chef), avaient permis au duc d’Hérouville d’imiter la
magnificence des gens qui lui étaient inférieurs, tels que les
d’Épernon, les Luynes, les Balagny, les d’O, les Zamet, regardés en
ce temps comme des parvenus, et qui néanmoins vivaient en
princes. Ce fut donc un spectacle imposant pour le pauvre Étienne
que de voir l’assemblée des gens attachés au service de son père.
Le duc monta sur une chaise placée sous un de ces solium ou dais
en bois sculpté garni d’une estrade élevée de quelques marches,
d’où, dans quelques provinces, certains seigneurs rendaient encore
des arrêts dans leurs châtellenies, rares vestiges de féodalité qui
disparurent sous le règne de Richelieu. Ces espèces de trônes,
semblables aux bancs d’œuvre dans les églises, sont devenus des
objets de curiosité. Quand Étienne se trouva là, près de son vieux
père, il frissonna de se voir le point de mire de tous les yeux.
—Ne tremble pas, lui dit le duc en abaissant sa tête chauve
jusqu’à l’oreille de son fils, car tout ça, c’est nos gens.
A travers les ténèbres à demi lumineuses produites par le soleil
couchant dont les rayons rougissaient les croisées de cette salle,
Étienne apercevait le bailli, les capitaines et les lieutenants en
armes, accompagnés de quelques soldats, les écuyers, le chapelain,
les secrétaires, le médecin, le majordome, les huissiers, l’intendant,
les piqueurs, les gardes-chasse, toute la livrée et les valets. Quoique
ce monde se tînt dans une attitude respectueuse commandée par la
terreur qu’inspirait le vieillard aux gens les plus considérables qui
vivaient sous son commandement et dans sa province, il se faisait
un bruit sourd produit par une curieuse attente. Ce bruit serra le
cœur d’Étienne qui, pour la première fois, éprouvait l’influence de la
lourde atmosphère d’une salle où respirait une assemblée
nombreuse; ses sens, habitués à l’air pur et sain de la mer, furent
offensés avec une promptitude qui indiquait la perfection de ses
organes. Une horrible palpitation, due à quelque vice dans
l’organisation de son cœur, l’agita de ses coups précipités, quand
son père, obligé de se montrer comme un vieux lion majestueux,
prononça, d’une voix solennelle, le petit discours suivant:—Mes
amis, voici mon fils Étienne, mon premier-né, mon héritier
présomptif, le duc de Nivron, à qui le roi confirmera sans doute les
charges de défunt son frère; je vous le présente afin que vous le
reconnaissiez et que vous lui obéissiez comme à moi-même. Je
vous préviens que si l’un de vous, ou si quelqu’un dans la province
dont j’ai le gouvernement, déplaisait au jeune duc ou le heurtait en
quoi que ce soit, il vaudrait mieux, cela étant et moi le sachant, que
ce quelqu’un ne fût jamais sorti du ventre de sa mère. Vous avez
entendu? retournez tous à vos affaires, et que Dieu vous conduise.
Les obsèques de Maximilien d’Hérouville se feront ici, lorsque son
corps y sera rapporté. La maison prendra le deuil dans huit jours.
Plus tard, nous fêterons l’avénement de mon fils Étienne.
—Vive monseigneur! vivent les d’Hérouville! fut crié de manière à
faire mugir le château.
Les valets apportèrent des flambeaux pour éclairer la salle. Ce
hourra, cette lumière et les sensations que donna à Étienne le
discours de son père, jointes à celles qu’il avait éprouvées déjà, lui
causèrent une défaillance complète, il tomba sur le fauteuil en
laissant sa main de femme dans la large main de son père. Quand le
duc, qui avait fait signe au lieutenant de sa compagnie d’approcher,
lui dit:—Eh! bien, baron d’Artagnon, je suis heureux de pouvoir
réparer ma perte, venez voir mon fils! il sentit dans sa main une
main froide, regarda le nouveau duc de Nivron, le crut mort, et jeta
un cri de terreur qui épouvanta l’assemblée.
Beauvouloir ouvrit l’estrade, prit le jeune homme dans ses bras,
et l’emmena en disant à son maître:—Vous l’avez tué en ne le
préparant pas à cette cérémonie.
—Il ne pourra donc pas avoir d’enfant, s’il en est ainsi? s’écria le
duc qui suivit Beauvouloir dans la chambre seigneuriale où le
médecin alla coucher le jeune héritier.
—Eh! bien, maître? demanda le père avec anxiété.
—Ce ne sera rien, répondit le vieux serviteur en montrant à son
seigneur Étienne ranimé par un cordial dont il lui avait donné
quelques gouttes sur un morceau de sucre, nouvelle et précieuse
substance que les apothicaires vendaient au poids de l’or.
—Prends, vieux coquin, dit le vieux seigneur, en tendant sa
bourse à Beauvouloir, et soigne-le comme le fils d’un roi. S’il mourait
par ta faute, je te brûlerais moi-même sur un gril.
 —Si vous continuez à vous montrer violent, le duc de Nivron
mourra par votre fait, dit brutalement le médecin à son maître,
laissez-le, il va s’endormir.
—Bonsoir, mon amour, dit le vieillard, en baisant son fils au front.
—Bonsoir, mon père, reprit le jeune homme dont la voix fit
tressaillir le duc qui pour la première fois s’entendait donner par
Étienne le nom de père.
Le duc prit Beauvouloir par le bras, l’emmena dans la salle
voisine, et le poussa dans l’embrasure d’une croisée en lui disant:—
Ha! çà, vieux coquin, à nous deux!
Ce mot, qui était la gracieuseté favorite du duc, fit sourire le
médecin, qui depuis longtemps avait quitté ses rebouteries.
—Tu sais, dit le duc en continuant, que je ne te veux pas de mal.
Tu as deux fois accouché ma pauvre Jeanne, tu as guéri mon fils
Maximilien d’une maladie, enfin tu fais partie de ma maison. Pauvre
enfant! je le vengerai, je me charge de celui qui me l’a tué! Tout
l’avenir de la maison d’Hérouville est donc entre tes mains. Je veux
marier cet enfant-là sans tarder. Toi seul peux savoir s’il y a chance
de trouver en cet avorton de l’étoffe à faire des d’Hérouville... Tu
m’entends. Que crois-tu?
—Sa vie, au bord de la mer, a été si chaste et si pure, que la
nature est plus drue chez lui qu’elle ne l’aurait été s’il eût vécu dans
votre monde. Mais un corps si délicat est le très-humble serviteur de
l’âme. Monseigneur Étienne doit choisir lui-même sa femme, car tout
en lui sera l’ouvrage de la nature, et non celui de vos vouloirs. Il
aimera naïvement, et fera, par désir de cœur, ce que vous souhaitez
qu’il fasse pour votre nom. Donnez à votre fils une grande dame qui
soit comme une haquenée, il ira se cacher dans ses rochers; bien
plus! si quelque vive terreur le tuerait à coup sûr, je crois qu’un
bonheur trop subit le foudroierait également. Pour éviter ce malheur,
m’est avis de laisser Étienne s’engager de lui-même, et à son aise,
dans la voie des amours. Écoutez, monseigneur, quoique vous
soyez un grand et puissant prince, vous n’entendez rien à ces sortes
de choses. Accordez-moi votre confiance entière, sans bornes, et
vous aurez un petit-fils.
—Si j’obtiens un petit-fils par quelque sortilége que ce soit, je te
fais anoblir. Oui, quoique ce soit difficile, de vieux coquin tu
deviendras un galant homme, tu seras Beauvouloir, baron de
Forcalier. Emploie le vert et le sec, la magie blanche et noire, les
neuvaines à l’Église et les rendez-vous au sabbat, pourvu que j’aie
une lignée mâle, tout sera bien.
—Je sais, dit Beauvouloir, un chapitre de sorciers capable de tout
gâter; ce sabbat n’est autre que vous-même, monseigneur. Je vous
connais. Vous désirez une lignée à tout prix aujourd’hui; demain
vous voudrez déterminer les conditions dans lesquelles doit venir
cette lignée, et vous tourmenterez votre fils.
—Dieu m’en garde!
—Eh! bien, allez à la cour, où la mort du maréchal et
l’émancipation du roi doit avoir mis tout sens dessus dessous, et où
vous avez affaire, ne fût-ce que pour vous faire donner le bâton de
maréchal qu’on vous a promis. Laissez-moi gouverner monseigneur
Étienne. Mais engagez-moi votre parole de gentilhomme de
m’approuver en quoi que je fasse.
Le duc frappa dans la main du vieillard en signe d’une entière
adhésion, et se retira dans son appartement.
Quand les jours d’un haut et puissant seigneur sont comptés, le
médecin est un personnage important au logis. Aussi, ne faut-il pas
s’étonner de voir un ancien rebouteur devenu si familier avec le duc
d’Hérouville. A part les liens illégitimes par lesquels son mariage
l’avait rattaché à cette grande maison, et qui militaient en sa faveur,
le duc avait si souvent éprouvé le grand sens du savant, qu’il en
avait fait l’un de ses conseillers favoris. Beauvouloir était le Coyctier
de ce Louis XI. Mais, de quelque prix que fût sa science, le médecin
n’avait pas, sur le gouverneur de Normandie, en qui respirait
toujours la férocité des guerres religieuses, autant d’influence que la
féodalité. Aussi, le serviteur avait-il deviné que les préjugés du noble
nuisaient aux vœux du père. En grand médecin qu’il était,
Beauvouloir comprit que, chez un être délicatement organisé comme
Étienne, le mariage devait être une lente et douce inspiration qui lui
communiquât de nouvelles forces en l’animant du feu de l’amour.
Comme il l’avait dit, imposer une femme à Étienne, c’était le tuer. On
devait éviter surtout que ce jeune solitaire s’effrayât du mariage dont
il ne savait rien, et qu’il connût le but dont se préoccupait son père.
Ce poëte inconnu n’admettait que la noble et belle passion de
Pétrarque pour Laure, de Dante pour Béatrix. Comme sa mère, il
était tout amour pur, et tout âme; on devait lui donner l’occasion
d’aimer, attendre l’événement et non le commander; un ordre aurait
tari en lui les sources de la vie.
Maître Antoine Beauvouloir était père, il avait une fille élevée
dans des conditions qui en faisaient la femme d’Étienne. Il était si
difficile de prévoir les événements qui rendraient un enfant destiné
par son père au cardinalat, l’héritier présomptif de la maison
d’Hérouville, que Beauvouloir n’avait jamais remarqué la
ressemblance des destinées d’Étienne et de Gabrielle. Ce fut une
idée subite inspirée par son dévouement à ces deux êtres plutôt que
par son ambition. Malgré son habileté, sa femme était morte en
couches en lui donnant une fille, dont la santé fut si faible, qu’il
pensa que la mère avait dû léguer à son fruit des germes de mort.
Beauvouloir aima sa Gabrielle comme tous les vieillards aiment leur
unique enfant. Sa science et ses soins constants prêtèrent une vie
factice à cette frêle créature, qu’il cultiva comme un fleuriste cultive
une plante étrangère. Il l’avait soustraite à tous les regards dans son
domaine de Forcalier, où elle fut protégée contre les malheurs du
temps par la bienveillance générale qui s’était attachée à un homme
auquel chacun devait un cierge, et dont le pouvoir scientifique
inspirait une sorte de terreur respectueuse. En s’attachant à la
maison d’Hérouville, il avait augmenté les immunités dont il jouissait
dans la province, et déjoué les poursuites de ses ennemis par sa
position formidable auprès du gouverneur; mais il s’était bien gardé,
en venant au château, d’y amener la fleur qu’il tenait enfouie à
Forcalier, domaine plus important par les terres qui en dépendaient
que par l’habitation, et sur lequel il comptait pour trouver à sa fille un
établissement conforme à ses vues. En promettant au vieux duc une
postérité, en lui demandant sa parole d’approuver sa conduite, il
pensa soudain à Gabrielle, à cette douce enfant, dont la mère avait
été oubliée par le duc, comme il avait oublié son fils Étienne. Il
attendit le départ de son maître avant de mettre son plan à
exécution, en prévoyant que si le duc en avait connaissance, les
énormes difficultés qui pourraient être levées à la faveur d’un
résultat favorable, seraient dès l’abord insurmontables.
La maison de maître Beauvouloir était exposée au midi, sur le
penchant d’une de ces douces collines qui cerclent les vallées de
Normandie; un bois épais l’enveloppait au nord; des murs élevés et
des haies normandes à fossés profonds, y faisaient une
impénétrable enceinte. Le jardin descendait, en pente molle, jusqu’à
la rivière qui arrosait les herbages de la vallée, et à laquelle le haut
talus d’une double haie formait en cet endroit un quai naturel. Dans
cette haie tournait une secrète allée, dessinée par les sinuosités des
eaux, et que les saules, les hêtres, les chênes rendaient touffue
comme un sentier de forêt. Depuis la maison jusqu’à ce rempart,
s’étendaient les masses de la verdure particulière à ce riche pays,
belle nappe ombragée par une lisière d’arbres rares, dont les
nuances composaient une tapisserie heureusement colorée: là, les
teintes argentées d’un pin se détachaient de dessus le vert foncé de
quelques aulnes; ici, devant un groupe de vieux chênes, un svelte
peuplier élançait sa palme, toujours agitée; plus loin, des saules
pleureurs penchaient leurs feuilles pâles entre de gros noyers à tête
ronde. Cette lisière permettait de descendre, à toute heure, de la
maison vers la haie, sans avoir à craindre les rayons du soleil. La
façade, devant laquelle se déroulait le ruban jaune d’une terrasse
sablée, était ombrée par une galerie de bois autour de laquelle
s’entortillaient des plantes grimpantes qui, dans le mois de mai,
jetaient leurs fleurs jusqu’aux croisées du premier étage. Sans être
vaste, ce jardin semblait immense par la manière dont il était percé;
et ses points de vue, habilement ménagés dans les hauteurs du
terrain, se mariaient à ceux de la vallée où l’œil se promenait
librement. Selon les instincts de sa pensée, Gabrielle pouvait, ou
rentrer dans la solitude d’un étroit espace sans y apercevoir autre
chose qu’un épais gazon et le bleu du ciel entre les cimes des
arbres, ou planer sur les plus riches perspectives en suivant les
nuances des lignes vertes, depuis leurs premiers plans si éclatants,
jusqu’aux fonds purs de l’horizon où elles se perdaient, tantôt dans
l’océan bleu de l’air, tantôt dans les montagnes de nuages qui y
flottaient.
Soignée par sa grand’mère, servie par sa nourrice, Gabrielle
Beauvouloir ne sortait de cette modeste maison que pour se rendre
à la paroisse, dont le clocher se voyait au faîte de la colline, et où
l’accompagnaient toujours son aïeule, sa nourrice et le valet de son
père. Elle était donc arrivée à l’âge de dix-sept ans dans la suave
ignorance que la rareté des livres permettait à une fille de conserver
sans qu’elle parût extraordinaire en un temps où les femmes
instruites étaient de rares phénomènes. Cette maison avait été
comme un couvent, plus la liberté, moins la prière ordonnée, et où
elle avait vécu sous les yeux d’une vieille femme pieuse, sous la
protection de son père, le seul homme qu’elle eût jamais vu. Cette
solitude profonde, exigée dès sa naissance par la faiblesse
apparente de sa constitution, avait été soigneusement entretenue
par Beauvouloir. A mesure que Gabrielle grandissait, les soins qui lui
étaient prodigués, l’influence d’un air pur avaient à la vérité fortifié sa
jeunesse frêle. Néanmoins le savant médecin ne pouvait se tromper
en voyant les teintes nacrées qui entouraient les yeux de sa fille
s’attendrir, se brunir, s’enflammer suivant ses émotions: la débilité du
corps et la force de l’âme se signaient là par des indices que sa
longue pratique lui permettait de reconnaître; puis, la céleste beauté
de Gabrielle lui avait fait redouter les entreprises si communes par
un temps de violence et de sédition. Mille raisons avaient donc
conseillé à ce bon père d’épaissir l’ombre et d’agrandir la solitude
autour de sa fille dont l’excessive sensibilité l’effrayait; une passion,
un rapt, un assaut quelconque la lui aurait blessée à mort. Quoique
sa fille encourût rarement des reproches, un mot de réprimande la
bouleversait; elle le gardait au fond du cœur où il pénétrait et
engendrait une mélancolie méditative; elle allait pleurer, et pleurait
longtemps. Chez Gabrielle, l’éducation morale n’avait donc pas
voulu moins de soins que l’éducation physique. Le vieux médecin
avait dû renoncer à conter à sa fille les histoires qui charment les
enfants, elle en recevait de trop vives impressions. Aussi, cet
homme, qu’une longue pratique avait rendu si savant, s’était-il
empressé de développer le corps de sa fille afin d’amortir les coups
qu’y portait une âme aussi vigoureuse. Comme Gabrielle était toute
sa vie, son amour, sa seule héritière, il n’avait jamais hésité à se
procurer les choses dont le concours devait amener le résultat
souhaité. Il écarta soigneusement les livres, les tableaux, la
musique, toutes les créations des arts qui pouvaient réveiller la
pensée. Aidé par sa mère, il intéressait Gabrielle à des ouvrages
manuels. La tapisserie, la couture, la dentelle, la culture des fleurs,
les soins du ménage, la récolte des fruits, enfin les plus matérielles
occupations de la vie étaient données en pâture à l’esprit de cette
charmante enfant; Beauvouloir lui apportait de beaux rouets, des
bahuts bien travaillés, de riches tapis, de la poterie de Bernard de
Palissy, des tables, des prie-Dieu, des chaises sculptées et garnies
d’étoffes précieuses, du linge ouvré, des bijoux. Avec l’instinct que
donne la paternité, le vieillard choisissait toujours ses cadeaux parmi
les œuvres dont les ornements appartenaient à ce genre fantasque
nommé arabesque, et qui ne parlant ni aux sens ni à l’âme,
s’adressent seulement à l’esprit par les créations de la fantaisie
pure. Ainsi, chose étrange! la vie que la haine d’un père avait
commandée à Étienne d’Hérouville, l’amour paternel avait dit à
Beauvouloir de l’imposer à Gabrielle. Chez l’un et l’autre de ces
deux enfants, l’âme devait tuer le corps; et sans une profonde
solitude, ordonnée par le hasard chez l’un, voulue par la science
chez l’autre, tous deux pouvaient succomber, celui-ci à la terreur,
celle-là sous le poids d’une trop vive émotion d’amour. Mais, hélas!
au lieu de naître dans un pays de landes et de bruyères, au sein
d’une nature sèche aux formes arrêtées et dures, que tous les
grands peintres ont donné comme fonds à leurs vierges, Gabrielle
vivait au fond d’une grasse et plantureuse vallée. Beauvouloir n’avait
pu détruire l’harmonieuse disposition des bosquets naturels, le
gracieux agencement des corbeilles de fleurs, la fraîche mollesse du
tapis vert, l’amour exprimé par les entrelacements des plantes
grimpantes. Ces vivaces poésies avaient leur langage, plutôt
entendu que compris de Gabrielle qui se laissait aller à de confuses
rêveries sous les ombrages; à travers les idées nuageuses que lui
suggéraient ses admirations sous un beau ciel, et ses longues
études de ce paysage observé dans tous les aspects qu’y
imprimaient les saisons et les variations d’une atmosphère marine
où viennent mourir les brumes de l’Angleterre, où commencent les
clartés de la France, il s’élevait dans son esprit une lointaine lumière,
une aurore qui perçait les ténèbres dans lesquelles la maintenait son
père.
Beauvouloir n’avait pas soustrait non plus Gabrielle à l’influence
de l’amour divin, elle joignait à l’admiration de la nature l’adoration
du Créateur; elle s’était élancée dans la première voie ouverte aux
sentiments féminins: elle aimait Dieu, elle aimait Jésus, la Vierge et
les saints, elle aimait l’Église et ses pompes; elle était catholique à la
manière de sainte Thérèse qui voyait dans Jésus un infaillible époux,
un continuel mariage. Mais Gabrielle se livrait à cette passion des
âmes fortes avec une simplicité si touchante, qu’elle aurait désarmé
la séduction la plus brutale par l’enfantine naïveté de son langage.
Où cette vie d’innocence conduisait-elle Gabrielle? Comment
instruire une intelligence aussi pure que l’eau d’un lac tranquille qui
n’aurait encore réfléchi que l’azur des cieux? Quelles images
dessiner sur cette toile blanche? Autour de quel arbre tourner les
clochettes de neige épanouies sur ce liseron? Jamais le père ne
s’était fait ces questions sans éprouver un frisson intérieur. En ce
moment, le bon vieux savant cheminait lentement sur sa mule,
comme s’il eût voulu rendre éternelle la route qui menait du château
d’Hérouville à Ourscamp, nom du village auprès duquel se trouvait
son domaine de Forcalier. L’amour infini qu’il portait à sa fille lui avait
fait concevoir un si hardi projet! un seul être au monde pouvait la
rendre heureuse, et cet homme était Étienne. Certes, le fils
angélique de Jeanne de Saint-Savin et la candide fille de Gertrude
Marana étaient deux créations jumelles. Toute autre femme que
Gabrielle devait effrayer et tuer l’héritier présomptif de la maison
d’Hérouville; de même qu’il semblait à Beauvouloir que Gabrielle
devait périr par le fait de tout homme de qui les sentiments et les
formes extérieures n’auraient pas la virginale délicatesse d’Étienne.
Certes le pauvre médecin n’y avait jamais songé, le hasard s’était
complu à ce rapprochement, et l’ordonnait. Mais, sous le règne de
Louis XIII, oser amener le duc d’Hérouville à marier son fils unique à
la fille d’un rebouteur normand! Et cependant de ce mariage
seulement pouvait résulter cette lignée que voulait impérieusement
le vieux duc. La nature avait destiné ces deux beaux êtres l’un à
l’autre. Dieu les avait rapprochés par une incroyable disposition
d’événements, tandis que les idées humaines, les lois mettaient
entre eux des abîmes infranchissables. Quoique le vieillard crût voir
en ceci le doigt de Dieu, et malgré la parole qu’il avait surprise au
duc, il fut saisi par de telles appréhensions en pensant aux violences
de ce caractère indompté, qu’il revint sur ses pas au moment où,
parvenu sur le haut de la colline opposée à celle d’Ourscamp, il
aperçut la fumée qui s’élevait de son toit entre les arbres de son
enclos. Il fut décidé par son illégitime parenté, considération qui
pouvait influer sur l’esprit de son maître. Puis une fois décidé,
Beauvouloir eut confiance dans les hasards de la vie, il se pourrait
que le duc mourût avant le mariage; et d’ailleurs il compta sur les
exemples: une paysanne du Dauphiné, Françoise Mignot, venait
d’épouser le maréchal de l’Hopital; le fils du connétable Anne de
Montmorency avait épousé Diane, la fille de Henri II et d’une dame
piémontaise nommée Philippe Duc.
Pendant cette délibération, où l’amour paternel estimait toutes les
probabilités, discutait les bonnes comme les mauvaises chances, et
tâchait d’entrevoir l’avenir en en pesant les éléments, Gabrielle se
promenait dans le jardin où elle choisissait des fleurs pour garnir les
vases de l’illustre potier qui fit avec l’émail ce que Benvenuto Cellini
avait fait avec les métaux. Gabrielle avait mis ce vase, orné
d’animaux en relief, sur une table, au milieu de la salle, et le
remplissait de fleurs pour égayer sa grand’mère, et peut-être aussi
pour donner une forme à ses propres pensées. Le grand vase de
faïence, dite de Limoges, était plein, achevé, posé sur le riche tapis
de la table, et Gabrielle disait à sa grand’mère:—«Regardez donc!»
quand Beauvouloir entra. La fille courut se jeter dans les bras du
père. Après les premières effusions de tendresse, Gabrielle voulut
que le vieillard admirât le bouquet; mais après l’avoir regardé,
Beauvouloir plongea sur sa fille un regard profond qui la fit rougir.
—Il est temps, se dit-il en comprenant le langage de ces fleurs
dont chacune avait été sans doute étudiée et dans sa forme et dans
sa couleur, tant chacune était bien mise à sa place, où elle produisait
un effet magique dans le bouquet.
 Gabrielle resta debout, sans penser à la fleur commencée sur
son métier. A l’aspect de sa fille, une larme roula dans les yeux de
Beauvouloir, sillonna ses joues qui contractaient encore difficilement
une expression sérieuse, et tomba sur sa chemise que, selon la
mode du temps, son pourpoint ouvert sur le ventre laissait voir au-
dessus de son haut-de-chausses. Il jeta son feutre orné d’une vieille
plume rouge, pour pouvoir faire avec sa main le tour de sa tête
pelée. En contemplant de nouveau sa fille qui, sous les solives
brunes de cette salle tapissée de cuir, ornée de meubles en ébène,
de portières en grosses étoffes de soie, parée de sa haute
cheminée, et qu’éclairait un jour doux, était encore bien à lui, le
pauvre père sentit des larmes dans ses yeux et les essuya. Un père
qui aime son enfant voudrait le garder toujours petit; quant à celui
qui peut voir, sans une profonde douleur, sa fille passant sous la
domination d’un homme, il ne remonte pas vers les mondes
supérieurs, il redescend dans les espèces infimes.
—Qu’avez-vous, mon fils? dit la vieille mère en ôtant ses lunettes
et cherchant dans l’attitude ordinairement joyeuse du bonhomme le
sujet du silence qui la surprenait.
Le vieux médecin montra du doigt sa fille à l’aïeule qui hocha la
tête par un signe de satisfaction, comme pour dire: Elle est bien
mignonne!