BONE DYSPLASIAS

1

BONE DYSPLASIASAn Atlas of Genetic Disorders of Skeletal Development

F O U R T H E D I T I O N

Jürgen W. Spranger, MD

Paula W. Brill, MD

Christine Hall, MD

Gen Nishimura, MD

Andrea Superti- Furga, MD

Sheila Unger, MD

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v

CONTENTS

Foreword xi

John M. Opitz

Acknowledgments xiii

Introduction xv

1. ACHONDROPLASIA AND RELATED FGFR3 CONDITIONS 1

1.1 Thanatophoric Dysplasia, Types 1 and 2 (MIM 187600, 187601) 1

1.2 Achondroplasia (MIM 100800) 5

1.3 Hypochondroplasia (MIM 146000) 12

1.4 SADDAN (Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans) (MIM 616482) 19

2. PSEUDOACHONDROPLASIA AND DOMINANT EPIPHYSEAL DYSPLASIA 23

2.1 Pseudoachondroplasia (MIM 177170) 23

2.2 Multiple Epiphyseal Dysplasias, Autosomal Dominant (MIM 132400, 614135, 600204, 600969, 607078) 27

3. DYSPLASIAS WITH PREDOMINANT METAPHYSEAL INVOLVEMENT 33

3.1 Metaphyseal Chondrodysplasia, Schmid Type (MIM 156500) 33

3.2 Cartilage- Hair Hypoplasia (MIM 250250, 607095) 37

3.3 Metaphyseal Dysplasia, Spahr Type (MIM 250400) 41

3.4 Metaphyseal Anadysplasia (MIM 602111, 613073) 44

3.5 Shwachman Syndrome (MIM 260400) 50

3.6 Metaphyseal Chondrodysplasia, Jansen Type (MIM 156400) 54

3.7 Eiken Dysplasia (MIM 600002) 58

3.8 CINCA (Chronic Infantile Neurologic Cutaneous and Articular Syndrome) (MIM 607115) 61

4. SPONDYLO EPIPHYSEAL DYSPLASIA CONGENITA AND RELATED TYPE 2/ TYPE 11 COLLAGEN DISORDERS 65

4.1 Achondrogenesis II, Hypochondrogenesis (MIM 200610) 65

4.2 Platyspondylic Dysplasia, Torrance Type (MIM 151210) 68

4.3 Spondyloepiphyseal Dysplasia Congenita (MIM 183900) 72

4.4 Spondylo- epi- metaphyseal Dysplasia, Strudwick Type (MIM 183900, 184250, 184253) 80

4.5 Kniest Dysplasia (MIM 156550) 85

4.6 Spondyloepiphyseal Dysplasia, Stanescu Type (MIM 616538) 90

4.7 Spondyloperipheral Dysplasia (MIM 271700) 92

4.8 Spondyloepiphyseal Dysplasia with Short Metatarsals (MIM 609162) 95

4.9 Stickler Dysplasia (MIM 108300, 604841) 97

4.10 Fibrochondrogenesis (MIM 228520) 101

4.11 Oto- Spondylo- Megaepiphyseal Dysplasia (MIM 184840, 277610, 215150) 103

5. MUCOPOLYSACCHARIDOSES AND OLIGOSACCHARIDOSES 109

5.1 Dysostosis Multiplex 109

5.2 Mucopolysaccharidosis IV (MIM 253000, 253010) 117

5.3 Mucolipidosis II (MIM 252500) 124

5.4 Mucolipidosis III (MIM 252600, 252605) 129

6. METATROPIC DYSPLASIA AND OTHER TRPV4- RELATED SKELETAL DYSPLASIAS 135

6.1 Metatropic Dysplasia (MIM 156530, 168400) 135

6.2 Spondyloepiphyseal Dysplasia, Maroteaux Type (MIM 184095) 143

6.3 Spondylometaphyseal Dysplasia, Kozlowski Type (MIM 184252) 146

6.4 Brachyolmia, Autosomal Dominant (MIM 113500) 151

6.5 Familial Digital Arthropathy with Brachydactyly (MIM 606835) 154

7. SPONDYLO- EPI- METAPHYSEAL AND SPONDYLO- METAPHYSEAL DYSPLASIAS 157

7.1 Achondrogenesis Type 1A (MIM 200600) 157

7.2 Odontochondrodysplasia (MIM 184260) 160

7.3 Schneckenbecken Dysplasia (MIM 269250) 163

7.4 Opsismodysplasia (MIM 258480) 165

7.5 Spondylometaphyseal Dysplasia— Sedaghatian Type (MIM 250220) 169

7.6 Spondyloenchondrodysplasia (SPENCD; MIM 607944) 172

vi C O N T E N T S

7.7 Spondyloepimetaphyseal Dysplasia, PAPSS2 Type, and Brachyolmia, Autosomal Recessive Type (MIM 271530, 271630) 175

7.8 Dyggve- Melchior- Clausen Dysplasia (MIM 223800) 178

7.9 Spondylometaepiphyseal Dysplasia, Short Limb- Abnormal Calcification Type (MIM 271665) 183

7.10 Spondylometaphyseal Dysplasia with Cone- Rod Dystrophy (MIM 608940) 189

7.11 Dyssegmental Dysplasia (MIM 224400, MIM 244110) 194

7.12 Schwartz- Jampel Syndrome (MIM 255800) 199

7.13 Spondyloepiphyseal Dysplasia Tarda, X- Linked (MIM 313400) 205

7.14 Aggrecan- Associated Skeletal Dysplasias (MIM 608361, 612813) 209

7.15 Wolcott- Rallison Syndrome (MIM 226980) 214

7.16 Schimke Immunoosseous Dysplasia (MIM 242900) 218

7.17 Progressive Pseudo- Rheumatoid Dysplasia (MIM 208230) 222

7.18 Spondylometaphyseal Dysplasia, Corner Fracture Type (MIM 184255) 228

7.19 Sponastrime Dysplasia (MIM 271510) 230

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

8.2 Atelosteogenesis, Type 2 (MIM 256050) 247

8.3 Diastrophic Dysplasia (MIM 222600) 250

8.4 Multiple Epiphyseal Dysplasia, Recessive Type (rMED; MIM 226900) 256

8.5 Desbuquois Dysplasia (MIM 251450) 260

8.6 Chondrodysplasia with Joint Dislocations, IMPAD1/ gPAPP Type (MIM 614078) 266

8.7 Catel- Manzke Syndrome (MIM 616145) 270

8.8 Chondrodysplasia with Congenital Joint Dislocations, CHST3 Type (MIM 143095) 272

8.9 Temtamy Preaxial Brachydactyly Syndrome (MIM 605282) 276

8.10 B4GALT7 Deficiency (MIM 130070) 279

8.11 B3GAT3 Deficiency (MIM 245600) 281

8.12 XYLT1 Deficiency (MIM 251450) 284

8.13 Spondyloepimetaphyseal Dysplasia with Joint Laxity, Beighton Type (MIM 271640) 287

8.14 Spondyloepimetaphyseal Dysplasia with Joint Laxity, Leptodactylic Type (MIM 603546) 292

8.15 Pseudodiastrophic Dysplasia (MIM 264180) 298

8.16 Steel Syndrome (MIM 615155) 302

9. FILAMIN- ASSOCIATED DYSPLASIAS/ DYSOSTOSES AND RELATED DISORDERS 307

9.1 Otopalatodigital Syndrome Type I (MIM 311300) 307

9.2 Otopalatodigital Syndrome Type II (MIM 304120) 314

9.3 Melnick- Needles Osteodysplasty (MIM 309350) 320

9.4 Frontometaphyseal Dysplasia (MIM 305620, 617137) 326

9.5 Boomerang Dysplasia/ Atelosteogenesis Type I (MIM 112310, 108720) 331

9.6 Atelosteogenesis Type III (MIM 108721) 335

9.7 Larsen Syndrome, Autosomal Dominant (MIM 150250) 339

9.8 Spondylocarpotarsal Synostosis Syndrome (MIM 272460) 344

9.9 Frank- Ter Haar Syndrome (MIM 249420) 346

10. PUNCTATE CALCIFICATION GROUP 351

10.1 Greenberg Dysplasia (MIM 215140) 351

10.2 Chondrodysplasia Punctata Conradi, Hünermann Type (MIM 302960) 353

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

10.7 Chondrodysplasia Punctata, Tibia- Metacarpal Type (MIM 118651) 371

10.8 Keutel Syndrome (MIM 245150) 375

11. SHORT- RIB (±POLYDACTYLY) DYSPLASIAS 379

11.1 Asphyxiating Thoracic Dysplasia (MIM 208500) 380

11.2 Ellis Van Creveld Syndrome (MIM 255500) 385

11.3 Short Rib (±Polydactyly) Syndrome, Saldino- Noonan and Verma- Naumoff Types (MIM 613091) 390

11.4 Short Rib (±Polydactyly) Syndrome, Majewski Type (MIM 263520) 394

11.5 Short Rib (±Polydactyly) Syndrome, Beemer- Langer Type (MIM 269860) 396

11.6 Cranioectodermal Dysplasia (MIM 218330) 398

11.7 Mainzer- Saldino Syndrome (MIM 266920) 403

11.8 Axial Spondylometaphyseal Dysplasia (MIM 602271) 406

12. RHIZO- MESOMELIC DYSPLASIAS 409

12.1 Omodysplasia, Autosomal Recessive (MIM 258315, 268250) 409

viiC O N T E N T S

12.2 Robinow Syndrome (MIM 180700, 616331, 616894, 268310) 412

12.3 Dyschondrosteosis (MIM 127300) 419

12.4 Mesomelic Dysplasia, Langer Type (MIM 249700) 422

12.5 Mesomelic Dysplasia, Kantaputra Type (MIM 156232) 425

12.6 Mesomelic Dysplasia, Werner Type (MIM 188740, 135750) 429

12.7 Mesomelic Dysplasia, Reardon- Kozlowski Type (MIM 249710) 432

12.8 Mesomelic Dysplasia, Nievergelt- Savarirayan Type (MIM 163400, 605274) 435

12.9 Mesomelic Dysplasia with Acral Synostoses (MIM 600383) 439

13. ACROMESOMELIC AND ACROMELIC DYSPLASIAS/ DYSOSTOSES 443

13.1 Acromesomelic Dysplasia, Maroteaux Type (MIM 602875) 443

13.2 Grebe Dysplasia (MIM 200700, 201250, 228900) 447

13.3 Brachydactyly A1 (MIM 112500) 453

13.4 Brachydactyly B (MIM 113000) 455

13.5 Brachydactyly C (MIM 113100) 457

13.6 Brachydactyly D (MIM 113200) 460

13.7 Brachydactyly E (MIM 113300, 613380) 462

13.8 Brachydactyly, Christian Type (MIM 112450) 465

13.9 Tricho- Rhino- Phalangeal Dysplasia, Type I (MIM 190350) 467

13.10 Tricho- Rhino- Phalangeal Dysplasia, Type II (MIM 150230) 471

13.11 Acrocapitofemoral Dysplasia (MIM 607778) 473

13.12 Albright Hereditary Osteodystrophy (MIM 103580, 600430, 612462, 612463) 475

13.13 Acrodysostosis (MIM 101800, 614613) 481

13.14 Geleophysic Dysplasia (MIM 231050) 484

13.15 Acromicric Dysplasia (MIM 102370) 487

13.16 Myhre Syndrome (MIM 139210) 490

13.17 Soft Syndrome (MIM 614813) 494

14. OSTEOGENESIS IMPERFECTA AND OTHER DISORDERS WITH DECREASED BONE DENSITY 497

14.1 Osteogenesis Imperfecta 497

14.2 Osteogenesis Imperfecta, Type I (MIM 116200) 501

14.3 Osteogenesis Imperfecta, Type IIA (MIM 166210) 506

14.4 Osteogenesis Imperfecta, Type IIC 509

14.5 Osteogenesis Imperfecta, Type III/ IIB (MIM 259420) 511

14.6 Osteogenesis Imperfecta, Type IV (MIM 166220) 517

14.7 Osteogenesis Imperfecta, Type V (MIM 610967) 521

14.8 Idiopathic Juvenile Osteoporosis (MIM 259750) 526

14.9 Bruck Syndrome (MIM 259450, 609220, 610968) 529

14.10 Cole- Carpenter Syndrome (MIM 112240, 616294) 532

14.11 Stüve- Wiedemann Syndrome (MIM 601559) 535

14.12 Osteoporosis- Pseudoglioma Syndrome (MIM 259770) 540

14.13 Spondyloocular Dysplasia (MIM 605822) 543

14.14 Geroderma Osteodysplasticum (MIM 231070) 545

14.15 Calvarial Doughnut Lesions- Osteoporosis Syndrome (MIM 126550) 548

14.16 Gnathodiaphyseal Dysplasia (MIM 166260) 552

15. DYSORDERS WITH DEFECTIVE MINERALIZATION 557

15.1 Hypophosphatasia (MIM 146300, 241500, 251510) 557

15.2 Neonatal Severe Primary Hyperparathyroidism (MIM 239200) 564

15.3 Hereditary Rickets (MIM 307800, 193100, 241520, 613312, 241530, 264700, 600081, 277440, 600785, 300554, 612089) 568

16. DENSE BONE DYSPLASIAS WITH NORMAL BONE SHAPE 575

16.1 Osteopetroses 575

16.2 Raine Dysplasia (MIM 259775) 577

16.3 Infantile Osteopetrosis (MIM 259700, 259710, 259720, 611490) 580

16.4 Osteopetrosis, Intermediate (MIM 259710, 611497) 584

16.5 Osteopetrosis, Late Onset Forms (MIM 607634, 166660) 587

16.6 Osteopetrosis with Renal Tubular Acidosis (MIM 259730) 591

16.7 Dysosteosclerosis (MIM 224300) 596

16.8 Pyknodysostosis (MIM 265800) 601

16.9 Osteomesopyknosis (MIM 166450) 604

16.10 Osteopetrosis, Lymphedema, Ectodermal Dysplasia, Immune Defect (MIM 300301) 607

16.11 Osteopoikilosis (MIM 166700) 611

16.12 Melorheostosis (MIM 155950) 613

16.13 Osteopathia Striata with Cranial Sclerosis (MIM 300373) 616

17. DENSE BONE DYSPLASIAS WITH META- DIAPHYSEAL MODELING DEFECTS 621

17.1 Blomstrand Chondrodysplasia (MIM 215045) 621

17.2 Infantile Cortical Hyperostosis (MIM 114000) 623

17.3 Dysplastic Cortical Hyperostosis Type Kozlowski- Tsuruta 627

17.4 Osteoectasia with Hyperphosphatasia (MIM 239000) 629

viii C O N T E N T S

17.5 Endosteal Hyperostosis, van Buchem Type (MIM 239100, 269500) 634

17.6 Camurati- Engelmann Disease (MIM 131300) 639

17.7 Ghosal Hematodiaphyseal Dysplasia (MIM 231095) 644

17.8 Lenz- Majewski Hyperostotic Dysplasia (MIM 151050) 647

17.9 Hypertrophic Osteoarthropathy, Autosomal Recessive (MIM 259100) 653

17.10 Pachydermoperiostosis, Autosomal Dominant (MIM 167100) 656

17.11 Sclerosteo- Cerebellar Syndrome (MIM 213002) 660

17.12 Craniodiaphyseal Dysplasia (MIM 122860, 218300) 663

17.13 Craniometaphyseal Dysplasia (MIM 123000, 218400) 666

17.14 Craniometadiaphyseal Dysplasia, Wormian Bone Type (MIM 269300) 670

17.15 Pyle Disease (MIM 265900) 673

17.16 Metaphyseal Dysplasia, Braun- Tinschert Type (MIM 605946) 676

17.17 Oculodentoosseous Dysplasia (MIM 164200) 679

17.18 Tricho- Dento- Osseous Dysplasia (MIM 190320) 683

17.19 Diaphyseal Medullary Stenosis with Bone Malignancy (MIM 112250) 685

18. OSTEOLYSES 689

18.1 Familial Expansile Osteolysis (MIM 174810) 689

18.2 Hyaline Fibromatosis (MIM 228600) 692

18.3 Mandibuloacral Dysplasia (MIM 248370, 608612) 695

18.4 Progeria (MIM 176670) 699

18.5 Winchester- Torg Syndrome (MIM 259600) 703

18.6 Hajdu- Cheney Osteolysis (MIM 102500) 707

18.7 Multicentric Carpal- Tarsal Osteolysis (MIM 166300) 711

19. DISORDERS CAUSED BY DISORGANIZATION OF SKELETAL CONSTITUENTS 717

19.1 Fibrous Dysplasia (MIM 174800) 717

19.2 Cherubism (MIM 118400) 723

19.3 Progressive Osseous Heteroplasia (MIM 166350) 725

19.4 Multiple Cartilaginous Exostoses (MIM 133700, 133701, 600209) 728

19.5 Osteoglophonic Dysplasia (MIM 166250) 732

19.6 Fibrodysplasia Ossificans Progressiva (MIM 135100) 737

19.7 Dysplasia Epiphysealis Hemimelica (MIM 127800) 741

19.8 Enchondromatosis (MIM 166000) 744

19.9 Metaphyseal Chondromatosis with 2- Hydroxyglutaric Aciduria 748

19.10 Genochondromatosis (MIM 137360) 750

19.11 Metachondromatosis (MIM 156250) 753

20. POLYTOPIC DYSOSTOSES 757

20.1 Campomelic Dysplasia (MIM 211990, 114290) 757

20.2 Cousin Dysplasia (MIM 260660) 762

20.3 Spondylo- Megaepiphyseal- Metaphyseal Dysplasia (MIM 613330) 765

20.4 Cleidocranial Dysplasia (MIM 119600) 767

20.5 Yunis- Varon Syndrome (MIM 216340) 773

20.6 CDAGS (MIM 603116) 776

20.7 Nail- Patella Syndrome (MIM 161200) 779

20.8 Ischio- Pubic- Patellar Dysplasia (MIM 147891) 782

20.9 Ischiospinal Dysostosis (MIM 608020) 785

20.10 Cerebro- Costo- Mandibular Syndrome (MIM 117650) 790

20.11 SAMS Syndrome (MIM 602471) 793

21. DISORDERS WITH PRENATAL SHORT STATURE AND SLENDER BONES 795

21.1 3M Syndrome (MIM 273750, 612921, 614205) 795

21.2 Kenny- Caffey Syndrome (MIM 127000) 798

21.3 Osteocraniostenosis (OCS; MIM 602361) 802

21.4 Microcephalic Osteodysplastic Primordial Dwarfism, Types 1 and 3 (MIM 210710, 210730) 804

21.5 Microcephalic Osteodysplastic Primordial Dwarfism, Type 2 (MIM 210720) 807

21.6 IMAGE (Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies) Syndrome (MIM 614732) 812

22. OVERGROWTH/ ACCELERATED SKELETAL MATURATION SYNDROMES (SELECTED) 815

22.1 Marshall- Smith Syndrome (MIM 602535) 815

22.2 Moreno- Nishimura- Schmidt Overgrowth Syndrome (MIM 608811) 820

22.3 Weaver Syndrome (MIM 277590) 824

22.4 CNP- Overexpression Overgrowth Syndrome (MIM 615923) 826

23. CRANIOSYNOSTOSIS SYNDROMES 829

23.1 Apert Syndrome (MIM 101200) 829

23.2 Pfeiffer Syndrome (MIM 101600, 136350) 834

23.3 Antley- Bixler Syndrome (MIM 201750) 837

23.4 Saethre- Chotzen Syndrome (MIM 101400) 840

23.5 Baller- Gerold Syndrome (MIM 218600, 266280) 843

23.6 Carpenter Syndrome (MIM 201000, 614970) 848

23.7 Muenke Syndrome (MIM 602849) 851

23.8 Bent Bone Dysplasia- FGFR2 Type (MIM 614592) 853

ixC O N T E N T S

24. SPONDYLOCOSTAL DYSOSTOSES 857

25. LIMB APLASIAS AND HYPOPLASIAS (SELECTED) 863

25.1 Al- Awadi Raas- Rothschild Syndrome (MIM 276820, 228930) 863

25.2 Roberts/ SC Phocomelia Syndrome (MIM 268300, 269000) 866

25.3 Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/ Palate Syndrome (MIM 129900, 604292) 869

25.4 Split- Hand/ Foot Malformation with Long Bone Deficiency (MIM 119100, 610685, 612576) 872

25.5 Femoral- Facial Syndrome (MIM 134780) 876

25.6 Femur- Fibula- Ulna Syndrome (MIM 228200) 880

25.7 Poland Syndrome (MIM 173800) 883

25.8 Nager Syndrome (MIM 154400, 201170) 886

26. DISORDERS WITH DEFECTIVE JOINT FORMATION 889

26.1 Multiple Synostoses Syndrome (MIM 186500, 186570, 610017, 612961) 889

26.2 Liebenberg Syndrome (MIM 186550) 894

Index 897

xi

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

xii F O R E W O R D

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

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. OpitzUniversity of Utah, Salt Lake City

April 2012

BIBLIOGRAPHY

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.

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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

xv

INTRODUCTION

HISTORICAL PERSPECTIvE

S H O R T S T A T U R E , D W A R F S , L I L L I P U T I A N S , A N D S U P E R S T I T I O U S B E L I E F S

Disorders of bone are part of humankind’s genetic burden. Their existence in prehistory is documented by archaeo-logical findings. A  large number of paintings, engravings, and sculptures depict short- statured individuals, often in great detail (Enderle et al., 1994). Individuals with consti-tutional diseases of the skeleton attract attention because of their smaller size, because of deformities, and/ or because of the disproportion between body parts. Individuals with achondroplasia, a common skeletal short- stature condi-tion, have short arms and legs, a head that is usually larger than normal, and a typical facial appearance with a prom-inent forehead and a sunken nasal bridge. They are usually healthy (at least as children and young adults) and are said to be witty. Although there are no scientific data to con-firm the latter claim, their personal perspective on life may lead to particular insights. Perhaps for these reasons, individuals with achondroplasia (along with individuals with other deformities) have often played special social roles in human societies, from being members of royal courts to participating in circus shows or other public entertainment. Short- statured individuals have also fu-eled the fantasy of writers, and indirectly of the public, like in Jonathan Swift’s Gulliver’s Travels. The misconcep-tion of a separate race (such that of the Lilliputians) was frequent in the past and still lingers even in the present. Around the turn of the twentieth century, in Paris, there existed an institution called le jardin d’acclimatation where short- statured individuals (with diverse diagnoses ranging from achondroplasia to growth hormone deficiency) were offered a place to live; perhaps this was an act of charity but certainly also one of segregation (Bloch, 1909). The halo around individuals with short stature, deformity, or dispro-portion has thus stood in the way of a scientific or med-ical approach to the definition of their conditions, so much so that still, in 1886, when the French physician Joseph Marie Jules Parrot described a short- limbed patient and coined the name achondroplasie, he believed that achon-droplasia was a manifestation of rickets and that rickets itself was a consequence of hereditary syphilis (Parrot, 1886). As late as 1912, the Dutch orthopedist Murk Jansen supported the concept that achondroplasia was caused by “amnion- pressure” ( Jansen, 1912). Another popular be-lief was that achondroplasia was caused by “weak semen” (this latter belief may have been prompted by the observa-tion that achondroplasia individuals are often the youngest

siblings, in accordance with the paternal age effect on de novo FGFR3 mutations). The strong aura surrounding little people, dwarfs, or Lilliputians is surprising and in contrast to the notion that the genetic difference between an indi-vidual with achondroplasia (or pseudoachondroplasia, or spondylo- epiphyseal dysplasia congenita) and a normal- stature individual is a single nucleotide at heterozygosity.

Although medical descriptions of rare cases can be found in the seventeenth and eighteenth centuries, it was only in the nineteenth century that physicians and scientists began to approach affected individuals more systematically and to describe the aberrant growth pattern by observation of anatomy and pathology. In 1878, the French physician Parrot described an individual with short- limb dwarfism and coined the name achondroplasia, but in 1886, in his treatise on child diseases, he expressed the belief that achon-droplasia was a manifestation of congenital syphilis (Parrot, 1878, 1886). In 1892, the German pathologist Eduard Kaufmann studied the macroscopy and pathology of a series of 13 stillborns with what was then called “fetal rickets” and concluded that there were at least three different patterns of anatomical changes; this was the first recognition of het-erogeneity and attempt at classification (Kaufmann, 1892). Regarding achondroplasia, it is interesting to note that even as late as in 1912, the Danish physician Murk Jansen (who also described the metaphyseal dysplasia that still bears his name) supported the view that it was due to intrauterine fetal restriction:  reduced growth as a consequence of “ex-ternal pressure” applied to the fetus ( Jansen, 1912).

Around the beginning of the twentieth century, the use of x- rays to investigate medical conditions, particularly those affecting the skeleton, opened the way to the recog-nition of several “new” conditions as defined by their pe-culiar, and sometimes specific, radiographic appearance. Among these conditions (the list is not exhaustive by far) are osteopetrosis (Albers- Schönberg, 1904), melorheostosis (Léri & Ioanni, 1922), diaphyseal dysplasia (Camurati, 1922; Engelmann, 1929), dyschondrosteosis (Leri & Weill, 1929), osteopoikilosis (Ledoux- Lebard et  al., 1916), Pyle disease (Cohn, 1933; Pyle, 1931), infantile hyperostosis (Caffey, 1946), and many others. In 1917, Hunter described two brothers with a “rare disease” affecting the skeleton (now known as mucopolysaccharidosis type 2), and in 1919 Gertrud Hurler described two unrelated patients with sim-ilar features including corneal clouding and mental retar-dation (later defined as mucopolysaccharidosis type I). In 1929, Luis Morquio reported on a siblingship with a form of

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“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.

T H E G O L D E N 1 9 6 0 S

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

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.

A T L A S E S A N D C L A S S I F I C A T I O N S

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

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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.

N O M E N C L A T U R E A N D N O S O L O G Y

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

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.

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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

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.

UNDERSTANDING DYSPLASIAS AND DYSOSTOSES THROUGH THE COMBINATION OF CL INICAL, PATHOGENETIC, AND MOLECULAR CRITERIA

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.

F O R M A T I O N O F   S K E L E T A L E L E M E N T S

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

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.

D Y S O S T O S E S

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.

D I S R U P T I O N S

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

xx I N T R O D U C T I O N

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).

D Y S P L A S I A S

Defects of genes that are expressed continuously, from in-trauterine to extrauterine life, lead to dysplasias (Figure 1.1).

ExamplesDefect

Holt-Oram SyndromeIsolated Polydactyly

TRANSIENT SIGNALING DEFECTDysostosis

PERMANENT SIGNALING DEFECT– early intrauterine expression

– late intrauterine expression

–

–

–

–

– Dysplasia, prenatal

– Dysplasia, postnatal

- Osteolysis

htriBsisenegoyrbmE

DEFECTIVE CELLULAR FUNCTION

Dysostosis – Dysplasia

Dysplasia

Cleidocranial dysplasiaFibrodysplasia ossificans

AchondroplasiaJansen metaphyseal dysplasia

SED congenitaDiastrophic dysplasia

Multiple epiphyseal dysplasia

Winchester-Torg syndrome

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

TABLE 1.1 EXAMPLES OF DYSOSTOSES CAUSED BY DEFECTS IN TRANSCRIPTION FACTORS OR SIGNAL TRANSDUCTION PROTEINS

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 syndrome, Postaxial polydactyly A

AD Gli3 GLI- Kruppel family member 3 transcription factor

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.

xxiI N T R O D U C T I O N

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

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

TABLE 1.2 EXAMPLES OF DYSPLASIAS ASSOCIATED WITH MUTATIONS IN TRANSCRIPTION FACTORS OR SIGNAL TRANSDUCING MOLECULES

Name Inheritance Gene Protein

Campomelic dysplasia AD SOX9 SOX9 transcription factor

Tricho- rhino- phalangeal syndrome AD TRPS1 TRPS1 transcription factor

Dyschondrosteosis XD SHOX SHOX transcription factor

Achondroplasia family (thanatophoric dysplasia, achondroplasia, hypochondroplasia, others)

AD FGFR3 Fibroblast growth factor receptor 3

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

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

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

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

xxii I N T R O D U C T I O N

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.

M I x E D D I S O R D E R S

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

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

R E C O G N I T I O N A N D P R A C T I C A L I M P L I C A T I O N S O F   D E v E L O P M E N T A L C A T E G O R I E S

Differential criteria of dysostoses, disruptions, and dysplasias are summarized in Table  1.5. Although

TABLE 1.3 EXAMPLES OF DYSPLASIAS AND OSTEOLYSES CAUSED BY DEFECTS IN CELLULAR FUNCTION AND/ OR 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, hypochondrogenesis, Kniest dysplasia, SEDC, Stickler arthroophthalmopathy, premature arthrosis, etc.)

AD COL2A1 Collagen 2

Metaphyseal dysplasia, Schmid type AD COL10A1 Collagen 10

Pseudoachondroplasia and Dominant multiple epiphyseal dysplasia (one form)

AD COMP Cartilage oligomeric matrix protein

SED tarda, X- linked XLR TRAPPC2 Sedlin

Achondrogenesis 1B, Diastrophic dysplasia, Recessive multiple epiphyseal dysplasia

AR SLC26A2 Cell membrane sulfate transporter DTDST

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.

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.

xxiiiI N T R O D U C T I O N

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

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.

TABLE 1.4 EXAMPLES OF DEFECTS LEADING TO COMBINED DISORDERS (DYSOSTO- DYSPLASIAS)

Name Inheritance Gene Protein

Cleidocranial dysostosis AD RUNX2 Runt transcription factor

Campomelic dysplasia AD SOX9 SOX9 transcription factor

Spondylo- megaepiphyseal- metaphyseal dysplasia AR NKX3– 2 NKX3– 2 homeobox transcription factor

Grebe/ Hunter- Thompson dysplasia AR GDF5 (CDMP1) Growth and differentiation factor 5 (Cartilage- derived morphogenic protein 1)

Nail- patella syndrome AD LMX1B Lmx1b homeodomain protein

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

TABLE 1.5 DIFFERENTIAL CRITERIA OF DYSOSTOSES AND DYSPLASIAS

Dysostoses Skeletal Dysplasias

Primary Secondary Primary Secondary

Affected structure Skeletal element as organ Bone and/ or cartilage as tissues

Distribution Mostly symmetric, often mildly asymmetric, in some cases even unilateral Mostly symmetric

Determination period Organogenesis Growth period Growth period

xxiv I N T R O D U C T I O N

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