American Journal of Semin. Med. Genet.) 106:282±293 2001) ARTICLE

Molecular-Pathogenetic Classi®cation of Genetic Disorders of the Skeleton

ANDREA SUPERTI-FURGA,* LUISA BONAFEÂ , AND DAVID L. RIMOIN

Genetic disorders of the skeleton skeletal dysplasias and dysostoses) are a large and disparate group of diseases whose unifying features are malformation, disproportionate growth, and deformation of the skeleton or of individual bones or groups of bones. To cope with the large number of different disorders, the ``Nosology and Classi®cation of the Osteochondrodysplasias,'' based on clinical and radiographic features, has been designed and revised periodically. Biochemical and molecular features have been partially implemented in the Nosology, but the rapid accumulation of knowledge on and proteins cannot be easily merged into the clinical±radiographic classi®cation. We present here, as a complement to the existing Nosology, a classi®cation of genetic disorders of the skeleton based on the structure and function of the causative genes and proteins. This molecular±pathogenetic classi®cation should be helpful in recognizing metabolic and signaling pathways relevant to skeletal development, in pointing out candidate genes and possible therapeutic targets, and more generally in bringing the clinic closer to the basic science laboratory and in promoting researchin this®eld. ß 2002 Wiley-Liss, Inc.

KEY WORDS: skeleton; genetic disorders; molecular classi®cation; pathogenic classi®cation

INTRODUCTION The complexity of skeletal±genetic have also been used. Biochemical data phenotypes has been long appreciated. have been incorporated as they became Genetic disorders of the skeleton are a Although single entities have been des- available. Based on this combination of group of disorders with diverse manifes- cribed in the nineteenth or in the ®rst criteria, more than 200 nosologic enti- tations. Although individually rare, the half of the twentieth century, most ties are distinguished currently. many different forms add to produce a individual entities we know today have signi®cant number of affected indivi- been delineated much more recently. duals with signi®cant morbidity and The criteria used for distinction and The criteria used for distinction mortality. Clinical manifestations in- classi®cation of genetic skeletal disorders and classi®cation of genetic clude short stature, malformation, and have been clinical features such as deformation. The clinical severity differs growth, age at onset of growth retar- skeletal disorders have been between individuals, ranging from dation, presence and nature of altered clinical features such as minor handicaps to death in the neonatal body proportions, and, because of the period. In surviving patients, secondary outstanding role of radiography in de- growth, age at onset of complications of skeletal deformity and ®ning skeletal disease, radiographic cri- growth retardation, presence manifestations in extraskeletal organs teria. The mode of genetic transmission and nature of altered body add to the burden of disease. and speci®c extra skeletal abnormalities proportions, and, because of

Andrea Superti-Furga is Professor of Pediatrics at the University of Zurich and Leitender Arzt at the outstanding role of radio- the Division of Metabolism and Molecular Diseases of the University Children's Hospital in Zurich, Switzerland. Dr. Superti-Furga is involved in clinical care, laboratory diagnosis, teaching, and graphy in de®ning skeletal researchin thearea of metabolic and genetic pediatrics. disease, radiographic criteria. Luisa Bonafe , a graduate and board-certi®ed pediatrician from the University of Padova, Italy, has a strong research interest in amino acid and biopterin disorders and in skeletal dysplasias and is currently a postgraduate fellow withDr. Superti-Furga. David L. Rimoin is the Steven Spielberg Chairman of Pediatrics, Director of the Medical The ``Nomenclature and Classi®ca- Genetics±BirthDefects Center and Director of theInternational Skeletal Dysplasia Registry at Cedars-Sinai Medical Center and Professor of Pediatrics and Medicine at UCLA School of tion of the Osteochondrodysplasias'' has Medicine in Los Angeles, California. He is currently President of the American College of Medical been a valuable instrument in de®ning Genetics Foundation and was past President of the American Society of Human Genetics, the existing entities and delineating new American College of Medical Genetics, and the American Board of Medical Genetics. Grant sponsor: Swiss National Science Foundation; Grant number: 31-57272.99; Grant ones. In the 1992 revision [Spranger, sponsor: USPHS NIH.; Grant number: HD 22657; Grant sponsor: The Hartmann-MuÈ ller 1992], the classi®cation was oriented Foundation. toward radiodiagnostic and morpholo- *Correspondence to: Andrea Superti-Furga, Division of Metabolism and Molecular Pediatrics, University Children's Hospital, Steinwiesstr. 75, CH-8032 ZuÈ rich, Switzerland. gic criteria and grouped morphologi- E-mail: [email protected] cally similar disorders into ``families'' of

ß 2002 Wiley-Liss, Inc. DOI 10.1002/ajmg.10233 ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS SEMIN. MED. GENET.) 283 disorders based on presumed pathoge- netic similarities. In the 1997 revision Nosology: catalog of de®ned conditions [International Working Group on Con- 3master book, encyclopedia) stitutional Diseases of Bone, 1998], the families of disorders were to some extent .& rearranged based on new etiopathoge- netic information concerning the Molecular-pathogenetic Clinical breakdown and/or protein defect in these disorders. breakdown 3help in diagnosis, Those disorders in which the basic 3research, candidate genes, diagnostic algorithms, defect was well documented were re- diagnostic tests, guide to appropriate grouped into distinct families based on pharmacological therapy, # laboratory tests) in the same gene 3e.g., the gene therapy) achondroplasia group, the type 2 col- Radiographic breakdown lagen group, the diastrophic dysplasia 3radiographic features and group). The Nomenclature was focused signs; atlas, computer on the osteochondrodysplasias 3as devel- program for diagnostic opmental disorders of chondro-osseous help) tissue) but neglected the classi®cation of the dysostoses 3malformations of indivi- Figure 1. Classi®cation of skeletal genetic disorders by three categories. dual bones or groups of bones), although certain dysostoses 3e.g., C) were included because they were caused by mutations in genes associated presentations and clinical signs, to be of unprecedented and has turned the with dysplasias. The 1997 revision did, help in the diagnostic approach; and a skeletal system into a unique biologic however, come with the comment that molecular±pathogenetic classi®cation model. The multitude and variety of ``with the rapid evolution of our knowl- based on affected genes and pathoge- genes and proteins calls for a molecular edge concerning developmental genes netic mechanisms. Ultimately, they can and pathogenetic classi®cation. Such a in man, the group of disorders be cross-correlated in an electronic classi®cation should assist in the follow- is in dire need of reclassi®cation'' [Inter- database. Books and computer programs ing purposes: national Working Group on Constitu- using a gamut of radiographic signs are tional Diseases of Bone, 1998]. already widely used [Hall and Shaw, Toidentify metabolic pathways active In the 2001 revision,1 the dysostoses * 1994; Taybi and Lachman, 1996]. In this in cartilage and bone, and their regu- have been reviewed and incorporated in article, we present a classi®cation of latory mechanisms. the Nomenclature, which has been genetic disorders of the skeleton based To identify cellular signaling net- called Nosology [Hall, 2002]. At the * on structure and function of the respon- works and gene expression sequences same time, the Working Group believed sible genes and proteins 3Table I). implicated in skeletal development. that the Nomenclature was becoming a By the above mechanisms, to identify hybrid that would not meet clinical * other elements in those systems as criteria 3for example, grouping entities In the 2001 revision, the candidate genes for genetic disorders. such as achondrogenesis 2 and Stickler To facilitate integration of data com- syndrome, which are clinically very dif- dysostoses have been reviewed * ing from spontaneous and genetically ferent, because of their common origin and incorporated in the engineered mouse mutants. in the COL2A1 gene) but also would To help in developing diagnostic not fully re¯ect genetic±molecular cri- Nomenclature, which has * strategies. teria, because those disorders with been called Nosology. To stimulate the design and explora- unknown defect were still grouped by * tion of new therapeutic possibilities. radiographic criteria. The genetic com- To provide a knowledge framework munity might therefore be better served * accessible to physicians as well as to with distinct classi®cations 3Fig. 1): the MOLECULAR± basic scientists and thus to facilitate Nosology as a catalog of de®ned entities PATHOGENETIC communication between clinical 3a sort of master book); a clinical CLASSIFICATION AS A genetics and pediatrics and the basic classi®cation, focused on age-speci®c WORKING INSTRUMENT sciences. 1The Nosology Committee of the Interna- The accumulation of knowledge on tional Skeletal Dysplasia Society met in Oxford on Sept. 4 and 5, 2001, under the genes and proteins responsible for Wetried to use classi®cation criteria presidency of Dr. Christine Hall. genetic disorders of the skeleton is similar to those used in the functional 284 AMERICAN JOURNAL OF MEDICAL GENETICS SEMIN. MED. GENET.) ARTICLE

TABLE I.Molecular±Pathogenetic Classi®cation of Genetic Disorders of the Skeleton Gene or protein Inheritance Clinical phenotype References

Group 1: Defects in extracellular structural proteins COL1A1, COL1A2 AD Family: Osteogenesis imperfecta Byers, 1990; Prockop et al., 3collagen 1 a1, a2 chains) 1994 COL2A1 3collagen 2 a1 chain) AD Family: achondrogenesis 2, hypochondrogenesis, Spranger et al., 1994 congenital spondyloepiphyseal dysplasia 3SEDC), Kniest, Stickler arthro-ophtalmopathy, familial osteoarthritis, other variants COL9A1,COL9A2, COL9A3 AD Multiple epiphyseal dysplasia 3MED; two or Lohiniva et al., 2000; 3collagen 9 a1, a2, a3 chains) more variants) Spayde et al., 2000 COL10A1 3collagen 10 AD Schmid Wallis et al., 1996 a1chain) Col11A1, Col11A2 3collagen AR, AD Oto-spondylo-megaepiphyseal dysplasia Melkoniemi et al., 2000; 11 a1, a2 chains) 3OSMED); Stickler 3variant), Marshall Spranger, 1998 syndrome COMP 3cartilage oligomeric AD Pseudoachondroplasia, multiple epiphyseal Briggs et al., 1998 matrixprotien) dysplasia 3MED, one form) MATN3 3matrilin-3) AD Multiple epiphyseal dysplasia 3MED; one variant) Chapman et al., 2001 Perlecan AR Schwartz-Jampel type 1; dyssegmental dysplasia Arikawa-Hirasawa et al., 2001 Group 2: Defects in metabolic pathways 2including enzymes, ion channels, and transporters) TNSALP 3tissue nonspeci®c AR, AD Hypophosphatasia 3several forms) Mornet et al., 1998 alkaline ) ANKH 3pyrophosphate AD Craniometaphyseal dysplasia Nurnberg et al., 2001; transporter) Reichenberger et al., 2001 DTDST/SLC26A2 AR Family: achondrogenesis 1B, atelosteogenesis 2, Rossi and Superti-Furga, 3diastrophic dysplasia diastrophic dysplasia, recessive multiple 2001; Superti-Furga sulfate transporter) epiphyseal dysplasia 3rMED) et al., 1996a; Superti- Furga et al., 1996b PAPSS2, phosphoadenosine- AR Spondylo-epi-metaphyseal dysplasia Pakistani ul Haque et al., 1998 phosphosulfate-synthase 2 type TCIRGI, osteoblast proton AR Severe infantile osteopetrosis Frattini et al., 2000 pump subunit CIC-7 3chloride channel 7) AR Severe osteopetrosis Kornak et al., 2001 Carboanhydrase II AR Osteopetrosis with intracranial calci®cations and Venta et al., 1991 renal tubular acidosis Vitamin K-epoxide reductase AR Chondrodysplasia punctata with vitamin Oldenburg et al., 2000; complex K-dependent coagulation defects Pauli, 1988; Pauli et al., 1987 MGP 3matrixGla protein) AR Keutel syndrome 3pulmonary stenosis, Munroe et al., 1999 brachytelephalangism, cartilage calci®cations and short stature) ARSE 3arylsulfatase E) XLR X-linked chondrodysplasia punctata 3CDPX1) Franco et al., 1995 3-b-hydroxysteroid- XLD CHILD syndrome Konig et al., 2000 dehydrogenase 3-b-hydroxysteroidD38)D37)- XLD X-linked chondrodysplasia punctata, Conradi- Braverman et al., 1999; isomerase HuÈnermann type 3CDPX2); CHILD syndrome Grange et al., 2000 PEX7 3peroxisomal receptor/ AR Rhizomelic chondrodysplasia punctata 1 Motley et al., 1997 importer) ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS SEMIN. MED. GENET.) 285

TABLE I.2 Continued) Gene or protein Inheritance Clinical phenotype References

DHAPAT 3Di-hydroxy- AR Rhizomelic chondrodysplasia punctata 2 Ofman et al., 1998 acetonphosphate- acyltransferase, peroxisomal enzyme) Alkyl-di-hydroxy- AR Rhizomelic chondrodysplasia punctata 3 de Vet et al., 1998 diacetonphosphate synthase 3AGPS; peroxisomal enzyme) Group 3: Defects in folding and degradation of macromolecules Sedlin 3endoplasmic reticulum XR X-linked spondyloepiphyseal dysplasia 3SED-XL) Gedeon et al., 1999 protein with unknown function) Cathepsin K 3lysosomal AR Pycnodysostosis Hou et al., 1999 proteinase) Lysosomal acid and AR, XLR Lysosomal storage diseases: mucopolysacchari- Leroy and Wiesmann, transporters 3sulfatase, doses, oligosaccharidoses, glycoproteinoses 1993 glycosidase, translocase, etc.) 3several forms) Targeting system of lysosomal AR Mucolipidosis 3II 3I-cell disease), mucolipidosis III Leroy and Wiesmann, enzymes 3GlcNAc-1- 1993 phosphotransferase) MMP2 3matrix AR Torg type osteolysis 3nodulosis arthropathy and Martignetti et al., 2001 metalloproteinase 2) osteolysis syndrome) Group 4: Defects in hormones and signal transduction mechanisms 25-a-hydroxycholecalciferol- AR Vitamin D-dependent rickets type 1 3VDDR1) Kitanaka et al., 1998 1-hydroxylase 1,25-a-dihydroxy-vitamin D3 AR Vitamin D-resistant rickets with end-organ Hughes et al., 1988 receptor unresponsiveness to vitamin D3 3VDDR2) CASR 3calcium ``sensor''/ AD Neonatal severe hyperparathyroidism with bone Bai et al., 1997 receptor) disease 3if affected fetus in unaffected mother); familial hypocalciuric hypercalcemia PTH/PTHrP receptor AD 3activating Metaphyseal dysplasia Jansen Schipani et al., 1996 mutations) AR 3inactivating Lethal dysplasia Blomstrand Zhang et al., 1998 ) GNAS1 3stimulatory Gs alpha AD Pseudohypoparathyroidism 3Albright hereditary Patten et al., 1990 protein of adenylate cyclase) osteodystrophy and several variants) with constitutional haploinsuf®ciency mutations; McCune-Albright syndrome with somatic mosaicism for activating mutations PEX proteinase XL Hypophosphatemic rickets, X-linked The HYP Consortium, semidominant type 3impaired cleavage of 1995; Sabbagh et al., FGF23) 2000 FGF23, ®broblasts growth AD Hypophosphatemic rickets, autosomal dominant The ADHR Consortium, factor 23 type 3resistance to PEX cleavage) 2000 FGFR1 3®broblast growth AD syndromes 3Pfeiffer, Wilkie, 1997 factor receptor 1) other variants) FGFR2 AD Craniosynostosis syndromes 3Apert, Crouzon, Wilkie, 1997 Pfeiffer; several variants) 286 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE

TABLE I. (Continued) Gene or protein Inheritance Clinical phenotype References

FGFR3 AD Thanatophoric dysplasia, achondroplasia, Passos-Bueno et al., 1999; hypochondroplasia, SADDAN; craniosynostosis Wilkie, 1997 syndromes (Crouzon with acanthosis nigricans, Muenke nonsyndromic craniosynostosis) ROR-2 (``orphan receptor AR Robinow syndrome Afzal et al., 2000; van tyrosine kinase'') Bokhoven et al., 2000 AD Brachydactyly type B Oldridge et al., 2000 TNFRSF11A (receptor activator AD Familial expansile osteolysis Hughes et al., 2000 of nuclear factor kB; RANK) TGFb1 AD Diaphyseal dysplasia (Camurati-Engelmann) Janssens et al., 2000 CDMP1 (cartilage-derived AR Acromesomelic dysplasia Grebe/Hunter- Thomas et al., 1997; morphogenetic protein 1) Thompson Thomas et al., 1996 AD Brachydactyly type C Polinkovsky et al., 1997 Noggin (``growth factor,'' TGF AD Multiple syndrome; synphalangism Gong et al., 1999 antagonist) and hypoacusis syndrome DLL3 (delta-like 3, intercellular AR Spondylocostal dysostosis (one form) Bulman et al., 2000 signaling) IHH (Indian hedgehog signal AD Brachydactyly A1 Gao et al., 2001 molecule) C7orf2 (orphan receptor) AR Acheiropodia Ianakiev et al., 2001 SOST (sclerostin; cystine knot AR Sclerosteosis, van Buchem disease Balemans et al., 2001 secreted protein) LRP5 (LDL receptor-related AR Osteoporosis±pseudoglioma syndrome Gong et al., 2001 protein 5) WISP3 (growth regulator/ AR Progressive pseudorheumatoid dysplasia Hurvitzet al., 1999 growth factor) Group 5: Defects in nuclear proteins and factors SOX9 (HMG-type DNA AD Campomelic dysplasia Wagner et al., 1994 binding protein/ transcription factor) GlI3 (zinc ®nger gene) AD Greig cephalopolysyndactyly, type A Kalff-Suske et al., 1999; and others, Pallister-Hall syndrome Radhakrishna et al., 1999 TRPS1 (zine-®nger gene) AD Tricho-rhino-phalangeal syndrome (types 1±3) Momeni et al., 2000 EVC (leucine-zipper gene) AR Chondroectodermal dysplasia (Ellis-van Creveld) Ruiz-Perez et al., 2000 TWIST (helix-loop-helix AD Craniosynostosis Saethre-Chotzen el Ghouzzi et al., 1997 transcription factor) P63 (p53 related transcription AD EEC syndrome, Hay-Wells syndrome, Celli et al., 1999; McGrath factor) limby±mammary syndrome, split ±split et al., 2001; van foot malformation (some forms) Bokhoven et al., 2001 CBFA-1 (core binding factor AD Cleidocranial dysplasia Mundlos et al., 1997 A1; runt-type transcription factor) LXM1B (LIM homeodomain AD Nail±patella syndrome Dreyer et al., 1998 protein) DLX3 (distal-less 3 homeobox AD Trichodentoosseous syndrome Price et al., 1998 gene) HOXD13 (homeobox gene) AD Akarsu et al., 1996 MSX2 (homeobox gene) AD (gain of Craniosynostosis, Boston type Jabs et al., 1993 function) AD (loss of Parietal foramina Wilkie et al., 2000 function) ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS SEMIN. MED. GENET.) 287

TABLE I.2 Continued) Gene or protein Inheritance Clinical phenotype References

ALX4 3homeoboxgene) AD Parietal foramina 3cranium bi®dum) Mavrogiannis et al., 2001 SHOX 3short stature- Pseudoautosomal LeÂri-Weill dyschondrosteosis, idiopathic short Shears et al., 1998 homeoboxgene) stature? TBX3 3T-box3, transcription AD Ulnar±mammary syndrome Bamshad et al., 1997 factor) TBX5 3T-box5, transcription AD Holt-Oram syndrome Li et al., 1997 factor) EIF2AK3 3transcription AR Wolcott-Rallison syndrome 3neonatal diabetes Delepine et al., 2000 initiation factor kinase) mellitus and spondyloepiphyseal dysplasia) NEMO 3NFkB essential XL Osteopetrosis, lymphedema, ectodermal dysplasia Dof®nger et al., 2001; modulator; kinase activity) and immunode®ciency 3OLEDAID) Smahi et al., 2000 Group 6:Defects in oncogenes and tumor suppressor genes EXT1, EXT2 3exostosin-1, AD Multiple exostoses syndrome types 1, type 2 Cheung et al., 2001; exostosin-2; heparan-sulfate Duncan et al., 2001; polymerases) Lind et al., 1998 SH3BP2 3c-Abl-binding AD Cherubism Ueki et al., 2001 protein)

Group 7: Defects in RNA and DNA processing and metabolism RNAse MRP-RNA AR Cartilage±hair±hypoplasia Ridanpaa et al., 2001 component Bonafe et al., 2002 ADA 3adenosine deaminase) AR Severe combined immunode®ciency 3SCID) Hirschhorn, 1995 with 3facultative) metaphyseal changes

classi®cation of proteins in S. cerevisiae, * Group 7: Defects in RNA and DNA Any attempt to reduce biological C. elegans, and disease-related human processing and metabolism. complexity into a straightforward clas- genes and proteins proposed in the 8th si®cation is forceful. The following edition of The Metabolicand Molecular Skeletal disorders with a well- remarks should be considered: Bases of Inherited Disease [Jimenez-San- documented genetic and biochemical chez et al., 2001]. We also tried to take basis have been assigned to one of these * By analogy to the S. cerevisiae/C. into account the peculiarities intrinsic to groups. The interpretation proposed in elegans/MMBID8 classi®cation skeletal biology. We grouped molecular the original reports has been used as the [Jimenez-Sanchez et al., 2001], a defects as follows 3Table I). basis for classi®cation, and other litera- group consisting of skeletal dysplasias ture pertinent to the proposed mole- caused by defects in intracellular struc-

* Group 1: Defects in extracellular cular mechanism3s) has been consulted tural proteins can be predicted, but structural proteins. when the original description of the none seems to have been identi®ed so * Group 2: Defects in metabolic path- genetic defect fell short of suggesting a far. Secondary cytoskeletal abnorm- ways 3including enzymes, ion chan- plausible pathogenetic mechanism or alities occur in chondrocytes from nels, transporters). when new data have been published multiple exostoses patients with

* Group 3: Defects in folding, proces- subsequently. The bibliographic refer- mutations in EXT1 and EXT2 [Ber- sing, and degradation of macromole- ences included are limited to the original nard et al., 2000]. Similarly, no defects cules. description of the molecular defect in ribosomal proteins have been identi-

* Group 4: Defects in hormones and or, in some cases 3e.g., the lysosomal ®ed yet 3but see the CHH gene in signal transduction mechanisms. disorders), to review reports; those group 7). * Group 5: Defects in nuclear proteins looking for further details should consult * Some genes and proteins would and transcription factors. that literature and/or the online version fall into two categories: e.g., the

* Group 6: Defects in oncogenes and of Mendelian Inheritance in Man, heparan glycosyltransferases respon- tumor-suppressor genes. OMIM. sible for the multiple cartilaginous 288 AMERICAN JOURNAL OF MEDICAL GENETICS SEMIN. MED. GENET.) ARTICLE

exostoses syndromes are ``metabolic'' If compared to the other groups, the channels and ion pumps in the same enzymes, but because of their pheno- impression arises that the number of group as enzymes. Three as yet not typic associations they are best clas- different ``raw materials`` used in skeletal completely understood disorders may si®ed as tumor-suppressor genes). development and growth is comparati- point to a vitamin K-dependent pathway The reader may recognize further vely small, but this simply may be re¯ect- of calcium regulation: vitamin K epox- examples. ing the current state of our knowledge, ide reductase complex3only biochem- and further research may disprove this. ical evidence so far), matrixGLA protein * The function of some proteins is not 3MGP; a gamma-carboxylated matrix known precisely.It is likely that future protein), and E. The group insights will lead to reclassi®cation. The phenotypic manifestations also includes two peroxisomal enzymes * This classi®cation is a hybrid between caused by mutations in 3the two initial enzymes of plasmalogen a pathogenetic±functional classi®ca- biosynthesis; the causal link between tion and a strictly molecular one. cartilage collagens are plasmalogens and calci®cation is still Where the precise function of a gene dependent on the tissue unclear), and a peroxisomal biogenesis product is known, or the gene protein 3PEX-7) that acts as a receptor product could be clearly positioned expression of the respective and importer for peroxisomal enzymes. within a metabolic or regulatory genes. The two related Included are also two enzymes of pathway, the functional criterion has proteins, COMP and cholesterol biosynthesis. Whether cho- been given priority over the bio- lesterol biosynthesis defects act patho- chemical and molecular one, to high- MATN-3, are believed to genetically through disturbed hedgehog light the pathogenetic aspects. Where serve a bridging function signaling, as proposed for the Smith- the pathogenetic context is not Lemli-Opitz syndrome, is unclear. Both known yet, purely molecular criteria between extracellular the peroxisomal and the cholesterol have been used. matrix proteins. biosynthesis defects are associated with various forms of chondrodysplasia punctata. EXPLANATION AND Group 2: Defects in Metabolic COMMENTARY ON THE Pathways 2Including Enzymes, Two proteins are involved in INDIVIDUAL GROUPS Ion Channels, and Transporters) sulfate metabolism (the sulfate The emergence of pathways whose Group 1: Defects in Extracellular function is essential for proper skeletal transporter, DTDST and Structural Proteins 2Table I) development is clearly recognizable in the PAPS-synthetase, This group includes some of the best- this group. Two proteins 3TNSALP, and PAPSS2); other enzymes characterized dysplasia ``families,'' those the pyrophosphate transporter ANKH); of the main bone collagen, collagen 1, are involved in phosphate and/or of this pathway, particularly and of the main cartilage collagen, pyrophosphate metabolism and thus in the sulfotransferases, are collagen 2. Other cartilage collagens mineralization; the existence of another are also listed 3collagens 9, 10, and 11). disorder, IACI [Rutsch et al., 2001], candidates for other The phenotypic manifestations caused featuring ectopic calci®cation and disorders. by mutations in cartilage collagens are related to pyrophosphate de®ciency dependent on the tissue expression of points to a complexpathway. These the respective genes. The two related three disorders would not have been Group 3: Defects in Folding, proteins, COMP and MATN-3, are related to each other on a phenotypic Processing, and Degradation of believed to serve a bridging function level. Two proteins are involved in Macromolecules between extracellular matrix proteins. sulfate metabolism 3the sulfate transpor- Given the role of proteoglycans in the ter, DTDST and the PAPS-synthetase, The main category of disorders in this cartilage matrix, the presence of only a PAPSS2); other enzymes of this pathway, group are the lysosomal storage disor- single proteoglycan, perlecan, in this list particularly the sulfotransferases, are ders, particularly the mucopolysacchar- is surprising. The gene coding for the candidates for other disorders. Three idoses, which have been among the ®rst core protein of aggrecan, the most abun- proteins are involved in acidi®cation of skeletal dysplasias to be described and dant cartilage proteoglycan, remains a the osteoclast ruf¯e border 3TCIRG2; also among the ®rst to be understood at candidate for this group, as do the genes ClC7; and carboanhydrase 2); all three the biochemical level. The individual for several other proteoglycans and gly- are associated with osteopetrosis. The acid hydrolases and transporters respon- coproteins. Absence of several noncol- two pathways, ``acidi®cation'' and ``sul- sible for the mucopolysaccharidoses and lagenous proteins of bone is also notable. fation,'' appear to justify inclusion of ion glycoproteinoses have not been listed ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS SEMIN. MED. GENET.) 289 individually; the Nosology should be 3the calcium sensor CASR, which con- putative receptor whose ligand is not consulted for a detailed list [Interna- trols PTH release, and the PTH-related known; it may act by repressing sonic tional Working Group on Constitu- peptide receptor). Downstream in the hedgehog; its function is crucial because tional Diseases of Bone, 1998; Hall, pathway, the GNAS1 adenylate cyclase its absence results in acheiropodia 2002]. The lysosomal targeting system subunit is implied in PTH signal trans- 3absence of and feet). The RANK involves an N-acetylglucosamine-1- duction 3pseudohypoparathyroidism) receptor, a member of the TNF receptor phosphotransferase activity, the gene3s) but may serve other functions as well. superfamily, has been implicated in for which have still eluded identi®ca- A third, recently identi®ed pathway osteoclast differentiation and response tion. Cathepsin K is so far the only relates to FGF23 as a phosphaturic hor- to PTH as well as to osteoprotegerin lysosomal proteinase involved in a mone: structural mutations in FGF23 ligand; activating mutations have been of the skeleton. Matrix rendering it resistant to cleavage by the associated with expansile osteolysis metalloproteinase 2 3MMP2), the single PEX proteinase are associated with 3inactivating mutations result in osteo- extracellular proteinase in this group, has autosomal-dominant hyperphosphatu- porosis in the mouse). The recently recently been linked to one of the ric hypophosphatemic rickets, whereas identi®ed LDR5, related to lipoprotein osteolysis syndromes; because many defects in the PEX proteinase, respon- receptors, is involved in a signaling other matrixproteinases are known, this sible for the much more common X- pathway controlling bone mass. Finally, is an area of potential future expansion. linked hypophosphatemic rickets, it is notable that for CDMP-1 and Sedlin is a protein predicted to be impair cleavage of FGF23. ROR2, distinct phenotypes associated resident in the endoplasmic reticulum The paracrine-autocrine signal systems with either heterozygosity or homozyg- and as such may be involved in protein in the group comprise secreted proteins osity for mutations are known; in both folding or protein transport, again a with putative growth factor, regulatory, cases, the heterozygous state is a form of single representative in this group so far. or signaling functions, as well as recep- brachydactyly, whereas the homozygous tors and membrane signaling proteins. state results in more severe phenotypes. Genes and proteins are grouped here Group 4: Defect in Hormones and solely because of their involvement in Signal Transduction Mechanisms2 signal transduction, with little consid- The paracrine-autocrine This is a complexand heterogeneous eration 3and sometimes little informa- signal systems in the group group that includes signaling systems tion) regarding the signaling pathways that act at distance 3endocrine) as well as they belong to. Among the secreted comprise secreted proteins others that may act over short distances proteins are transforming growth factor with putative growth factor, 3paracrine), sometimes as gradients, or 3TGF)b1, CDMP-1 3a member of the even on the same cell where they TGFb superfamily), and a TGFb anta- regulatory or signaling originate from 3autocrine). In addition, gonist, noggin. Another secreted protein, functions, as well as receptors although certain mechanisms are func- SOST, appears to be a regulator of new and membrane signaling tional until adulthood, others may be bone deposition during the whole life restricted to the embryonic period. span 3but when mutated may also cause proteins. Genes and proteins Although this group may appear to be ). A further secreted protein, are grouped here solely because too heterogeneous, it is dif®cult to draw WISP3, appears to be a requisite for clear separation lines at present, and we cartilage trophism, its absence leading to of their involvement in signal suggest that the group may be revised in severe cartilage degeneration. The transduction, with little the future. absence of any FGF from this group so In the endocrine subgroup, a ®rst far is notable 3but see FGF23, above). consideration (and sometimes pathway is de®ned by vitamin D3 Two proteins, IHH and DLL3, may little information) regarding synthesis 31-hydroxylase) and action function both as diffusible and as cell the signaling pathways 3vitamin D3 receptor; the bioactive membrane±associated receptors or form of vitamin D is generally consid- ligands: IHH, a member of the hedge- they belong to. ered a steroid hormone, and its receptor hog family, is cleaved into a membrane- is related to other steroid receptors). A associated and a diffusible fragment. second pathway involves calcium and DLL3 3delta-like 3) is cell associated Group 5: Defects in Nuclear the parathyroid hormone 3PTH) axis but is itself a ligand 3``transmembrane Proteins and Transcription Factors ligand'') for another membrane recep- 2Defects in growth hormone hGH), the tor, notch. On the receptor side are the This is a group assembled purely on hGH receptor, and in the IGF pathways have receptor tyrosine kinases FGFR1, structural features of the proteins rather not been included because they produce FGFR2, and FGFR3 3that are respon- than by pathways 3although for some short stature but are not considered genetic disorders of the skeleton; they are not sible for a number of relatively frequent factors, such as Gli3, connected regula- included in the Nosology either. disorders) and ROR2. C7orf2 is a tory pathways are known). DNA-bind- 290 AMERICAN JOURNAL OF MEDICAL GENETICS SEMIN. MED. GENET.) ARTICLE ing motifs such as HMG 3SOX9), zinc regulated bone overgrowth. The cascades, and regulatory networks. After ®nger 3GLI3 and TRPS), leucine zipper SH3BP2 gene can thus be tentatively its completion, it becomes clear that 3EvC), helix±loop±helix 3TWIST), classi®ed as an oncogene. The Nosology many black holes exist, and many more homeodomains or homeoboxes comprises several other disorders with genes and proteins still have to be 3LXM1B, HOXD13, MSX2, ALX4, disorganized development of cartilage discovered. The classi®cation will have and SHOX), T-boxes 3TBX3, TBX5), and ®brous tissues; it will be of interest to to be revised as more pieces will become runt 3CBFA1), or p53-related see whether common pathways exist or available. We will be grateful to readers domain 3p63) characterize the genes and whether disorganized expression may for pointing out omissions, inaccuracies, proteins grouped here. Many of the arise from mutations in genes from and errors. associated phenotypes are dysostoses different pathways. At the present stage, the classi®ca- rather than generalized dysplasias, lend- tion can be compared to the reconstruc- ing support to the general concept of tion of a mosaic where many pieces are dysostoses being caused by embryonic EXT1 and EXT2 are the missing and only partial fragments of the developmental errors as opposed to two genes responsible for the big picture start to become visible 3or, dysplasias that exert their effect acting perhaps more appropriately, like a during the whole period of skeletal multiple cartilaginous reconstruction of a dinosaur's skeleton growth. There are two exceptions: both exostoses syndromes types with only a few bones available). Despite the EIF2AK3 3transcription initiation these shortcomings, we hope that the factor kinase) and the NEMO 3NFkB 1 and 2. Both code for classi®cation may be useful to stimulate essential modulator) gene are not tran- membrane-associated thoughts, discussions, and research. scription factors themselves but kinases endoplasmic reticulum that phosphorylate and activate tran- ACKNOWLEDGMENTS scription factors. Interestingly, muta- proteins. tions in both of these genes produce We thank Dr. Christine Hall and the pleiotropic phenotypes 3diabetes, liver Members of the Nosology Committee of the International Skeletal Dysplasia disease, and spondyloepiphyseal dyspla- Group 7: Defects in RNA and Society for their input, and Drs. Dan sia in the Wolcott-Rallison syndrome; DNA Processing and Metabolism osteopetrosis, ectodermal dysplasia and Cohn, Debbie Krakow, Sheila Unger, immunode®ciency in males, and in- This group is justi®ed essentially by the and Bill Wilcoxwho also reviewed the continentia pigmenti in females with special features of the cartilage-hair manuscript. 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