Nosology and classification of genetic skeletal disorders: 2006 revision


  • Andrea Superti-Furga,

    Corresponding author
    1. Center for Pediatrics and Adolescent Medicine, Department of Pediatrics, University of Freiburg, Freiburg, Germany
    • Center for Pediatrics and Adolescent Medicine, University Hospital, Mathildenstr. 1, DE-79106 Freiburg, Germany.
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  • Sheila Unger

    1. Center for Pediatrics and Adolescent Medicine, Department of Pediatrics, University of Freiburg, Freiburg, Germany
    2. Institute for Human Genetics, University of Freiburg, Freiburg, Germany
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  • How to cite this article: Superti-Furga A, Unger S, and the Nosology Group of the International Skeletal Dysplasia Society. 2007. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet Part A 143A:1–18.

  • This paper was prepared by Drs. Superti-Furga and Unger on behalf of the International Skeletal Dysplasia Society and in collaboration with the 2006 Nosology Group: Peter Beighton*, Cape Town; Luisa Bonafé*, Lausanne; Nancy Braverman*, Baltimore; Michael Briggs, Manchester; Dan Cohn, Los Angeles; Valérie Cormier-Dairé*, Paris; Clair Francomano*, Baltimore; Christine Hall*, London; William Horton*, Portland; Ilkka Kaitila, Helsinki; Deborah Krakow, Los Angeles; Ralph Lachman*, Los Angeles; Brendan Lee, Houston; Martine LeMerrer*, Paris; Geert Mortier*, Gent; Stephan Mundlos*, Berlin; Gen Nishimura*, Tokyo; Andrew Poznanski*, Chicago; David Rimoin*, Los Angeles; Stephen Robertson*, Dunedin; Ravi Savarirayan*, Melbourne; Jürgen Spranger*, Mainz; David Sillence*, Sydney; Andrea Superti-Furga*, Freiburg; Sheila Unger*, Freiburg; Matthew Warman, Boston; William Wilcox, Los Angeles; Andrew Wilkie, Oxford; Bernhard Zabel*, Freiburg; Andreas Zankl*, Lausanne. Members marked with an asterisk participated in the compilation workshop held at the 7th ISDS meeting in Martigny (


The objective of the paper is to provide the revision of the Nosology of Constitutional Disorders of Bone that incorporates newly recognized disorders and reflects new molecular and pathogenetic concepts. Criteria for inclusion of disorders were (1) significant skeletal involvement corresponding to the definition of skeletal dysplasias, metabolic bone disorders, dysostoses, and skeletal malformation and/or reduction syndromes, (2) publication and/or MIM listing, (3) genetic basis proven or very likely, and (4) nosologic autonomy confirmed by molecular or linkage analysis and/or distinctive diagnostic features and observation in multiple individuals or families. Three hundred seventy-two different conditions were included and placed in 37 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 215 were associated with one or more of 140 different genes. Nosologic status was classified as final (mutations or locus identified), probable (pedigree evidence), or bona fide (multiple observations and clear diagnostic criteria, but no pedigree or locus evidence yet). The number of recognized genetic disorders with a significant skeletal component is growing and the distinction between dysplasias, metabolic bone disorders, dysostoses, and malformation syndromes is blurring. For classification purposes, pathogenetic and molecular criteria are integrating with morphological ones but disorders are still identified by clinical features and radiographic appearance. Molecular evidence leads to confirmation of individual entities and to the constitution of new groups, but also allows for delineation of related but distinct entities and indicates a previously unexpected heterogeneity of molecular mechanisms; thus, molecular evidence does not necessarily simplify the Nosology, and a further increase in the number of entities and growing complexity is expected. By providing an updated overview of recognized entities with skeletal involvement and of the underlying gene defects, the new Nosology can provide practical diagnostic help, facilitate the recognition of new entities, and foster and direct research in skeletal biology and genetic disorders. © 2006 Wiley-Liss, Inc.


Following the discovery on numeric chromosomal aberrations medical genetics experienced a historical boost in the early 1960s, culminating in the Birth Defects Conferences. Shortly thereafter, the accumulating evidence of the great heterogeneity of genetic skeletal disorders prompted a group of experts from various countries to prepare a document to reach an agreement on the nomenclature of what was then called “Constitutional (or Intrinsic) Disorders of Bone” [INCDB, 1970; NCDB, 1971a,b; McKusick and Scott, 1971]. The “Nomenclature” was meant to bring together experts in radiology, clinical genetics and pediatrics to agree on the denomination and classification of the skeletal disorders, syndromes and metabolic diseases that were being described at a rapid pace. Much has changed since the first Nomenclature was published in 1970. Revision has been prepared in 1977, 1983, 1992, 1997, and 2001 [INCDB, 1978, 1983; INCO, 1998; Hall, 2002]. Electronic means have tremendously accelerated the pace at which new observations and results can be made public; knowledge on the molecular basis of disorders has increased to the point that the causative gene is known for approximately one-half of the close to 400 disorders included today. Because of the wealth of available data on the clinical and radiographic features, inheritance pattern, and—in many cases—the molecular basis, the determination of nomenclature name and classification of each disorder should now be called “nosology,” while the term “constitutional” can be replaced with “genetic.” Following the establishment of the International Skeletal Dysplasia Society in 1999, and to cope with the increasing complexity of information, revisions of the Nosology have been delegated to an expert group nominated ad hoc within the ISDS to guarantee balanced representation of clinical, radiological and molecular expertise.


The Nosology Group of the International Skeletal Dysplasia Society met in August 2005 to revise the 2001 edition of the Nosology [Hall, 2002]. In the preceding months, curators (usually two to three for every group of disorders) had been appointed who were responsible for reviewing the recent literature and discussing possible changes ahead of the meeting. During the meeting, a consensus was reached for changes to be made, and the drafts were circulated for correction after the meeting. The criteria used for inclusion of individual disorders were:

  • (1)significant skeletal involvement, corresponding to the definition of skeletal dysplasias, metabolic bone disorders, dysostoses, and skeletal malformation and/or reduction syndromes,
  • (2)publication and/or listing in OMIM (meaning that observations should not find their way into the Nosology before they achieve peer-reviewed publication status),
  • (3)genetic basis proven by pedigree or very likely based on homogeneity of phenotype in unrelated families,
  • (4)nosologic autonomy confirmed by molecular or linkage analysis and/or distinctive diagnostic features and observation in multiple individuals or families.


Three hundred seventy-two different conditions were included and placed in 37 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 215 were associated with one or more of 140 different genes. Nosologic status was classified as final (mutations or locus identified), probable (pedigree evidence), or bona fide (multiple observations and clear diagnostic criteria, but no pedigree or locus evidence yet). The results are presented in Table I. Within a group, disorders with known molecular basis have been listed preceding those with lesser degree of evidence; however, variants of the same disorder have been kept together. The Table I features direct links to OMIM entries.

Table I. 2006 Revision of the Nosology and Classification of Genetic Disorders of Bone
Name of DisorderInheritanceMIM No.LocusGeneProteinMIM No.Notes
1. FGFR3 group       
 Thanatophoric dysplasia type 1 (TD1)AD1876004p16.3FGFR3FGFR3134934Includes previous San Diego type
 Thanatophoric dysplasia type 2 (TD2)AD1876014p16.3FGFR3FGFR3134934 
 SADDAN (severe achondroplasia-developmental delay-acanthosis nigricans)ADSee


 Hypochondroplasia-like dysplasiaAD, SP     Similar to hypochondroplasia but unlinked to FGFR3, probably heterogeneous
See also Group 30 for craniosynostoses syndromes linked to FGFR3 mutations; LADD in Group 36 for another FGFR3-related phenotype; and Torrance dysplasia (Group 2) and the severe spondylodysplastic dysplasias (Group 12) for the differential diagnosis of TD1 and TD2       
2. Type 2 collagen group       
 Achondrogenesis type 2 (ACG2; Langer-Saldino)AD20061012q13.1COL2A1Type 2 collagen120140 
 Platyspondylic dysplasia, torrance typeAD151210 (erroneous)12q13.1COL2A1Type 2 collagen120140See also Severe Spondylodysplastic dysplasias (Group 13)
 HypochondrogenesisAD20061012q13.1COL2A1Type 2 collagen120140 
 Spondyloepiphyseal dysplasia congenital (SEDC)AD18390012q13.1COL2A1Type 2 collagen120140 
 Spondyloepimetaphyseal dysplasia (SEMD) Strudwick typeAD18425012q13.1COL2A1Type 2 collagen120140 
 Kniest dysplasiaAD15655012q13.1COL2A1Type 2 collagen120140 
 Spondyloperipheral dysplasiaAD27170012q13.1COL2A1Type 2 collagen120140 
 Mild SED with premature onset arthrosisAD 12q13.1COL2A1Type 2 collagen120140Includes SED Namaqualand type
 Stickler syndrome type 1AD10830012q13.1COL2A1Type 2 collagen120140 
 Stickler-like syndrome      Unlinked to either COL2A1, COL11A1 or COL11A2
3. Type 11 collagen group       
 Stickler syndrome type 2AD6048411p21COL11A1Type 11 collagen alpha-1 chain120280 
 Marshall syndromeAD1547801p21COL11A1Type 11 collagen alpha-1 chain120280 
 Otospondylomegaepiphyseal dysplasia (OSMED), recessive typeAR2151506p21.3COL11A2Type 11 collagen alpha-2 chain120290 
 Otospondylomegaepiphyseal dysplasia (OSMED), dominant type (Weissenbacher–Zweymüller syndrome, Stickler syndrome type 3)AD2151506p21.3COL11A2Type 11 collagen alpha-2 chain120290 
See also Stickler syndrome type 1 in Group 2       
4. Sulphation disorders group       
 Achondrogenesis type 1B (ACG1B)AR6009725q32-33DTDSTSLC26A2 sulfate transporter606718 
 Atelosteogenesis type 2 (AO2)AR2560505q32-33DTDSTSLC26A2 sulfate transporter606718Includes de la Chapelle dysplasia and McAlister dysplasia
 Diastrophic dysplasia (DTD)AR2226005q32-33DTDSTSLC26A2 sulfate transporter606718 
 MED, autosomal recessive type (rMED; EDM4)AR2269005q32-33DTDSTSLC26A2 sulfate transporter606718See also multiple epiphyseal dysplasias and pseudoachondroplasia Group (Group 9)
 SEMD Omani typeAR60863710q22.1CHST3Chondroitin 6-sulfotransferase603799See also SEMD Group (Group 11)
 SEMD Pakistani typeAR60300510q23-q24PAPSS2PAPS-Synthetase 2603005See also SEMD Group (Group 11)
5. Perlecan group       
 Dyssegmental dysplasia, Silverman-Handmaker typeAR2244101q36-34PLC (HSPG2)Perlecan142461Relationship to dyssegmental dysplasia, Rolland-Desbuquois type (Group 11) unclear
 Schwartz–Jampel syndrome (myotonic chondrodystrophy)AR2558001q36-34PLC (HSPG2)Perlecan142461Includes previous Burton dysplasia
6. Filamin group       
 Frontometaphyseal dysplasiaXLD305620Xq28FLNAFilamin A300017 
 Osteodysplasty Melnick-NeedlesXLD309350Xq28FLNAFilamin A300017 
 Otopalatodigital syndrome type 1 (OPD1)XLD311300Xq28FLNAFilamin A300017 
 Otopalatodigital syndrome type 2 (OPD2)XLD304120Xq28FLNAFilamin A300017 
 Atelosteogenesis type 1 (AO1)AD1087203p14.3FLNBFilamin B603381Includes Boomerang dysplasia, Piepkorn dysplasia, and spondylohumerofemoral (giant cell) dysplasia
 Atelosteogenesis type 3 (AO3)AD1087213p14.3FLNBFilamin B603381 
 Larsen syndromeAD1502503p14.3FLNBFilamin B603381 
 Spondylo-carpal-tarsal dysplasiaAR2724603p14.3FLNBFilamin B603381 
7. Short-rib dysplasia (with or without polydactyly) group       
 Chondroectodermal dysplasia (Ellis-van Creveld)AR2255004p16EVC1EvC gene 1604831 
   4p16EVC2EvC gene 2607261 
 SRP type 1/3 (Saldino-Noonan/Verma-Naumoff)AR263510     
 SRP type 2 (Majewski)AR263520     
 SRP type 4 (Beemer)AR269860     
 Oral-Facial-Digital syndrome type 4 (Mohr-Majewski)AR258860     
 Asphyxiating thoracic dysplasia (ATD; Jeune)AR208500     
 Thoracolaryngopelvic dysplasia (Barnes)AD187760     
8. Multiple epiphyseal dysplasia and pseudoachondroplasia group       
 Pseudoachondroplasia (PSACH)AD17717019p12-13.1COMPCOMP600310 
 Multiple epiphyseal dysplasia (MED) type 1 (EDM1)AD13240019p13.1COMPCOMP600310 
 Multiple epiphyseal dysplasia (MED) type 2 (EDM2)AD6002041p32.2-33COL9A2Collagen 9 alpha-2 chain120260 
 Multiple epiphyseal dysplasia (MED) type 3 (EDM3)AD60096920q13.3COL9A3Collagen 9 alpha-3 chain120270 
 Multiple epiphyseal dysplasia (MED) type 5 (EDM5)AD6070782p23-24MATN3Matrilin 3602109 
 Multiple epiphyseal dysplasia (MED) type 6 (EDM6)AD1202106q13COL9A1Collagen 9 alpha-1 chain120210 
 Multiple epiphyseal dysplasia (MED), other types      Some MED cases unlinked to known genes
 Familial hip dysplasia (Beukes)AD1426694q35    
See also multiple epiphyseal dysplasia, recessive type (rMED; EDM4) in sulphation disorders (Group 4)       
9. Metaphyseal dysplasias       
 Metaphyseal dysplasia, Schmid type (MCS)AD1565006q21-22.3COL10A1Collagen 10 alpha-1 chain120110 
 Cartilage-hair-hypoplasia (CHH; metaphyseal dysplasia, McKusick type)AR2502509p13RMRPRNA component of RNAse H157660Includes Anauxetic dysplasia
 Metaphyseal dysplasia, Jansen typeAD1564003p22-21.1PTHR1PTH/PTHrP receptor 1168468Activating mutations—see also: Eiken dysplasia in Group 25
 Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia (Shwachman–Bodian–Diamond syndrome, SBDS)AR2604007q11SBDSSBDS gene, function still unclear607444 
 Metaphyseal anadysplasiaAD309645 MMP13Matrix metalloproteinase 13600108See also SEMD Missouri type in Group 11
 Chronic infantile neurologic cutaneous articular syndrome (CINCA)/neonatal onset multisystem inflammatory disease (NOMID)AD6071151q44CIAS1Cryopyrin606416 
 Metaphyseal dysplasia, Spahr typeAR250400     
 Metaphyseal acroscyphodysplasia (various types)AR250215     
10. Spondylometaphyseal dysplasias (SMD)       
 Spondylometaphyseal dysplasia Kozlowski typeAD184252     
 Spondylometaphyseal dysplasia, Sutcliffe/corner fracture typeAD184255     
 SMD with severe genu valgumAD184253    Includes SMD Schmidt type and SMD Algerian type
 SMD with cone-rod dystrophyAR608940     
See also disorders in Group 11 as well as SMD Sedaghatian type in Group 12       
11. Spondylo-epi(-meta)physeal dysplasias (SE(M)D)       
 Dyggve-Melchior-Clausen dysplasia (DMC)AR22380018q12-21.1DYMDymeclin607461Includes Smith-McCort dysplasia
 Immuno-osseous dysplasia (Schimke)AR2429002q34-36SMARCAL1SWI/SNF-related regulator of chromatin subfamily A-like protein 1606622 
 Progressive pseudorheumatoid dysplasia (PPRD)AR2082306q22-23WISP3WNT1-inducible signaling pathway protein 3603400 
 SED Kimberley typeAD60836115q26.1AGC1Aggrecan core protein155760 
 SED Wolcott-Rallison typeAR2269802p12EIF2AK3Translation initiation factor 2-alpha kinase-3604032 
 SEMD Matrilin typeAR6087282p23-p24MATN3Matrilin 3602109See also matrilin-related MED in Group 8
 SEMD Missouri typeAD60211111q22.3MMP13Matrix metalloproteinase 13600108See also Metaphyseal Anadysplasia in Group 9
 Metatropic dysplasia (various forms)AD/AR156530     
 SED tarda, X-linked (SED-XL)XLR313400Xp22SEDLSedlin300202 
 Dyssegmental dysplasia, Rolland-Desbuquois typeAR224400    Unclear whether related to perlecan or not
 SPONASTRIME dysplasiaAR271510     
 SEMD Maroteaux type (pseudo-Morquio type 2)AR184095     
 SEMD short limb—abnormal calcification typeAR271665    See also other dysplasias with stippling in Group 20
 SEMD with joint laxity (SEMD-JL) Beighton typeAR271640     
 SEMD with joint laxity (SEMD-JL) leptodactylic or Hall typeAD603546     
 SEMD Handigodu typeAD     Includes Mseleni joint disease
 Late onset SED, recessive typeAR      
See also: Opsismodysplasia (Group 14), SEMDs (Group 11), mucopolysaccharidosis type 4 (Morquio syndrome) and other conditions in Group 26       
12. Severe spondylodysplastic dysplasias       
 Achondrogenesis type 1A (ACG1A)AR200600     
 SMD Sedaghatian typeAR250220     
 Schneckenbecken dysplasiaAR269250     
See also: Thanatophoric dysplasia, types 1 and 2 (Group 1); Achondrogenesis type 1B (ACG1B, Group 4), ACG2 and Torrance dysplasia (Group 2)       
13. Moderate spondylodysplastic dysplasias (brachyolmias)       
 Brachyolmia, Hobaek/Toledo typesAR271530     
 Brachyolmia, autosomal dominant typeAD113500     
See also SED tarda (SED-XL) and late-onset recessive SED (both in Group 11)       
14. Acromelic dysplasias       
 Trichorhinophalangeal dysplasia types 1/3AD1903508q24TRPS1Zinc finger transcription factor604386 
 Trichorhinophalangeal dysplasia type 2 (Langer-Giedion)AD1502308q24TRPS1Zinc finger transcription factor604386Microdeletion syndrome; see also Multiple Cartilagineous Exostoses in Group 28
    EXT1Exostosin 1608177 
 Acrocapitofemoral dysplasiaAR6077782q33-q35IHHIndian hedgehog600726 
 Angel-shaped phalangoepiphyseal dysplasia (ASPED)AD10583520q11.2GDF5Growth and differentiation factor 5601146See also Brachydactyly type C (Group 34)
 Weill–Marchesani syndrome, recessive typeAR27760019p13ADAMTS10Metalloproteinase with thrombospondin-like repeats608990 
 Weill–Marchesani syndrome, dominant typeAD60832815q21.1FBN1Fibrillin 1134797See also Shprintzen-Goldberg syndrome (Group 30)
 Brachydactyly–Hypertension syndrome (Bilginturian)AD11241012p12.2-11.2    
 Acrolaryngeal dysplasiaAD      
 Acromicric dysplasiaAD?102370     
 Cranioectodermal dysplasia (Sensenbrenner)AR218330     
 Craniofacial conodysplasiaAD      
 Familial digital arthropathy with brachydactylyAD606835     
 Geleophysic dysplasiaAD?231050     
 Saldino-Mainzer dysplasiaAR266920     
See also Short rib dysplasias (Group 7)       
15. Acromesomelic dysplasias       
 Acromesomelic dysplasia type MaroteauxAR6028759p13-12NPR2Natriuretic peptide receptor 2108961 
 Grebe dysplasiaAR20070020q11.2GDF5Growth and differentiation factor 5601146Includes acromesomelic dysplasia Hunter-Thompson type; see also Brachydactylies (Group 34)
 Fibular hypoplasia and complex brachydactyly (Du Pan)AR22890020q11.2GDF5Growth and differentiation factor 5601146see also Brachydactylies (Group 34)
 Acromesomelic dysplasia with genital anomaliesAR6094414q23-24BMPR1BBone morphogenetic protein receptor 1B603248 
 Acromesomelic dysplasia, Osebold-Remondini typeAD112910     
16. Mesomelic and rhizo-mesomelic dysplasias       
 Dyschondrosteosis (Leri-Weill)Pseudo-AD127300Xpter-p22.32 (pseudo-autosomal)SHOXShort stature—homeobox gene312865Includes Reinhardt-Pfeiffer dysplasia, MIM 191400
 Langer type (homozygous dyschondrosteosis)Pseudo-AR249700Xpter-p22.32 (pseudo-autosomal)SHOXShort stature—homeobox gene312865 
 Robinow syndrome, recessive typeAR2683109q22ROR2Receptor tyrosine kinase-like orphan receptor 2602337Includes previous COVESDEM (costo-vertebral segmentation defect with mesomelia); see also brachydactyly type B, Group 34
 Robinow syndrome, dominant typeAD180700     
 Mesomelic dysplasia, Kantaputra typeAD1562322q24-32    
 Mesomelic dysplasia, Nievergelt typeAD163400     
 Mesomelic dysplasia, Kozlowski-Reardon typeAR249710     
 Mesomelic dysplasia with acral synostoses (Verloes-David-Pfeiffer type)AD600383     
 Mesomelic dysplasia, Savarirayan type (Triangular Tibia-Fibular Aplasia)SP605274    Possibly related to Nievergelt dysplasia
 Omodysplasia, dominant typeAD164745     
 Omodysplasia, recessive typeAR108721     
17. Bent bones dysplasias       
Campomelic dysplasia (CD)AD11429017q24.3-25.1SOX9SRY-box 9211970Includes acampomelic campomelic dysplasia (ACD) as well as mild campomelic dysplasia (MIM 602196)
 Stüve-Wiedemann dysplasiaAR6015595p13.1LIFRLeukemia inhibitory factor receptor151443Includes formerly neonatal Schwartz-Jampel syndrome or SJS type 2
 Cumming syndrome 211890    syndromal status uncertain
 Kyphomelic dysplasia, several forms 211350    probably heterogeneous
Bent bones at birth can be seen in a variety of conditions, including Antley-Bixler syndrome, cartilage-hair hypoplasia, hypophosphatasia, osteogenesis imperfecta, dyssegmental dysplasia, and others       
18. Slender bone dysplasia Group       
 3M syndromeAR2737506p21.1CUL7Cullin 7609577 
 Kenny-Caffey dysplasia type 1AR2444601q42-q43TBCEtubulin-specific chaperone E604934 
 Kenny-Caffey dysplasia type 2AD127000     
 Microcephalic osteodysplastic primordial dwarfism type 1/3 (MOPD1)AR210710    Includes Taybi-Linder cephaloskeletal dysplasia
 Microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2; Majewski type)AR210720     
Microcephalic osteodysplastic dysplasia, Saul-Wilson typeAR      
 IMAGE syndrome (Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia, and Genital Anomalies)XLR300290Chr. X    
19. Dysplasias with multiple joint dislocations       
 Desbuquois dysplasiaAR25145017q25.3    
 Recessive Larsen-like syndromeAR245600    Includes La Reunion Island dysplasia
 Pseudodiastrophic dysplasiaAR264180     
See also: Atelosteogenesis type 3 and Larsen syndrome (Group 6); SEMDs with joint laxity (Group 11)       
20. Chondrodysplasia punctata (CDP) Group       
 CDP Conradi-Hünermann type (CDPX2)XLD302960Xp11EBPEmopamil-binding protein300205 
 CDP X-linked recessive, brachytelephalangic type (CDPX1)XLR302950Xp22.3ARSEArylsulfatase E300180 
 CHILD (congenital hemidysplasia, icthyosis, limb defects)XLD308050Xp11NSDHLNAD(P)H steroid dehydrogenase-like protein300275 
 CHILD (congenital hemidysplasia, icthyosis, limb defects)XLD308050Xq28EBPEmopamil-binding protein300205 
 Greenberg dysplasiaAR2151401q42.1LBRLamin B receptor, 3-beta-hydroxysterol delta (14)-reductase600024Includes hydrops-ectopic calcification-moth-eaten appearance dysplasia (HEM)
 Rhizomelic CDP type 1AR2151006q22-24PEX7Peroxysomal PTS2 receptor601757 
 Rhizomelic CDP type 2AR2227651q42DHPATDihydroxyacetonephosphate acyltransferase (DHAPAT)602744 
 Rhizomelic CDP type 3AR6001212q31AGPSAlkylglycerone-phosphate synthase (AGPS)603051 
 Astley-Kendall dysplasiaSP      
 CDP tibial-metacarpal typeAD118651     
 Dappled diaphyseal dysplasiaAR     Possibly identical to Greenberg dysplasia
See also SEMD short limb—abnormal calcification type in Group 11. Stippling can occur in several syndromes such as Zellweger, Smith-Lemli-Opitz and others       
21. Neonatal osteosclerotic dysplasias       
 Blomstrand dysplasiaAR2150453p22-21.1PTHR1PTH/PTHrP receptor 1168468Caused by recessive inactivating mutations; see also Eiken dysplasia (Group 25) and Jansen dysplasia (Group 9)
 DesmosterolosisAR6023981p33-31.1DHCR243-beta-hydroxysterol delta-24-reductase606418See also other sterol-metabolism related conditions in Group 20
 Caffey disease (including infantile and attenuated forms)AD11400017q21-22COL1A1Collagen 1, alpha-1 chain120150See also the various forms of osteogenesis imperfecta related to collagen 1 genes (Group 24)
 Caffey disease (severe variants with prenatal onset)AR114000     
 Raine dysplasiaAR259775     
See also Astley-Kendall dysplasia in Group 20       
22. Increased bone density group (without modification of bone shape)       
 Osteopetrosis, severe neonatal or infantile formsAR25970011q13TCIRG1Subunit of ATPase proton pump604592 
 AR 16p13CLCN7Chloride channel602727 
 AR 6q21GL(OSTM1)Osteopetrosis associated transmembrane protein607649 
 Osteopetrosis, intermediate formAR25971016p13CLCN7Chloride channel pump602727 
 Osteopetrosis with renal tubular acidosisAR2597308q22CA1Carbonic anhydrase 1114800 
 Osteopetrosis, late-onset form type 1AD16660011q13.4LRP5Low density lipoprotein receptor-related protein 5603506Includes Worth type osteosclerosis (MIM 144750)
 Osteopetrosis, late-onset form type 2AD16660016p13CLCN7Chloride channel pump602727 
 Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID)XL300301Xq28IKBKG (NEMO)Inhibitor of kappa light polypeptide gene enhancer, kinase of300301 
 PyknodysostosisAR2658001q21CTSKCathepsin K601105 
 OsteopoikilosisAD15595012q14LEMD3LEM domain-containing 3607844Includes Buschke-Ollendorff syndrome (MIM 166700 )
 Melorheostosis with osteopoikilosisAD15595012q14LEMD3LEM domain-containing 3607844Includes mixed sclerosing bone dysplasia
 Melorheostosis      no germline LEMD3 mutations identified so far
 Osteopathia striata with cranial sclerosisXLD166500     
 Osteopetrosis with infantile neuroaxonal dysplasiaAR?600329     
 Osteosclerosis, Stanescu typeAD122900     
23. Increased bone density group with metaphyseal and/or diaphyseal involvement       
 Craniometaphyseal dysplasia, autosomal dominant typeAD1230005p15.2-14.2ANKHHomolog of mouse ANK (ankylosis) gene605145 
 Diaphyseal dysplasia Camurati-EngelmannAD13130019q13TGFbeta1Transforming growth factor beta 1190180 
 Diaphyseal dysplasia Camurati-Engelmann, type 2      Unlinked to TGFbeta1
 Oculodentoosseous dysplasia (ODOD) mild typeAD1642006q22-23GJA1Gap junction protein alpha-1121014 
 Oculodentoosseous dysplasia (ODOD) severe typeAR257850    Possibly homozygous form of mild ODOD
 Osteoectasia with hyperphosphatasia (Juvenile Paget disease)AR2390008q24OPGOsteoprotegerin602643 
 Endosteal hyperostosis, van Buchem typeAR23910017q12-21SOSTSclerostin60574052 kb deletion downstream from SOST
 Trichodentoosseous dysplasiaAD19032017q21DLX3Distal-less homeobox 3600525 
 Craniometaphyseal dysplasia, autosomal recessive typeAR2184006q21-22    
 Diaphyseal medullary stenosis with bone malignancyAD1122509p21-p22    
 Craniodiaphyseal dysplasiaAR/AD?218300/     
 Craniometadiaphyseal dysplasia, Wormian bone typeAR      
 Cranio-osteoarthropathy 259100     
 Endosteal sclerosis with cerebellar hypoplasiaAR213002     
 Lenz-Majewski hyperostotic dysplasia 151050     
 Metaphyseal dysplasia, Braun-Tinschert typeXL605946     
Pyle diseaseAR265900     
 Diaphyseal dysplasia with anemia (Ghosal)AR231095    Syndromic status uncertain
24. Decreased bone density group       
 Osteogenesis imperfecta type 1AD16620017q21-22COL1A1Collagen 1, alpha-1 chain120150 
 AD1662407q22.1COL1A2Collagen 1, alpha-2 chain120160 
 Osteogenesis imperfecta type 2AD16621017q21-22COL1A1Collagen 1, alpha-1 chain120150 
 AD1662107q22.1COL1A2Collagen 1, alpha-2 chain120160 
 AR1662103p22-p24.1CRTAPCartilage-associated protein605497 
 AR1662103p22-p24.1P3H1/LEPRE1Prolyl 3-Hydroxylase 1 (Leprecan)610339 
 Osteogenesis imperfecta type 3AD25942017q21-22COL1A1Collagen 1, alpha-1 chain120150 
 AD2594207q22.1COL1A2Collagen 1, alpha-2 chain120160 
 AR2594203p22-p24.1CRTAPCartilage-associated protein605497see also Osteogenesis imperfecta type 7, below
 AR2594203p22-p24.1P3H1/LEPRE1Prolyl 3-Hydroxylase 1 (Leprecan)610339 
 AR2037607q22.1COL1A2Collagen 1, alpha-2 chain120160Extremely rare instances of recessive COL1A2 mutations giving OI at homozygosity
 Osteogenesis Imperfecta, recessive, unlinked to COL1A1 and COL1A2AR259440    Includes recessive OI, South African form; at present unclear whether mutations in CRTAP and P3H1/LEPRE1 account for all cases or whether further genes involved
 Osteogenesis imperfecta type 4AD16622017q21-22COL1A1Collagen 1, alpha-1 chain120150 
 AD1662207q22.1COL1A2Collagen 1, alpha-2 chain120160 
 Osteogenesis imperfecta type 5AD      
 Osteogenesis imperfecta type 6      Nosologic dignity uncertain
 Osteogenesis imperfecta type 7 (so-called “rhizomelic form”)AR 3p22-p24.1CRTAPCartilage-associated protein605497OI type 7 described in a large Quebec kindred; see also recessive form of OI type 3, above
 Osteoporosis-pseudoglioma syndromeAR25977011q12-13LRP5LDL-receptor related protein 5603506 
 Bruck syndrome type 2 (Osteogenesis Imperfecta with pterygia)AR6092203q23-24PLOD2Procollagen lysyl hydroxylase 2601865 
 Bruck syndrome type 1 (Osteogenesis Imperfecta with pterygia)AR25945017p12    
 Singleton-Merten dysplasiaAD182250     
 Geroderma osteodysplasticumAR231070     
 Calvarial doughnut lesions with bone fragilityAD126550     
 Idiopathic juvenile osteoporosisSP259750     
 Cole-Carpenter dysplasia (bone fragility with craniosynostosis)SP112240    See also craniosynostosis syndromes in Group 30
 Spondylo-ocular dysplasiaAR605822    Unlinked to collagen 1 and collagen 2 genes or to LRP5
 Osteopenia with radiolucent lesions of the mandibleAD166260     
25. Defective mineralization group       
 Hypophosphatasia, perinatal lethal and infantile formsAR2415001p36.1-p34ALPLAlkaline phosphatase, tisssue non-specific (TNSALP)171760 
 Hypophosphatasia, adult formAD1463001p36.1-p34ALPLAlkaline phosphatase, tisssue non-specific (TNSALP)171760Includes odontohypophosphatasia
 Hypophosphatemic ricketsXLD307800Xp22PHEXX-linked hypophosphatemia membrane protease300550 
 Hypophosphatemic ricketsAD19310012p13.3FGF23Fibroblast growth factor 23605380 
 Hypophosphatemic rickets with hypercalciuriaAR 9pSLC34A3Sodium-phosphate cotransporter  
 Neonatal hyperparathyroidism, severe formAR2392003q13.3-21CASRCalcium-sensing receptor601199 
 Familial hypocalciuric hypercalcemia with transient neonatal hyperparathyroidismAD1459803q13.3-21CASRCalcium-sensing receptor601199 
 Eiken dysplasiaAR6000023p22-21.1PTHR1PTH/PTHrP receptor 1168468See also Blomstrand dysplasia (Group 21) and Metaphyseal dysplasia Jansen type (Group 9)
26. Lysosomal storage diseases with skeletal involvement (Dysostosis Multiplex Group)       
 Mucopolysaccharidosis type 1H/1SAR6070144p16.3IDAalpha-1-Iduronidase252800 
 Mucopolysaccharidosis type 2XLR309900Xq27.3-28IDSIduronate-2-sulfatase309900 
 Mucopolysaccharidosis type 3AAR25290017q25.3HSSHeparan sulfate sulfatase605270 
 Mucopolysaccharidosis type 3BAR25292017q21NAGLUN-Ac-beta-D-glucosaminidase252920 
 Mucopolysaccharidosis type 3CAR2529308p11-q13 Ac-CoA:alpha-glucosaminide N-acetyltransferase  
 Mucopolysaccharidosis type 3DAR25294012q14GNSN-Acetylglucosamine 6-sulfatase607664 
 Mucopolysaccharidosis type 4AAR25300016q24.3GALNSGalactosamine-6-sulfate sulfatase253000 
 Mucopolysaccharidosis type 4BAR2530103p21.33GLBIbeta-Galactosidase230500 
 Mucopolysaccharidosis type 6AR2532005q13.3ARSBArylsulfatase B253200 
 Mucopolysaccharidosis type 7AR2532207q21.11GUSBbeta-Glucuronidase253220 
 GMI Gangliosidosis, several formsAR2305003p21-14.2GLB1beta-Galactosidase230500 
 Sialidosis, several formsAR2565506p21.3NEU1Neuraminidase (sialidase)608272 
 Sialic acid storage disease SIASDAR2699206q14-q15SLC17A5Sialin (sialic acid transporter)604322 
 Galactosialidosis, several formsAR25654020q13.1PPGBbeta-Galactosidase protective protein256540 
 Multiple sulfatase deficiencyAR2722003p26SUMF1Sulfatase-modifying factor-1607939 
 Mucolipidosis II (I-cell disease)AR2525004q21-23GNPTAN-Acetylglucosamine 1-phosphotransferase607840 
 Mucolipidosis III (Pseudo-Hurler polydystrophy)AR2526004q21-23GNPTAN-Acetylglucosamine 1-phosphotransferase607840 
27. Osteolysis group       
 Familial expansile osteolysisAD17481018q22.1TNFRSF11ARANK603499 
 Infantile systemic hyalinosisAR2364904q21CMG2Capillary morphogenesis gene 2608041Includes Juvenile Hyaline Fibromatosis (JHF, 228600 ) and Puretic syndrome
 Mandibuloacral dysplasia type AAR2483701q21.2LMNALamin A/C150330 
 Progeria, Hutchinson-Gilford typeAD1766701q21.2LMNALamin A/C150330 
 Mandibuloacral dysplasia type BAR6086121p34ZMPSTE24Zinc metalloproteinase606480 
 Torg–Winchester syndromeAR25960016q13MMP2Matrix metalloproteinase 2120360Includes Nodulosis-Arthropathy-Osteolysis syndrome (MIM 605156)
 Hadju–Cheney syndromeAD102500     
 Multicentric carpal-tarsal osteolysis with and without nephropathyAD166300     
28. Disorganized development of skeletal components group       
CherubismAD1184004p16SH3BP2SH3 domain-binding protein 2602104 
 Fibrous dysplasia, polyostotic formSP17480020q13GNAS1Guanine nucleotide-binding protein, alpha-stimulating activity subunit 1139320Somatic mosaicism and imprinting phenomena; includes McCune-Albright syndrome
 Progressive osseous heteroplasiaAD16635020q13GNAS1Guanine nucleotide-binding protein, alpha-stimulating activity subunit 1139320Gene subject to imprinting
 Gnathodiaphyseal dysplasiaAD16626011p15.1-14.3TMEM16ETransmembrane protein 16E608662 
 Multiple cartilaginous exostoses 1AD1337008q23-24.1EXT1Exostosin-1608177 
 Multiple cartilaginous exostoses 2AD13370111p12-11EXT2Exostosin-2608210 
 Multiple cartilaginous exostoses 3AD60020919p    
 Osteoglophonic dysplasiaAD1662508p11FGFR1Fibroblast growth factor receptor 1136350See also Craniosynostosis syndromes in Group 30
 Fibrodysplasia ossificans progressiva (FOP)AD, SP1351002q23-24ACVR1Activin A (BMP type 1) receptor102576 
 Carpotarsal osteochondromatosisAD127820     
 Cherubism with gingival fibromatosis (Ramon syndrome)AR266270     
 Dysplasia epiphysealis hemimelica (Trevor)SP127800     
 Enchondromatosis (Ollier)SP166000    PTHR1 mutations found in a few cases only
 Spondyloenchondrodysplasia (SPENCD)AR, AD?271550    Includes SPENCD with spasticity and basal ganglia calcifications
 Enchondromatosis with hemangiomata (Maffucci)SP166000     
 Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduriaSPsee


29. Cleidocranial dysplasia group       
 Cleidocranial dysplasiaAD1196006p21RUNX2Runt related transcription factor 2600211 
 CDAGS syndrome (craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, genital anomalies, skin eruption)AR60311622q12-13    
 Yunis-Varon dysplasiaAR216340     
30. Craniosynostosis syndromes and other cranial ossification disorders       
 Pfeiffer syndrome (FGFR1-related)AD1016008p12FGFR1Fibroblast growth factor receptor 1136350All have FGFR1 P252R mutation (phenotype generally milder than FGFR2-related Pfeiffer)
 Apert syndromeAD10120010q26.12FGFR2Fibroblast growth factor receptor 2176943 
 Craniosynostosis with cutis gyrata (Beare-Stevenson)AD12379010q26.12FGFR2Fibroblast growth factor receptor 2176943 
 Crouzon syndromeAD12350010q26.12FGFR2Fibroblast growth factor receptor 2176943 
 Pfeiffer syndrome (FGFR2-related)AD10160010q26.12FGFR2Fibroblast growth factor receptor 2176943Includes Jackson-Weiss syndrome (MIM 123150) and Antley-Bixler variants caused by FGFR2 mutations (see below)
 Crouzon-like craniosynostosis with acanthosis nigricans (Crouzonodermoskeletal syndrome)AD 4p16.3FGFR3Fibroblast growth factor receptor 3134934Defined by specific FGFR3 A391E mutation
 Craniosynostosis Muenke typeAD6028494p16.3FGFR3Fibroblast growth factor receptor 3134934FGFR3 P250R mutation
 Antley–Bixler syndromeAR2017507q11.23PORCytochrome P450 oxidoreductase124015Cases with FGFR2 mutations classified as Pfeiffer syndrome (MIM 207410)
 Craniofrontonasal syndromeXLD304110Xq13.1EFNB1Ephrin B1300035 
Craniosynostosis Boston typeAD6047575q35.2MSX2MSX2123101Heterozygous P148H mutation in a single family
 Saethre–Chotzen syndromeAD1014007p21.1TWIST1TWIST601622 
 Shprintzen–Goldberg syndromeAD182212    Some affected individuals reported to have FBN1 mutations (MIM 134797)
 Baller–Gerold syndromeAR2186008q24.3RECQL4RECQ Protein-like 4603780RECQL4 might not account for all cases of Baller-Gerold
 Parietal foramina (isolated)AD16850011q11.2ALX4Aristaless-like 4605420 
 Parietal foramina (isolated)AD1685005q34-35MSX2Muscle segment homeobox 2123101 
 Carpenter syndromeAR201000     
See also Cole–Carpenter syndrome in Group 24 and CDAGS syndrome in Group 29       
31. Dysostoses with predominant craniofacial involvement       
 Mandibulo-facial dysostosis (Treacher-Collins, Franceschetti-Klein)AD1545005q32TCOF1 606847 
 Oral-facial-digital syndrome type I (OFD1)XLR311200Xp22.3CXORF5 300170 
 Weyer acrofacial (acrodental) dysostosisAD1935304p16EVC1 604831 
 Acrofacial dysostosis, Nager typeAD/AR154400     
 Frontonasal dysplasiaSP136760     
 Hemifacial microsomiaSP/AD164210    Includes Goldenhar syndrome and Oculo-Auriculo-Vertebral spectrum; probably genetically heterogeneous
 Miller syndrome (postaxial acrofacial dysostosis)AR263750     
See also Oral-facial-digital syndrome type IV in the Short Rib Dysplasias (Group 7)       
32. Dysostoses with predominant vertebral and costal involvement       
 Currarino syndromeAD1764507q36HLXB9Homeobox gene HB9142994 
 Spondylocostal dysostosis type 1 (SCD1)AR27730019q13Dll3Delta-like 3602768 
 Spondylocostal dysostosis type 2 (SCD2)AR60868115q26MESP2Mesoderm posterior (expressed in) 2605195 
 Spondylocostal dysostosis type 3 (SCD3)AR6097137p22LFNGLunatic fringe602576 
 Spondylocostal dysostosis, dominant typeAD     Includes previous spondylothoracic dysostosis, dominant type
Jarcho–Levin syndromeAR     Unlinked to Dll3 or MESP2; includes previous spondylothoracic dysostosis, recessive type
 Cerebro-costo-mandibular syndrome (rib gap syndrome)AD/AR117650     
 Ischio-spinal dysostosisSP/AR      
 Klippel-Feil anomaly with laryngeal malformationAD148900     
See also Spondylocarpotarsal dysplasia in Group 26       
33. Patellar dysostoses       
 Ischiopubic patellar dysplasiaAD14789117q21-q22TBX4T-box gene 4601719 
 Nail-patella syndromeAD1612009q34.1LMX1BLIM homeobox transcription factor 1602575 
 Genitopatellar syndromeAR?606170     
 Ear-patella-short stature syndrome (Meier-Gorlin)AR224690     
34. Brachydactylies (with or without extraskeletal manifestations)       
 Brachydactyly type A1AD1125002q35-36IHHIndian Hedgehog600726 
 Brachydactyly type A1AD 5q31    
 Brachydactyly type A2AD1126004q23BMPR1BBone Morphogenetic Protein Receptor, 1B603248 
 Brachydactyly type A2AD112600    Not linked to BMRP1B
 Brachydactyly type A3AD112700     
 Brachydactyly type BAD1130009q22ROR2Receptor tyrosine kinase-like orphan Receptor 2602337 
 Brachydactyly type B      Not linked to ROR2
 Brachydactyly type CAD, AR11310020q11.2GDF5Growth and differentiation factor 5601146See also ASPED (group 14) and other GDF5 disorders
 Brachydactyly type DAD1132002q31HOXD13Homeobox D13142989 
 Brachydactyly type D      Not linked to HOXD13
 Brachydactyly type EAD1133002q31HOXD13Homeobox D13142989 
 Brachydactyly type E      Not linked to HOXD13
 Feingold syndrome (microcephaly-oculo-digito-esophageal-duodenal syndrome)AD1642802p24.1MYCNnMYC oncogene164840 
 Hand-Foot-GenitalAD1400007p14.2HOXA13Homeobox A13142959 
 Keutel syndromeAR24515012p13.1-12.3MGPMatrix Gla protein154870 
 Albright hereditary osteodystrophy (AHO)AD10358020q13GNAS1Guanine nucleotide binding protein of adenylate cyclase—subunit139320See also Polyostotic fibrous dysplasia and Progressive osseous heteroplasia, Group 28
 AHO-like syndrome (Brachydactyly-Mental retardation syndrome)SP6004302q37   Microdeletion syndrome
 Rubinstein–Taybi syndromeAD18084916p13.3CREBBPCREB-Binding Protein600140 
 Catel–Manzke syndromeXLR?302380     
 Christian type brachydactylyAD112450     
 Coffin–Siris syndromeAR135900     
 Mononen type brachydactylyXLD?301940     
 Poland syndromeSP173800     
See also Group 20 for other conditions with brachydactyly       
35. Limb hypoplasia-reduction defects group       
 AcheiropodiaAR2005007q36LMBR1Putative receptor protein605522Partial LMBR1 deletion affecting expression of Sonic Hedgehog (SHH) gene
 De Lange SyndromeAD1224705p13.1NIPBLNipped-B-like608667 
 Fanconi anemiaAR227650(several)(several)  Several complementation groups and genes
 Holt–Oram syndromeAD14290012q24.1TBX5T-box gene 5601620 
 Okihiro syndrome (Duane-Radial Ray anomaly)AD60732320q13SALL4SAL-like 4607343 
 Roberts SyndromeAR2683008p21.1ESCO2Homolog of Establishment of Cohesion-2609353 
 Tetra-ameliaAR27339517q21WNT3Wingless-type MMTV integration site family, member 3165330 
 Ulnar-mammary syndromeAD18145012q24.1TBX3T-box gene 3601621 
 Ankyloblepharon-Ectodermal dysplasia-Cleft lip/palate (AEC)AD1062603q27P63 (TP63)Tumor Protein p63603273 
 Ectrodactyly-ectodermal dysplasia cleft-palate syndrome type 3 (EEC3)AD6042923q27P63 (TP63)Tumor Protein p63603273 
 Ectrodactyly-ectodermal dysplasia cleft-palate syndrome type 1 (EEC1)AD1299007q11.2-12.3    
 Ectrodactyly-ectodermal dysplasia cleft-palate syndrome type 2 (EEC2)AD602077Chr.19    
 Ectrodactyly-ectodermal dysplasia-macular dystrophy syndrome (EEM)AR22528016q22CDH3Cadherin 3114021 
 Limb-mammary syndrome (including ADULT syndrome)AD6032733q27P63 (TP63)Tumor Protein p63603273 
 Split Hand-Foot malformation, isolated form, type 4 (SHFM4)AD6052893q27P63 (TP63)Tumor Protein p63603273 
 Split Hand-Foot malformation, isolated form, type 1 (SHFM1)AD1836007q21.3-22.1    
 Split Hand-Foot Malformation, isolated form, type 2 (SHFM2)XL313350Xq26    
 Split Hand-Foot malformation, isolated form, type 3 (SHFM3)AD60009510q24DactylinDactylin608071 
 Split Hand-Foot malformation, isolated form, type 5 (SHFM5)AD6067082q31    
 Split Hand-Foot malformation with tibial hypoplasiaAD119100     
 Adams–Oliver syndromeAD100300     
 Al-Awadi Raas-Rothschild limb-pelvis hypoplasia-aplasiaAR276820     
 Femoral hypoplasia-Unusual facies syndromeSP/AD?134780    Syndromic status uncertain
 Femur–Fibula–Ulna syndromeSP?228200     
 Fuhrmann syndromeAR228930     
 Hanhart syndrome (Hypoglossia-hypodactylia)AD103300     
 Scapulo-iliac dysplasia (Kosenow)AD169550     
 Thrombocytopenia-Absent Radius (TAR)AR?/AD?274000     
See also CHILD in Group 20       
36. Polydactyly-Syndactyly-Triphalangism group       
 Preaxial Polydactyly type 1 (PPD1)AD1744007q36SHHSonic Hedgehog600725Regulatory mutation
 Preaxial Polydactyly type 1 (PPD1)AD174400    Some instances not linked to SHH
 Preaxial Polydactyly type 2 (PPD2)/Triphalangeal Thumb (TPT)AD1745007q36SHHSonic Hedgehog600725Regulatory mutation
 Preaxial Polydactyly type 2 (PPD2)/Triphalangeal Thumb (TPT)AD174500    some instances not linked to SHH
 Preaxial Polydactyly type 3(PPD3)AD174600     
 Preaxial Polydactyly type 4 (PPD4)AD1747007p13GLI3Gli-Kruppel Family Member 3165240 
 Greig Cephalopolysyndactyly syndromeAD1757007p13GLI3Gli-Kruppel Family Member 3165240 
 Pallister–Hall syndromeAD1465107p13GLI3Gli-Kruppel Family Member 3165240 
 Fibulin1—associated complex synpolydactylyAD60818022q13.3FBLN1Fibulin 1135820 
 SynpolydactylyAD1860002q31HOXD13Homeobox D13142989 
 Syndactyly type 3AD1861006q22-24CX43Connexin 43121014 
 Townes–Brocks syndrome (Renal-Ear-Anal-Radial syndrome)AD10748016q12.1SALL1SAL-like 1602218 
 Lacrimo-Auriculo-Dento-Digital syndrome (LADD)AD14973010q26.12FGFR2Fibroblast growth factor receptor 2176943 
   4p16.3FGFR3Fibroblast growth factor receptor 3134934 
   5p13-p12FGF10Fibroblast growth factor 10602115 
 Acrocallosal syndromeAR2009907p13    
 Acro-pectoral syndromeAD6059677q36    
 Acro-pectoro-vertebral dysplasia (F-syndrome)AD1025102q36    
 Mirror-image polydactyly of hands and feet (Laurin–Sandrow syndrome)AD13575014q13    
 Mirror-image polydactyly of feet with tibial hypoplasiaAD188770     
 Syndactyly type 1AD1859002q34-36    
 Postaxial Polydactyly  Several loci   Heterogeneous
37. Defects in joint formation and synostoses       
 Multiple synostoses syndrome type 1AD18650017q22NOGNoggin602991Includessymphalangism-brachydactyly-deafness syndrome
 Multiple synostoses syndrome type 2AD18650020q11.2GDF5Growth and Differentiation Factor 5601146 
 Proximal symphalangism type 1AD18580017q22NOGNoggin602991 
 Proximal symphalangism type 2AD18580020q11.2GDF5Growth and Differentiation Factor 5601146 
 Radio-ulnar synostosis with amegakaryocytic thrombocytopeniaAD6054327p15-14.2HOXA11Homeobox A11142958 
See also Spondylo-Carpal-Tarsal dysplasia (Group 6); Mesomelic Dysplasia with Acral Synostoses (Group 16); Antley Bixler syndrome (Group 30)       


The first criterion, the definition of “significant skeletal involvement,” leaves some degree of subjectivity. The 2001 revision of the Nosology began to include more dysostoses, and the present revision goes much farther in including disorders such as dysostoses or malformation syndromes that have a skeletal component. The MIM catalogue contains many entries that include some degree of skeletal involvement, and the decision on inclusion or exclusion on the basis of what is “significant” involvement can be arbitrary.

Similar considerations apply to criterion number 4—“nosologic autonomy.” Is the disorder in question an independent nosologic entity or perhaps a variant of some already existing entity? Are the diagnostic criteria specific enough to ensure accurate diagnosis? Can a genetic basis be assumed with reasonable confidence? Particularly among the disorders that have not yet benefited from molecular confirmation, the nosologic autonomy remains subject to a degree of arbitrariness. For these disorders, discussion within the Nosology group, where individual opinions can be harmonized and, if needed, corrected by the collective expertise, is of paramount importance. There are a relatively large number of disorders that are listed in MIM but have been found not to meet inclusion criteria, in most instances because of too few observations or because of the lack of features allowing clear diagnostic distinction from other disorders. It is likely that additional observations or molecular elucidation will allow for the inclusion of many of these disorders in the future, either as distinct entities or as “variants” of already existing ones. In this sense, the Nosology illustrates the many things we do not yet know.

The organization of disorders into Groups has been changed significantly compared to the 2001 version [Hall, 2002]. More groups based on a common affected molecule or biochemical pathway have been created (Groups 1–6). Several groups are based on the anatomical localization of radiographic changes (Groups 7–16). Groups 17–19 are defined by macroscopic criteria and clinical features (bent bones, slender bones, presence of multiple dislocations). Groups 20–25 and 27 take into account features of mineralization (increased or reduced bone density, disturbed mineralization stippling, osteolysis). Group 26 encompasses the large group of lysosomal disorders with skeletal involvement. Group 28 comprises disorders with so-called abnormal development of skeletal components such as exostoses, ecnhondromas, and ectopic calcification. This group is quite heterogeneous and may need to be revised in the future with the help of newer molecular data. Finally, Groups 29–37 are dedicated to the dysostoses (with Group 29 including cleidocranial dysplasia as a well-known example of transition between dysplasia and dysostosis) that follow again anatomical criteria (cranium, face, axial skeleton, extremities) with additional criteria reflecting principles of embryonal development such as limb reduction or hypoplasia (proximal-distal growth) versus terminal differentiation and patterning of the digits or joint formation. Additionally we have converted all Roman numerals to Arabic numbering to make electronic searches more straight forward.

Criticism to the previous versions of the Nosology has focussed on its “hybrid” nature, in the sense that it does not stick to a systematic approach, be it clinical or molecular. It is true that the Nosology is not necessarily aimed at being a diagnostic tool; other papers can be more useful in this respect [Unger, 2002; Offiah and Hall, 2003]. On a similar line, other papers have focused on the molecular aspects of genetic disorders of bone [Hermanns and Lee, 2001; Superti-Furga et al., 2001; Kornak and Mundlos, 2003]. Thus, the Nosology should coexist with other classifications based on the clinical and radiographic approach to diagnosis or based on the affected molecular systems and pathways, and it is hoped that electronic means will facilitate transition and interactions between the various classification criteria that can be applied. Efforts are in place to establish a web-based system enabling databases searches for molecular defects, pathways, and clinical features.

In spite of these limitations, the Nosology can offer a rapid help and orientation in this complex field. For the clinician who is struggling for a diagnosis, a simple listing of disorders grouped by cardinal features can help in indicating the way of further enquiries and consultation of appropriate sources. The boundaries between skeletal dysplasias and dysostoses, metabolic and molecular disorders, and multiple congenital anomalies syndromes is becoming progressively less sharp, and the diagnostic process requires knowledge that crosses the boundaries between these subspecialty areas. For the expert, the Nosology offers a quick reminder of the many differential diagnoses for one given disorder. In some instances, the Nosology as the list of currently recognized disorders will constitute the standard against which a possible “new” disorder should be compared. And last but not least, the Nosology offers a catalogue of genes involved in skeletal development and homeostasis and should be of interest and of inspiration to all those who are working in skeletal biology and medicine.


The 7th ISDS meeting and the Nosology workshop were supported by the March of Dimes and sponsored by BioMarin, Genzyme, Kenko, Nestlé, Novartis IBMR, and Milupa.