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Keywords:

  • skeletal genetics;
  • osteochondrodysplasias;
  • nosology;
  • dysostoses;
  • molecular basis of disease

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

In the 1960s, accumulating evidence that genetic skeletal disorders were clinically and genetically heterogeneous prompted a group of international experts to prepare a document to reach an agreement on the nomenclature of what was then called “constitutional (or intrinsic) disorders of bone” [1970, 1971a,b,c,d; 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 skeletal disorders, syndromes and metabolic diseases that were being newly described. Revisions have been prepared in 1977, 1983, 1992, and 1997 [1978, 1979, 1983, 1998, Rimoin, 1979; Spranger, 1992; Lachman, 1998]. Following the establishment of the International Skeletal Dysplasia Society (ISDS) 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 ensure an adequate representation of clinical, radiological and molecular expertise (2001 and 2006 revisions) [Hall, 2002; Superti-Furga and Unger, 2007].

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The Nosology Group of the International Skeletal Dysplasia Society met in August 2009. A consensus was reached for changes to be made to the grouping of disorders and about the inclusion of individual disorders. The drafts were circulated after the meeting and an effort was made to monitor recent publications up to November 2010. The criteria used for inclusion of individual disorders were unchanged from the previous revision. They 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 MIM (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 by the presence of distinctive diagnostic features and of observation in multiple individuals or families.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Four hundred fifty-six different conditions were included and placed in 40 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 316 (2006 revision: 215) were associated with one or more of 226 (2006 revision: 140) different genes. 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.

Table I. XX
Group/name of disorderInheritanceMIM No.LocusGeneProteinNotes
1. FGFR3 chondrodysplasia group
 Thanatophoric dysplasia type 1 (TD1)AD1876004p16.3FGFR3FGFR3Includes previous San Diego type
 Thanatophoric dysplasia type 2 (TD2)AD1876014p16.3FGFR3FGFR3
 Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)ADSee 1876004p16.3FGFR3FGFR3
 AchondroplasiaAD1008004p16.3FGFR3FGFR3
 HypochondroplasiaAD1460004p16.3FGFR3FGFR3
 Camptodactyly, tall stature, and hearing loss syndrome (CATSHL)AD1876004p16.3FGFR3FGFR3Inactivating mutation
 Hypochondroplasia-like dysplasia(s)AD, SP Similar to hypochondroplasia but unlinked to FGFR3, probably heterogeneous; uncertain diagnostic criteria
See also group 33 for craniosynostoses syndromes linked to FGFR3 mutations, as well as LADD syndrome in group 39 for another FGFR3-related phenotype
2. Type 2 collagen group and similar disorders
 Achondrogenesis type 2 (ACG2; Langer–Saldino)AD20061012q13.1COL2A1Type 2 collagen
 Platyspondylic dysplasia, Torrance typeAD15121012q13.1COL2A1Type 2 collagenSee also severe spondylodysplastic dysplasias (group 13)
 HypochondrogenesisAD20061012q13.1COL2A1Type 2 collagen
 Spondyloepiphyseal dysplasia congenita (SEDC)AD18390012q13.1COL2A1Type 2 collagen
 Spondyloepimetaphyseal dysplasia (SEMD) Strudwick typeAD18425012q13.1COL2A1Type 2 collagen
 Kniest dysplasiaAD15655012q13.1COL2A1Type 2 collagen
 Spondyloperipheral dysplasiaAD27170012q13.1COL2A1Type 2 collagen
 Mild SED with premature onset arthrosisAD 12q13.1COL2A1Type 2 collagenOften associated with p.R719C and p.G474S mutations
 SED with metatarsal shortening (formerly Czech dysplasia)AD60916212q13.1COL2A1Type 2 collagenOften associated with the p.R275C mutation
 Stickler syndrome type 1AD10830012q13.1COL2A1Type 2 collagen
 Stickler-like syndrome(s) Unlinked to either COL2A1, COL11A1, or COL11A2. See also COL9A1 for recessive form
3. Type 11 collagen group
 Stickler syndrome type 2AD6048411p21COL11A1Type 11 collagen alpha-1 chain
 Marshall syndromeAD1547801p21COL11A1Type 11 collagen alpha-1 chain
 FibrochondrogenesisAR2285201p21COL11A1Type 11 collagen alpha-1 chain
 Otospondylomegaepiphyseal dysplasia (OSMED), recessive typeAR2151506p21.3COL11A2Type 11 collagen alpha-2 chain
 Otospondylomegaepiphyseal dysplasia (OSMED), dominant type (Weissenbacher–Zweymüller syndrome, Stickler syndrome type 3)AD2151506p21.3COL11A2Type 11 collagen alpha-2 chain
See also Stickler syndrome type 1 in group 2
4. Sulfation disorders group
 Achondrogenesis type 1B (ACG1B)AR6009725q32–33DTDSTSLC26A2 sulfate transporterFormerly known as Fraccaro type achondrogenesis
 Atelosteogenesis type 2 (AO2)AR2560505q32–33DTDSTSLC26A2 sulfate transporterIncludes de la Chapelle dysplasia, McAlister dysplasia, and “neonatal osseous dysplasia”
 Diastrophic dysplasia (DTD)AR2226005q32–33DTDSTSLC26A2 sulfate transporter
 MED, autosomal recessive type (rMED; EDM4)AR2269005q32–33DTDSTSLC26A2 sulfate transporterSee also multiple epiphyseal dysplasias and pseudoachondroplasia group (group 9)
 SEMD, PAPSS2 typeAR60300510q23–q24PAPSS2PAPS-Synthetase 2Formerly “Pakistani type.” See also SEMD group (group 11)
 Chondrodysplasia with congenital joint dislocations, CHST3 type (recessive Larsen syndrome)AR60863710q22.1CHST3Carbohydrate sulfotransferase 3; chondroitin 6-sulfotransferaseIncludes recessive Larsen syndrome, humero-spinal dysostosis, and SED Omani type
 Ehlers–Danlos syndrome, CHST14 type (“musculo-skeletal variant”)AR60177615q14CHST14Carbohydrate sulfotransferase 14; dermatan 4-sulfotransferaseIncludes Adducted Thumb–Clubfoot syndrome
See also group 7 and group 26 for other conditions with multiple dislocations
5. Perlecan group
 Dyssegmental dysplasia, Silverman-Handmaker typeAR2244101q36–34PLC (HSPG2)Perlecan
 Dyssegmental dysplasia, Rolland-Desbuquois typeAR2244001q36–34PLC (HSPG2)Perlecan
 Schwartz–Jampel syndrome (myotonic chondrodystrophy)AR2558001q36–34PLC (HSPG2)PerlecanMild and severe forms; includes previous Burton dysplasia
6. Aggrecan group
 SED, Kimberley typeAD60836115q26AGC1Aggrecan
 SEMD, Aggrecan typeAR61281315q26AGC1Aggrecan
 Familial osteochondritis dissecansAD16580015q26AGC1Aggrecan
7. Filamin group and related disorders
 Frontometaphyseal dysplasiaXLD305620Xq28FLNAFilamin ASome cases apparently lack FLNA mutations
 Osteodysplasty Melnick–NeedlesXLD309350Xq28FLNAFilamin A
 Otopalatodigital syndrome type 1 (OPD1)XLD311300Xq28FLNAFilamin A
 Otopalatodigital syndrome type 2 (OPD2)XLD304120Xq28FLNAFilamin A
 Terminal osseous dysplasia with pigmentary defects (TODPD)XLD300244Xq28FLNAFilamin A
 Atelosteogenesis type 1 (AO1)AD1087203p14.3FLNBFilamin BIncludes Boomerang dysplasia, Piepkorn dysplasia, and spondylohumerofemoral (giant cell) dysplasia
 Atelosteogenesis type 3 (AO3)AD1087213p14.3FLNBFilamin B
 Larsen syndrome (dominant)AD1502503p14.3FLNBFilamin B
 Spondylo-carpal-tarsal dysplasiaAR2724603p14.3FLNBFilamin B
 Spondylo-carpal-tarsal dysplasiaAR272460 Unlinked to FLNB
 Franck–ter Haar syndromeAR2494205q35.1SH3PXD2BTKS4
 Serpentine fibula—polycystic kidney syndromeAD?600330
See also group 4 for recessive Larsen syndrome and group 26 for conditions with multiple dislocations
8. TRPV4 group
 Metatropic dysplasiaAD15653012q24.1TRPV4Transient receptor potential cation channel, subfamily V, member 4Includes lethal and non-lethal forms
 Spondyloepimetaphyseal dysplasia, Maroteaux type (Pseudo–Morquio syndrome type 2)AD18409512q24.1TRPV4Transient receptor potential cation channel, subfamily V, member 4
 Spondylometaphyseal dysplasia, Kozlowski typeAD18425212q24.1TRPV4Transient receptor potential cation channel, subfamily V, member 4
 Brachyolmia, autosomal dominant typeAD11350012q24.1TRPV4Transient receptor potential cation channel, subfamily V, member 4
 Familial digital arthropathy with brachydactylyAD60683512q24.1TRPV4Transient receptor potential cation channel, subfamily V, member 4
9. Short-ribs dysplasias (with or without polydactyly) group
 Chondroectodermal dysplasia (Ellis–van Creveld)AR2255004p16EVC1EvC gene 1
4p16EVC2EvC gene 2
 Short rib—polydactyly syndrome (SRPS) type 1/3 (Saldino-Noonan/Verma-Naumoff)AR26351011q22.3DYNC2H1Dynein, cytoplasmic 2, heavy chain 1
 SRPS type 1/3 (Saldino-Noonan/Verma-Naumoff)AR2635103q25.33IFT80Intraflagellar transport 80 (homolog of)
 SRPS type 1/3 (Saldino-Noonan/Verma-Naumoff)AR263510 Unlinked to either DYNC2H1 or IFT80
 SRPS type 2 (Majewski)AR263520 NEK1Nima related kinase 1
 SRPS type 4 (Beemer)AR269860
 Oral-facial-digital syndrome type 4 (Mohr–Majewski)AR258860
 Asphyxiating thoracic dysplasia (ATD; Jeune)AR2085003q25.33IFT80Intraflagellar transport 80 (homolog of)
 Asphyxiating thoracic dysplasia (ATD; Jeune)AR20850011q22.3DYNC2H1Dynein, cytoplasmic 2, heavy chain 1
 Asphyxiating thoracic dysplasia (ATD; Jeune)AR208500 Unlinked to either DYNC2H1 or IFT80
 Thoracolaryngopelvic dysplasia (Barnes)AD187760
See also paternal UPD14 and cerebro-costo-mandibular syndrome
10. Multiple epiphyseal dysplasia and pseudoachondroplasia group
 Pseudoachondroplasia (PSACH)AD17717019p12–13.1COMPCOMP
 Multiple epiphyseal dysplasia (MED) type 1 (EDM1)AD13240019p13.1COMPCOMP
 Multiple epiphyseal dysplasia (MED) type 2 (EDM2)AD6002041p32.2–33COL9A2Collagen 9 alpha-2 chain
 Multiple epiphyseal dysplasia (MED) type 3 (EDM3)AD60096920q13.3COL9A3Collagen 9 alpha-3 chain
 Multiple epiphyseal dysplasia (MED) type 5 (EDM5)AD6070782p23–24MATN3Matrilin 3
 Multiple epiphyseal dysplasia (MED) type 6 (EDM6)AD1202106q13COL9A1Collagen 9 alpha-1 chain
 Multiple epiphyseal dysplasia (MED), other types Some MED-like cases unlinked to known genes
 Stickler syndrome, recessive typeAR1202106q13COL9A1Collagen 9 alpha-1 chain
 Familial hip dysplasia (Beukes)AD1426694q35
 Multiple epiphyseal dysplasia with microcephaly and nystagmus (Lowry-Wood)AR226960
See also multiple epiphyseal dysplasia, recessive type (rMED; EDM4) in sulfation disorders (group 4), familial osteochondritis dissecans in the aggrecan group, as well as ASPED in the Acromelic group
11. Metaphyseal dysplasias
 Metaphyseal dysplasia, Schmid type (MCS)AD1565006q21–22.3COL10A1Collagen 10 alpha-1 chain
 Cartilage-hair hypoplasia (CHH; metaphyseal dysplasia, McKusick type)AR2502509p13RMRPRNA component of RNAse HIncludes anauxetic dysplasia
 Metaphyseal dysplasia, Jansen typeAD1564003p22–21.1PTHR1PTH/PTHrP receptor 1Activating mutations—see also Blomstrand dysplasia (group 22, 23)
 Eiken dysplasiaAR6000023p22–21.1PTHR1PTH/PTHrP receptor 1Activating mutations—see also Blomstrand dysplasia (group 22, 23)
 Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia (Shwachman–Bodian–Diamond syndrome, SBDS)AR2604007q11SBDSSBDS protein
 Metaphyseal anadysplasia type 1AD, AR30964511q22.2MMP13Matrix metalloproteinase 13Includes SEMD Missouri type. Both dominant and recessive mutations described
 Metaphyseal anadysplasia type 2AR 20q13.12MMP9Matrix metalloproteinase 9
 Metaphyseal dysplasia, Spahr typeAR250400
 Metaphyseal acroscyphodysplasia (various types)AR250215
 Genochondromatosis (type 1/type 2)AD/SP137360
 Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduriaAR/SPSee 271550
12. Spondylometaphyseal dysplasias (SMD)
 Spondyloenchondrodysplasia (SPENCD)AR27155019p13.2ACP5Tartrate-resistant acid phosphatase (TRAP)Includes combined immunodeficiency with autoimmunity and spondylometaphyseal dysplasia (MIM 607944)
 Odontochondrodysplasia (ODCD)AR184260
 Spondylometaphyseal dysplasia, Sutcliffe type or corner fractures typeAD184255
 SMD with severe genu valgumAD184253 Includes SMD Schmidt type and SMD Algerian type
 SMD with cone-rod dystrophyAR608940
 SMD with retinal degeneration, axial typeAR602271
 DysspondyloenchondromatosisSP
 Cheiro-spondyloenchondromatosisSP See also group 29
See also SMD Kozlowski (group TRPV4) disorders in group 11 as well as SMD Sedaghatian type in group 12; there are many individual reports of SMD variants
13. Spondylo-epi-(meta)-physeal dysplasias (SE(M)D)
 Dyggve–Melchior–Clausen dysplasia (DMC)AR22380018q12–21.1DYMDymeclinIncludes Smith–McCort dysplasia
 Immuno-osseous dysplasia (Schimke)AR2429002q34–36SMARCAL1SWI/SNF-related regulator of chromatin subfamily A-like protein 1
 SED, Wolcott–Rallison typeAR2269802p12EIF2AK3Translation initiation factor 2-alpha kinase-3
 SEMD, Matrilin typeAR6087282p23–p24MATN3Matrilin 3See also matrilin-related MED in group 8
 SEMD, short limb—abnormal calcification typeAR2716651q23DDR2Discoidin domain receptor family, member 2See also other dysplasias with stippling in group 20
 SED tarda, X-linked (SED-XL)XLR313400Xp22SEDLSedlin
 Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD)AR6133304p16.1NKX3-2NK3 Homeobox 2
 Spondylodysplastic Ehlers–Danlos syndromeAR61235011p11.2SLC39A13Zinc transporter ZIP13
 SPONASTRIME dysplasiaAR271510
 SEMD with joint laxity (SEMD-JL) leptodactylic or Hall typeAD603546
 SEMD with joint laxity (SEMD-JL) Beighton typeAR271640
 Platyspondyly (brachyolmia) with amelogenesis imperfectaAR601216
 Late onset SED, autosomal recessive typeAR609223
 Brachyolmia, Hobaek, and Toledo typesAR271530, 271630 Nosologic relationship between the Toleado and Hobaek types of brachyolmia and recessive late-onset SED are unclear, distinctive criteria lacking so far
See also Brachyolmia (group 8), Opsismodysplasia (group 14), SEMDs (group 11), mucopolysaccharidosis type 4 (Morquio syndrome) and other conditions in group 26, as well as PPRD (SED with progressive arthropathy) in group 31
14. Severe spondylodysplastic dysplasias
 Achondrogenesis type 1A (ACG1A)AR20060014q32.12TRIP11Golgi-microtubule-associated protein, 210-kDa; GMAP210
 Schneckenbecken dysplasiaAR2692501p31.3SLC35D1Solute carrier family 35 member D1; UDP-glucuronic acid/UDP-N-acetylgalactosamine dual transporter
 Spondylometaphyseal dysplasia, Sedaghatian typeAR250220
 Severe spondylometaphyseal dysplasia (SMD Sedaghatian-like)AR 7q11SBDSSBDS gene, function still unclear
 OpsismodysplasiaAR258480
See also Thanatophoric dysplasia, types 1 and 2 (group 1); ACG2 and Torrance dysplasia (group 2); Fibrochondrogenesis (group 3); Achondrogenesis type 1B (ACG1B, group 4); and Metatropic dysplasia (TRPV4 group)
15. Acromelic dysplasias
 Trichorhinophalangeal dysplasia types 1/3AD1903508q24TRPS1Zinc finger transcription factor
 Trichorhinophalangeal dysplasia type 2 (Langer–Giedion)AD1502308q24TRPS1 and EXT1Zinc finger transcription factor and Exostosin 1Microdeletion syndrome; see also Multiple Cartilagineous Exostoses in group 28
 Acrocapitofemoral dysplasiaAR6077782q33–q35IHHIndian hedgehog
 Cranioectodermal dysplasia (Levin–Sensenbrenner) type 1AR2183303q21IFT122Intraflagellar transport 122 (Chlamydomonas, homolog of)
 Cranioectodermal dysplasia (Levin–Sensenbrenner) type 2AR6136102p24.1WDR35WD repeat-containing protein 35
 Geleophysic dysplasiaAR2310509q34.2ADAMTSL2ADAMTS-like protein 2
 Geleophysic dysplasia, other typesAR Unlinked to ADAMTSL2
 Acromicric dysplasiaAD102370 Includes acrolaryngeal dysplasia, previously known as Fantasy Island dysplasia or Tattoo dysplasia
 AcrodysostosisAD101800
 Angel-shaped phalango-epiphyseal dysplasia (ASPED)AD105835 Possibly related or allelic to Brachydactyly type C
 Saldino–Mainzer dysplasiaAR266920
See also short rib dysplasias group
16. Acromesomelic dysplasias
 Acromesomelic dysplasia type Maroteaux (AMDM)AR6028759p13–12NPR2Natriuretic peptide receptor 2
 Grebe dysplasiaAR20070020q11.2GDF5Growth and differentiation factor 5Includes acromesomelic dysplasia Hunter-Thompson type; see also Brachydactylies (group 34)
 Fibular hypoplasia and complex brachydactyly (Du Pan)AR22890020q11.2GDF5Growth and differentiation factor 5See also Brachydactylies (group 34)
 Acromesomelic dysplasia with genital anomaliesAR6094414q23–24BMPR1BBone morphogenetic protein receptor 1B
 Acromesomelic dysplasia, Osebold-Remondini typeAD112910
17. Mesomelic and rhizo-mesomelic dysplasias
 Dyschondrosteosis (Leri–Weill)Pseudo-AD127300Xpter-p22.32SHOXShort stature—homeobox geneIncludes Reinhardt–Pfeiffer dysplasia, MIM 191400
 Langer type (homozygous dyschondrosteosis)Pseudo-AR249700Xpter-p22.32SHOXShort stature—homeobox gene
 OmodysplasiaAR25831513q31–q32GPC6Glypican 6Existence of “dominant omodysplasia” (MIM 164745) remains to be confirmed
 Robinow syndrome, recessive typeAR2683109q22ROR2Receptor tyrosine kinase-like orphan receptor 2Includes previous costo-vertebral segmentation defect with mesomelia (COVESDEM); see also brachydactyly type B
 Robinow syndrome, dominant typeAD180700
 Mesomelic dysplasia, Korean typeAD 2q24–32 Duplication in HOXD gene cluster
 Mesomelic dysplasia, Kantaputra typeAD1562322q24–32 Duplications in HOXD gene cluster
 Mesomelic dysplasia, Nievergelt typeAD163400
 Mesomelic dysplasia, Kozlowski-Reardon typeAR249710
 Mesomelic dysplasia with acral synostoses (Verloes–David–Pfeiffer type)AD6003838q13SULF1 and SLCO5A1Heparan sulfate 6-O-endosulfatase 1 and solute carrier organic anion transporter family member 5A1Microdeletion syndrome involving two adjacent genes
 Mesomelic dysplasia, Savarirayan type (Triangular Tibia–Fibular Aplasia)SP605274 Possibly related to Nievergelt dysplasia. One case reported with 2q11.2 microdeletion of unclear significance
18. Bent bones dysplasias
 Campomelic dysplasia (CD)AD11429017q24.3–25.1SOX9SRY-box 9Includes acampomelic campomelic dysplasia (ACD) as well as mild campomelic dysplasia (MIM 602196)
 Stüve–Wiedemann dysplasiaAR6015595p13.1LIFRLeukemia inhibitory factor receptorIncludes formerly neonatal Schwartz–Jampel syndrome or SJS type 2
 Kyphomelic dysplasia, several forms 211350 Probably heterogeneous
Bent bones at birth can be seen in a variety of conditions, including osteogenesis imperfecta, Antley–Bixler syndrome, cartilage-hair hypoplasia, Cummings syndrome, hypophosphatasia, dyssegmental dysplasia, TD, ATD, and others
19. Slender bone dysplasia group
 3-M syndrome (3M1)AR2737506p21.1CUL7Cullin 7Includes dolichospondylic dysplasia and Yakut short stature syndrome
 3-M syndrome (3M2)AR6129212q35OBSL1Obscurin-like 1
 Kenny–Caffey dysplasia type 1AR2444601q42–q43TBCETubulin-specific chaperone E
 Kenny–Caffey dysplasia type 2AD127000
 Microcephalic osteodysplastic primordial dwarfism type 1/3 (MOPD1)AR2107102q Includes Taybi–Linder cephaloskeletal dysplasia
 Microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2; Majewski type)AR21072021qPCNT2Pericentrin 2
 IMAGE syndrome (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies)XL/AD300290 Possibly heterogeneous
 OsteocraniostenosisSP602361 Occurrence in sibs reported, inheritance unclear
 Hallermann–Streiff syndromeAR234100 Mutations in GJA1 reported in one case only
See also Cerebro-arthro-digital dysplasia
20. Dysplasias with multiple joint dislocations
 Desbuquois dysplasia (with accessory ossification center in digit 2)AR25145017q25.3CANT1
 Desbuquois dysplasia with short metacarpals and elongated phalanges (Kim type)AR25145017q25.3CANT1
 Desbuquois dysplasia (other variants with or without accessory ossification center)AR Probably genetically heterogeneous
 Pseudodiastrophic dysplasiaAR264180
See also SED with congenital dislocations, CHST3 type (group 4); Atelosteogenesis type 3 and Larsen syndrome (group 6); SEMDs with joint laxity (group 11)
21. Chondrodysplasia punctata (CDP) group
 CDP, X-linked dominant, Conradi–Hünermann type (CDPX2)XLD302960Xp11EBPEmopamil-binding protein
 CDP, X-linked recessive, brachytelephalangic type (CDPX1)XLR302950Xp22.3ARSEArylsulfatase E
 Congenital hemidysplasia, ichthyosis, limb defects (CHILD)XLD308050Xp11NSDHLNAD(P)H steroid dehydrogenase-like protein
 Congenital hemidysplasia, ichthyosis, limb defects (CHILD)XLD308050Xq28EBPEmopamil-binding protein
 Greenberg dysplasiaAR2151401q42.1LBRLamin B receptor, 3-beta-hydroxysterol delta (14)-reductaseIncludes hydrops-ectopic calcification-moth-eaten appearance dysplasia (HEM) and dappled diaphyseal dysplasia
 Rhizomelic CDP type 1AR2151006q22–24PEX7Peroxisomal PTS2 receptor
 Rhizomelic CDP type 2AR2227651q42DHPATDihydroxyacetonephosphate acyltransferase (DHAPAT)
 Rhizomelic CDP type 3AR6001212q31AGPSAlkylglycerone-phosphate synthase (AGPS)
 CDP tibial-metacarpal typeAD/AR118651 Nosologic status uncertain
 Astley-Kendall dysplasiaAR? Relationship to OI and to Greenberg dysplasia unclear
Note that stippling can occur in several syndromes such as Zellweger, Smith–Lemli–Opitz and others. See also desmosterolosis as well as SEMD short limb—abnormal calcification type in group 11
22. Neonatal osteosclerotic dysplasias
 Blomstrand dysplasiaAR2150453p22–21.1PTHR1PTH/PTHrP receptor 1Caused by recessive inactivating mutations; see also Eiken dysplasia and Jansen dysplasia
 DesmosterolosisAR6023981p33–31.1DHCR243-beta-hydroxysterol delta-24-reductaseSee also other sterol-metabolism related conditions
 Caffey disease (including infantile and attenuated forms)AD11400017q21–22COL1A1Collagen 1, alpha-1 chainSee also osteogenesis imperfecta related to collagen 1 genes (group 24)
 Caffey disease (severe variants with prenatal onset)AR114000
 Raine dysplasia (lethal and non-lethal forms)AR2597757p22FAM20C Includes lethal and non-lethal cases
See also Astley-Kendall dysplasia and CDPs in group 21
23. Increased bone density group (without modification of bone shape)
 Osteopetrosis, severe neonatal or infantile forms (OPTB1)AR25970011q13TCIRG1Subunit of ATPase proton pump
 Osteopetrosis, severe neonatal or infantile forms (OPTB4)AR61149016p13CLCN7Chloride channel 7
 Osteopetrosis, infantile form, with nervous system involvement (OPTB5)AR2597206q21OSTM1Gray lethal/osteopetrosis associated transmembrane protein
 Osteopetrosis, intermediate form, osteoclast-poor (OPTB2)AR25971013q14.11RANKL (TNFSF11)Receptor activator of NF-kappa-B ligand (tumor necrosis factor ligand superfamily, member 11)
 Osteopetrosis, infantile form, osteoclast-poor with immunoglobulin deficiency (OPTB7)AR61230218q21.33RANK (TNFRSF11A)Receptor activator of NF-kappa-BSee also familial expansile osteolysis in Osteolysis group (group 28)
 Osteopetrosis, intermediate form (OPTB6)AR61149717q21.3PLEKHM1Pleckstrin homology domain-containing protein, family M, member 1
 Osteopetrosis, intermediate form (OPTA2)AR25971016p13CLCN7Chloride channel pump
 Osteopetrosis with renal tubular acidosis (OPTB3)AR2597308q22CA2Carbonic anhydrase 2
 Osteopetrosis, late-onset form type 1 (OPTA1)AD60763411q13.4LRP5Low density lipoprotein receptor-related protein 5Includes Worth type osteosclerosis (MIM 144750)
 Osteopetrosis, late-onset form type 2 (OPTA2)AD16660016p13CLCN7Chloride channel 7
 Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID)XL300301Xq28IKBKG (NEMO)Inhibitor of kappa light polypeptide gene enhancer, kinase of
 Osteopetrosis, moderate form with defective leucocyte adhesion (LAD3)AR61284011q12FERMT3 (KIND3)Fermitin 3 (Kindlin 3)
 Osteopetrosis, moderate form with defective leucocyte adhesionAR61284011q13RASGRP2 (CalDAG-GEF1)Ras guanyl nucleotide-releasing protein 2
 PyknodysostosisAR2658001q21CTSKCathepsin K
 OsteopoikilosisAD15595012q14LEMD3LEM domain-containing 3Includes Buschke–Ollendorff syndrome (MIM 166700)
 Melorheostosis with osteopoikilosisAD15595012q14LEMD3LEM domain-containing 3Includes mixed sclerosing bone dysplasia
 Osteopathia striata with cranial sclerosis (OSCS)XLD300373Xq11.1WTXFAM123B
 MelorheostosisSP No germ line LEMD3 mutations identified so far
 DysosteosclerosisAR224300 Possibly related to “osteosclerotic metaphyseal dysplasia”
 OsteomesopyknosisAD166450
 Osteopetrosis with infantile neuroaxonal dysplasiaAR?600329 Same as osteopetrosis with nervous system involvement (see above)?
24. Increased bone density group with metaphyseal and/or diaphyseal involvement
 Craniometaphyseal dysplasia, autosomal dominant typeAD1230005p15.2–14.2ANKHHomolog of mouse ANK (ankylosis) geneGain of function mutations
 Diaphyseal dysplasia Camurati-EngelmannAD13130019q13TGFbeta1Transforming growth factor beta 1
 Hematodiaphyseal dysplasia GhosalAR2310957q34TBXAS1Thromboxane A synthase 1
 Hypertrophic osteoarthropathyAR2591004q34–35HPGD15-alpha-hydroxyprostaglandin dehydrogenaseIncludes cranio-osteoarthropathy and cases of recessive pachydermoperiostosis
 Pachydermoperiostosis (hypertrophic osteoarthropathy, primary, autosomal dominant)AD167100 Relationship to recessive form (MIM 259100, HPGD deficiency) unclear
 Oculodentoosseous dysplasia (ODOD) mild typeAD1642006q22–23GJA1Gap junction protein alpha-1
 Oculodentoosseous dysplasia (ODOD) severe typeAR257850 Possibly homozygous form of mild ODOD
 Osteoectasia with hyperphosphatasia (juvenile Paget disease)AR2390008q24OPGOsteoprotegerin
 SclerosteosisAR26950017q12–21SOSTSclerostin
 Endosteal hyperostosis, van Buchem typeAR23910017q12–21SOSTSclerostinSpecific 52 kb deletion downstream of SOST
 Trichodentoosseous dysplasiaAD19032017q21DLX3Distal-less homeobox 3
 Craniometaphyseal dysplasia, autosomal recessive typeAR2184006q21–22
 Diaphyseal medullary stenosis with bone malignancyAD1122509p21–p22
 Craniodiaphyseal dysplasiaAD122860
 Craniometadiaphyseal dysplasia, Wormian bone typeAR
 Endosteal sclerosis with cerebellar hypoplasiaAR213002
 Lenz–Majewski hyperostotic dysplasiaSP151050
 Metaphyseal dysplasia, Braun–Tinschert typeXL605946
 Pyle diseaseAR265900
25. Osteogenesis imperfecta and decreased bone density group
 For comments the classification of osteogenesis imperfecta, please refer to the text
  Osteogenesis imperfecta, non-deforming form (OI type 1)AD COL1A1, COL1A2COL1A1: collagen 1 alpha-1 chain, COL1A2: collagen 1 alpha-2 chain, CRTAP: cartilage-associated protein, LEPRE1: leucine proline-enriched proteoglycan (leprecan) 1, PPIB: peptidylprolyl isomerase B (cyclophilin B), FKBP10: FK506 binding protein 10, SERPINH: serpin peptidase inhibitor clade H 1, SP7: SP7 transcription factor (Osterix)
  Osteogenesis imperfecta, perinatal lethal form (OI type 2)AD, AR COL1A1, COL1A2, CRTAP, LEPRE1, PPIB
  Osteogenesis imperfecta, progressively deforming type (OI type 3)AD, AR COL1A1, COL1A2, CRTAP, LEPRE1, PPIB, FKBP10, SERPINH1See also Bruck syndrome type 1 (below)
  Osteogenesis imperfecta, moderate form (OI type 4)AD, AR COL1A1, COL1A2, CRTAP, FKBP10, SP7
  Osteogenesis imperfecta with calcification of the interosseous membranes and/or hypertrophic callus (OI type 5)AD610967
  Osteogenesis imperfecta, other types
  Bruck syndrome type 1 (BS1)AR25945017q12FKBP10FK506 binding protein 10See autosomal recessive OI, above; intrafamilial variability between OI3 and BS1 documented
  Bruck syndrome type 2 (BS2)AR6092203q23–24PLOD2Procollagen lysyl hydroxylase 2
  Osteoporosis-pseudoglioma syndromeAR25977011q12–13LRP5LDL-receptor related protein 5
  Calvarial doughnut lesions with bone fragilityAD126550
  Idiopathic juvenile osteoporosisSP259750 Some patients reported with heterozygous mutations in the LRP5 gene
  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 LRP5
  Osteopenia with radiolucent lesions of the mandibleAD166260
  Ehlers–Danlos syndrome, progeroid formAR1300705q35B4GALT7Xylosylprotein 4-beta-galactosyltransferase deficiency
  Geroderma osteodysplasticumAR2310701q24.2GORABSCYL1-binding protein 1
  Cutis laxa, autosomal recessive form, type 2B (ARCL2B)AR61294017q25.3PYCR1Pyrroline-5-carboxylate reductase 1Skeletal features overlapping with progeroid EDS and geroderma osteodysplasticum
  Cutis laxa, autosomal recessive form, type 2A (ARCL2A) (Wrinkly skin syndrome)AR278250, 21920012q24.3ATP6VOA2ATPase, H+ transporting, lysosomal, V0 subunit A2Skeletal features overlapping with progeroid EDS and geroderma osteodysplasticum
  Singleton–Merten dysplasiaAD182250
26. Abnormal mineralization group
 Hypophosphatasia, perinatal lethal and infantile formsAR2415001p36.1–p34ALPLAlkaline phosphatase, tissue non-specific (TNSALP)Intrafamilial variability
 Hypophosphatasia, adult formAD1463001p36.1–p34ALPLAlkaline phosphatase, tissue non-specific (TNSALP)Includes odontohypophosphatasia
 Hypophosphatemic rickets, X-linked dominantXLD307800Xp22PHEXX-linked hypophosphatemia membrane protease
 Hypophosphatemic rickets, autosomal dominantAD19310012p13.3FGF23Fibroblast growth factor 23
 Hypophosphatemic rickets, autosomal recessive, type 1 (ARHR1)AR2415204q21DMP1Dentin matrix acidic phosphoprotein 1
 Hypophosphatemic rickets, autosomal recessive, type 2 (ARHR2)AR6133126q23ENPP1Ectonucleotide pyrophosphatase/phosphodiesterase 1
 Hypophosphatemic rickets with hypercalciuria, X-linked recessiveXLR300554Xp11.22ClCN5Chloride channel 5Part of Dent's disease complex
 Hypophosphatemic rickets with hypercalciuria, autosomal recessive (HHRH)AR2415399q34SLC34A3Sodium-phosphate cotransporter
 Neonatal hyperparathyroidism, severe formAR2392003q13.3–21CASRCalcium-sensing receptor
 Familial hypocalciuric hypercalcemia with transient neonatal hyperparathyroidismAD1459803q13.3–21CASRCalcium-sensing receptor
 Calcium pyrophosphate deposition disease (familial chondrocalcinosis) type 2AD1186005p15.2–14.2ANKHHomolog of mouse ANK (ankylosis) geneLoss of function mutations (see craniometaphyseal dysplasia in group 24)
See also Jansen dysplasia and Eiken dysplasia
27. Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group)
 Mucopolysaccharidosis type 1H/1SAR6070144p16.3IDAAlpha-1-Iduronidase
 Mucopolysaccharidosis type 2XLR309900Xq27.3–28IDSIduronate-2-sulfatase
 Mucopolysaccharidosis type 3AAR25290017q25.3HSSHeparan sulfate sulfatase
 Mucopolysaccharidosis type 3BAR25292017q21NAGLUN-Ac-beta-D-glucosaminidase
 Mucopolysaccharidosis type 3CAR2529308p11–q13HSGNATAc-CoA: alpha-glucosaminide N-acetyltransferase
 Mucopolysaccharidosis type 3DAR25294012q14GNSN-Acetylglucosamine 6-sulfatase
 Mucopolysaccharidosis type 4AAR25300016q24.3GALNSGalactosamine-6-sulfate sulfatase
 Mucopolysaccharidosis type 4BAR2530103p21.33GLBIbeta-Galactosidase
 Mucopolysaccharidosis type 6AR2532005q13.3ARSBArylsulfatase B
 Mucopolysaccharidosis type 7AR2532207q21.11GUSBbeta-Glucuronidase
 FucosidosisAR2300001p34FUCAalpha-Fucosidase
 alpha-MannosidosisAR24850019p13.2–12MANAalpha-Mannosidase
 beta-MannosidosisAR2485104q22–25MANBbeta-Mannosidase
 AspartylglucosaminuriaAR2084004q23–27AGAAspartyl-glucosaminidase
 GMI Gangliosidosis, several formsAR2305003p21–14.2GLB1beta-Galactosidase
 Sialidosis, several formsAR2565506p21.3NEU1Neuraminidase (sialidase)
 Sialic acid storage disease (SIASD)AR2699206q14–q15SLC17A5Sialin (sialic acid transporter)
 Galactosialidosis, several formsAR25654020q13.1PPGBbeta-Galactosidase protective protein
 Multiple sulfatase deficiencyAR2722003p26SUMF1Sulfatase-modifying factor-1
 Mucolipidosis II (I-cell disease), alpha/beta typeAR2525004q21–23GNPTABN-Acetylglucosamine 1-phosphotransferase, alpha/beta subunits
 Mucolipidosis III (Pseudo-Hurler polydystrophy), alpha/beta typeAR2526004q21–23GNPTABN-Acetylglucosamine 1-phosphotransferase, alpha/beta subunits
 Mucolipidosis III (Pseudo-Hurler polydystrophy), gamma typeAR2526054q21–23GNPTGN-Acetylglucosamine 1-phosphotransferase, gamma subunit
28. Osteolysis group
 Familial expansile osteolysisAD17481018q22.1RANK (TNFRSF11A) Includes expansile skeletal hyperphosphatasia (MIM 602080)
 Mandibuloacral dysplasia type AAD2483701q21.2LMNALamin A/C
 Mandibuloacral dysplasia type BAR6086121p34ZMPSTE24Zinc metalloproteinase
 Progeria, Hutchinson–Gilford typeAD1766701q21.2LMNALamin A/C
 Torg–Winchester syndromeAR25960016q13MMP2Matrix metalloproteinase 2Includes Nodulosis–Arthropathy–Osteolysis syndrome (MIM 605156)
 Hajdu–Cheney syndromeAD102500
 Multicentric carpal-tarsal osteolysis with and without nephropathyAD166300
 Lipomembraneous osteodystrophy with leukoencephalopathy (presenile dementia with bone cysts; Nasu–Hakola)AR2217706p21.2TREM2Triggering receptor expressed on myeloid cells 2
 Lipomembraneous osteodystrophy with leukoencephalopathy (presenile dementia with bone cysts; Nasu–Hakola)AR22177019q13.1TYROBPTyro protein tyrosine kinase-binding protein
See also Pycnodysostosis, cleidocranial dysplasia, and Singleton–Merten syndrome. Note: several neurologic conditions may cause acroosteolysis
29. Disorganized development of skeletal components group
 Multiple cartilaginous exostoses 1AD1337008q23–24.1EXT1Exostosin-1
 Multiple cartilaginous exostoses 2AD13370111p12–11EXT2Exostosin-2
 Multiple cartilaginous exostoses 3AD60020919p
 CherubismAD1184004p16SH3BP2SH3 domain-binding protein 2
 Fibrous dysplasia, polyostotic formSP17480020q13GNAS1Guanine nucleotide-binding protein, alpha-stimulating activity subunit 1Somatic mosaicism and imprinting phenomena; includes McCune–Albright syndrome
 Progressive osseous heteroplasiaAD16635020q13GNAS1Guanine nucleotide-binding protein, alpha-stimulating activity subunit 1Gene subject to imprinting
 Gnathodiaphyseal dysplasiaAD16626011p15.1–14.3TMEM16ETransmembrane protein 16E
 MetachondromatosisAD15625012q24PTPN11Protein-tyrosine phosphatase nonreceptor-type 11
 Osteoglophonic dysplasiaAD1662508p11FGFR1Fibroblast growth factor receptor 1See also Craniosynostosis syndromes in group 30
 Fibrodysplasia ossificans progressiva (FOP)AD, SP1351002q23–24ACVR1Activin A (BMP type 1) receptor
 Neurofibromatosis type 1 (NF1)AD16220017q11.2NF1Neurofibromin
 Carpotarsal osteochondromatosisAD127820
 Cherubism with gingival fibromatosis (Ramon syndrome)AR266270
 Dysplasia epiphysealis hemimelica (Trevor)SP127800
 Enchondromatosis (Ollier)SP166000 PTHR1 and PTPN11 mutations found in a few cases only, role still unclear
 Enchondromatosis with hemangiomata (Maffucci)SP166000 PTPN11 mutations found in a few cases only, role unclear
See also Proteus syndrome in group 30
30. Overgrowth syndromes with skeletal involvement
 Weaver syndromeSP/AD277590 Some cases reported with NSD1 mutations (see Sotos syndrome)
 Sotos syndromeAD1175505q35NSD1Nuclear receptor-binding su-var, enhancer of zeste, and trithorax domain protein 1Some cases may have NFIX mutations (see Marshall–Smith syndrome)
 Marshall–Smith syndromeSP60253519p13.3NFIXNuclear factor I/XSome clinical overlap with Sotos syndrome (see above)
 Proteus syndromeSP176920 Some Proteus-like cases have mutations in the PTEN gene
 Marfan syndromeAD15470015q21.1FBN1Fibrillin 1
 Congenital contractural arachnodactylyAD1210505q23.3FBN2Fibrillin 2
 Loeys–Dietz syndrome types 1A and 2AAD609192, 610168,9q22TGFBR1TGFbeta receptor subunit 1
 Loeys–Dietz syndrome types 1B and 2BAD608967, 6103803p22TGFBR2TGFbeta receptor subunit 2
 Overgrowth syndrome with 2q37 translocationsSP2q37NPPCNatriuretic peptide precursor COvergrowth probably caused by overexpression of NPPC
 Overgrowth syndrome with skeletal dysplasia (Nishimura–Schmidt, endochondral gigantism)SP? Nosologic status unclear but conspicuous skeletal phenotype(s)
See also Shprintzen–Goldberg syndrome in Craniosynostosis group
31. Genetic inflammatory/rheumatoid-like osteoarthropathies
 Progressive pseudorheumatoid dysplasia (PPRD; SED with progressive arthropathy)AR2082306q22–23WISP3WNT1-inducible signaling pathway protein 3
 Chronic infantile neurologic cutaneous articular syndrome (CINCA)/neonatal onset multisystem inflammatory disease (NOMID)AD6071151q44CIAS1Cryopyrin
 Sterile multifocal osteomyelitis, periostitis, and pustulosis (CINCA/NOMID-like)AR1476792q14.2IL1RNInterleukin 1 receptor antagonist
 Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia (CRMO with CDA; Majeed syndrome)AR60962818p11.3LPIN2Lipin 2
 Hyperostosis/hyperphosphatemia syndromeAR6102332q24–q31GALNT3UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3
 Infantile systemic hyalinosis/Juvenile hyaline fibromatosis (ISH/JHF)AR2364904q21ANTXR2Anthrax toxin receptor 2Includes Juvenile hyaline fibromatosis (JHF, 228600) and Puretic syndrome
32. Cleidocranial dysplasia and isolated cranial ossification defects group
 Cleidocranial dysplasiaAD1196006p21RUNX2Runt related transcription factor 2
 CDAGS syndrome (craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, genital anomalies, skin eruption)AR60311622q12–q13
 Yunis–Varon dysplasiaAR216340
 Parietal foramina (isolated)AD16850011q11.2ALX4Aristaless-like 4See also Frontonasal dysplasia type 1 (group 34)
 Parietal foramina (isolated)AD1685005q34–35MSX2Muscle segment homeobox 2
See also pycnodysostosis, wrinkly skin syndrome, and several others
33. Craniosynostosis syndromes
 Pfeiffer syndrome (FGFR1-related)AD1016008p12FGFR1Fibroblast growth factor receptor 1Most have FGFR1 P252R mutation (phenotype generally milder than FGFR2-related Pfeiffer)
 Pfeiffer syndrome (FGFR2-related)AD10160010q26.12FGFR2Fibroblast growth factor receptor 2Includes Jackson–Weiss syndrome (MIM 123150) and Antley–Bixler variants caused by FGFR2 mutations (see below)
 Apert syndromeAD10120010q26.12FGFR2Fibroblast growth factor receptor 2
 Craniosynostosis with cutis gyrata (Beare–Stevenson)AD12379010q26.12FGFR2Fibroblast growth factor receptor 2
 Crouzon syndromeAD12350010q26.12FGFR2Fibroblast growth factor receptor 2
 Crouzon-like craniosynostosis with acanthosis nigricans (Crouzonodermoskeletal syndrome)AD6122474p16.3FGFR3Fibroblast growth factor receptor 3Defined by specific FGFR3 A391E mutation
 Craniosynostosis, Muenke typeAD6028494p16.3FGFR3Fibroblast growth factor receptor 3Defined by specific FGFR3 P250R mutation
 Antley–Bixler syndromeAR2017507q11.23PORCytochrome P450 oxidoreductaseSimilar cases with FGFR2 mutations classified as Pfeiffer syndrome (MIM 207410)
 Craniosynostosis Boston typeAD6047575q35.2MSX2MSX2Heterozygous P148H mutation in a single family
 Saethre–Chotzen syndromeAD1014007p21.1TWIST1TWIST
 Shprintzen–Goldberg syndromeAD182212 Some cases reported with FBN1 mutations
 Baller–Gerold syndromeAR2186008q24.3RECQL4RECQ protein-like 4RECQL4 might not account for all cases of Baller–Gerold
 Carpenter syndromeAR201000 RAB23
See also Cole–Carpenter syndrome in group 24, CDAGS syndrome in group 29, and Craniofrontonasal syndrome in group 34
34. Dysostoses with predominant craniofacial involvement
 Mandibulo-facial dysostosis (Treacher Collins, Franceschetti-Klein)AD1545005q32TCOF1Treacher Collins-Franceschetti syndrome 1
 Mandibulo-facial dysostosis (Treacher-Collins, Franceschetti-Klein)AD15450013q12.2POLR1DPolymerase (RNA) I polypeptide D
 Mandibulo-facial dysostosis (Treacher-Collins, Franceschetti-Klein)AR1545006p21.1POLR1CPolymerase (RNA) I polypeptide C
 Oral-facial-digital syndrome type I (OFD1)XLR311200Xp22.3CXORF5chr. X open reading frame 5
 Weyer acrofacial (acrodental) dysostosisAD1935304p16EVC1Ellis–van Creveld 1 protein
 Endocrine-cerebro-osteodysplasia (ECO)AR6126516p12.3ICKIntestinal cell kinase
 Craniofrontonasal syndromeXLD304110Xq13.1EFNB1Ephrin B1
 Frontonasal dysplasia, type 1AR1367601p13.3ALX3Aristaless-like-3
 Frontonasal dysplasia, type 2AR61345111p11.2ALX4Aristaless-like-4
 Frontonasal dysplasia, type 3AR61345612q21.3ALX1Aristaless-like 1
 Hemifacial microsomiaSP/AD164210 Includes Goldenhar syndrome and Oculo-Auriculo-Vertebral spectrum; probably genetically heterogeneous
 Miller syndrome (postaxial acrofacial dysostosis)AR26375016q22DHODHDihydroorotate dehydrogenase
 Acrofacial dysostosis, Nager typeAD/AR154400
 Acrofacial dysostosis, Rodriguez typeAR201170
See also Oral-facial-digital syndrome type IV in the Short Rib Dysplasias group
35. Dysostoses with predominant vertebral with and without costal involvement
 Currarino triadAD1764507q36HLXB9Homeobox gene HB9
 Spondylocostal dysostosis type 1 (SCD1)AR27730019q13DLL3Delta-like 3
 Spondylocostal dysostosis type 2 (SCD2)AR60868115q26MESP2Mesoderm posterior (expressed in) 2
 Spondylocostal dysostosis type 3 (SCD3)AR?6098137p22LFNGLunatic fringe
 Spondylocostal dysostosis type 4 (SCD4)AR 17p13.1HES7Hairy-and-enhancer-of-split-7
 Spondylothoracic dysostosisAR 15q26MESP2Mesoderm posterior (expressed in) 2
 Klippel–Feil anomaly with laryngeal malformationAD1489008q22.1GDF6Growth and differentiation factor 6Role of GDF6 mutations in dominant spondylothoracic dysostosis unclear
 Spondylocostal/thoracic dysostosis, other formsAD/AR See also GDF6, above
 Cerebro-costo-mandibular syndrome (rib gap syndrome)AD/AR117650
 Cerebro-costo-mandibular-like syndrome with vertebral defectsAR61120917q25COG1Component of oligomeric Golgi complex 1Also classified as CDG type IIg
 DiaphanospondylodysostosisAR6080227p14BMPERBone morphogenetic protein-binding endothelial cell precursor-derived regulatorPossibly overlaps with ischiospinal dysostosis
See also Spondylocarpotarsal dysplasia in group 7 and spondylo-metaphyseal-megaepiphyseal dysplasia in group 13
36. Patellar dysostoses
 Ischiopatellar dysplasia (small patella syndrome)AD14789117q21–q22TBX4T-box gene 4
 Small patella—like syndrome with clubfootAD 5q31PITX1Paired-like homeodomain transcription factor 1 (pituitary homeobox 1)Includes isolated dominant familial clubfoot
 Nail-patella syndromeAD1612009q34.1LMX1BLIM homeobox transcription factor 1
 Genitopatellar syndromeAR?606170
 Ear-patella-short stature syndrome (Meier-Gorlin)AR224690
See also MED group for conditions with patellar changes as well as ischio-pubic-patellar dysplasia as mild expression of campomelic dysplasia
37. Brachydactylies (with or without extraskeletal manifestations)
 Brachydactyly type A1AD1125002q35–36IHHIndian Hedgehog
 Brachydactyly type A1AD 5p31
 Brachydactyly type A2AD1126004q23BMPR1BBone morphogenetic protein receptor, 1B
 Brachydactyly type A2AD112600 BMP2Bone morphogenetic protein type 2
 Brachydactyly type A2AD11260020q11.2GDF5Growth and differentiation factor 5
 Brachydactyly type A3AD112700
 Brachydactyly type BAD1130009q22ROR2Receptor tyrosine kinase-like orphan receptor 2See also Robinow syndrome/COVESDEM
 Brachydactyly type B2AD61137717qNOGNoggin
 Brachydactyly type CAD, AR11310020q11.2GDF5Growth and differentiation factor 5See also ASPED (group 14) and other GDF5 disorders
 Brachydactyly type DAD1132002q31HOXD13Homeobox D13
 Brachydactyly type EAD11330012p11.22PTHLHParathyroid hormone-like hormone (parathyroid hormone related peptide, PTHRP)
 Brachydactyly type EAD1133002q31HOXD13Homeobox D13
 Brachydactyly—mental retardation syndromeAD6004302q37.3HDAC4Histone deacetylase 4Some patients have microdeletions involving contiguous genes (chr. 2q37 deletion syndrome)
 Hyperphosphatasia with mental retardation, brachytelephalangy, and distinct faceAR 1p36.11PIGVPhosphatidylinositol-glycan biosynthesis class V protein (GPI mannosyltransferase 2)
 Brachydactyly-hypertension syndrome (Bilginturian)AD11241012p12.2–11.2 Possibly PTHLH
 Brachydactyly with anonychia (Cooks syndrome)AD10699517q24.3SOX9 Regulatory mutations
 Microcephaly-oculo-digito-esophageal-duodenal syndrome (Feingold syndrome)AD1642802p24.1MYCNnMYC oncogene
 Hand-foot-genital syndromeAD1400007p14.2HOXA13Homeobox A13
 Brachydactyly with elbow dysplasia (Liebenberg syndrome)AD186550
 Keutel syndromeAR24515012p13.1–12.3MGPMatrix Gla protein
 Albright hereditary osteodystrophy (AHO)AD10358020q13GNAS1Guanine nucleotide binding protein of adenylate cyclase—subunitSee also polyostotic fibrous dysplasia and progressive osseous heteroplasia, group 28
 Rubinstein–Taybi syndromeAD18084916p13.3CREBBPCREB-binding protein
 Rubinstein–Taybi syndromeAD18084922q13EP300E1A-binding protein, 300-kDa
 Catel–Manzke syndromeXLR?302380
 Brachydactyly, Temtamy typeAR605282
 Christian type brachydactylyAD112450
 Coffin–Siris syndromeAR135900
 Mononen type brachydactylyXLD?301940
 Poland anomalySP173800
See also group 20 for other conditions with brachydactyly as well as brachytelephalangic CDP
38. Limb hypoplasia—reduction defects group
 Ulnar-mammary syndromeAD181450 TBX3T-box gene 3
 de Lange syndromeAD1224705p13.1NIPBLNipped-B-like
 Fanconi anemia (see note below)AR227650SeveralSeveral Several complementation groups and genes
 Thrombocytopenia-absent radius (TAR)AR?/AD?2740001q21.1Several Microdeletion on 1q21.1
 Thrombocythemia with distal limb defectsAD 3q27THPOThrombopoietinDistal limb defects postulated as consequence of vascular occlusions
 Holt–Oram syndromeAD14290012q24.1TBX5T-box gene 5
 Okihiro syndrome (Duane—radial ray anomaly)AD60732320q13SALL4SAL-like 4
 Cousin syndromeAR2606601p13TBX15T-box gene 15
 Roberts syndromeAR2683008p21.1ESCO2Homolog of establishment of cohesion—2
 Split-hand-foot malformation with long bone deficiency (SHFLD1)AD1191001q42.2–q43
 Split-hand-foot malformation with long bone deficiency (SHFLD2)AD6106856q14.1
 Split-hand-foot malformation with long bone deficiency (SHFLD3)AD61257617p13.1
 Tibial hemimeliaAR275220
 Tibial hemimelia-polysyndactyly-triphalangeal thumbAD188770
 AcheiropodiaAR2005007q36LMBR1Putative receptor proteinPartial LMBR1 deletion affecting expression of Sonic Hedgehog (SHH) gene
 Tetra-ameliaXL301090
 Tetra-ameliaAR27339517q21WNT3Wingless-type MMTV integration site family, member 3
 Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC)AD1062603q27P63 (TP63)Tumor protein p63
 Ectrodactyly-ectodermal dysplasia cleft-palate syndrome Type 3 (EEC3)AD6042923q27P63 (TP63)Tumor protein p63
 Ectrodactyly-ectodermal dysplasia cleft-palate syndrome type 1 (EEC1)AD1299007q11.2–12.3
 Ectrodactyly-ectodermal dysplasia-macular dystrophy syndrome (EEM)AR22528016q22CDH3Cadherin 3
 Limb-mammary syndrome (including ADULT syndrome)AD6032733q27P63 (TP63)Tumor protein p63
 Split hand-foot malformation, isolated form, type 4 (SHFM4)AD6052893q27P63 (TP63)Tumor protein p63
 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)AD60009510q24FBXW4Dactylin
 Split hand-foot malformation, isolated form, type 5 (SHFM5)AD6067082q31
 Al-Awadi Raas–Rothschild limb-pelvis hypoplasia–aplasiaAR2768203p25WNT7AWingless-type MMTV integration site family, member 7A
 Fuhrmann syndromeAR2289303p25WNT7AWingless-type MMTV integration site family, member 7A
 RAPADILINO syndromeAR2662808q24.3RECQL4RECQ protein-like 4
 Adams–Oliver syndromeAD/AR100300
 Femoral hypoplasia-unusual face syndrome (FHUFS)SP/AD?134780 Some phenotypic overlap with FFU syndrome (below)
 Femur-fibula-ulna syndrome (FFU)SP?228200
 Hanhart syndrome (hypoglossia–hypodactylia)AD103300
 Scapulo-iliac dysplasia (Kosenow)AD169550
Note: the particularly complex genetic basis of Fanconi anemia and its complementation groups are acknowledged but not further listed in this Nosology. The Reader is referred to MIM or to specialized reviews. See also CHILD in group 20 and the mesomelic and acromesomelic dysplasias
39. Polydactyly–Syndactyly–Triphalangism group
 Preaxial polydactyly type 1 (PPD1)AD1744007q36SHHSonic HedgehogRegulatory mutation
 Preaxial polydactyly type 1 (PPD1)AD174400 Some instances not linked to SHH
 Preaxial polydactyly type 2 (PPD2)/triphalangeal thumb (TPT)AD1745007q36SHHSonic HedgehogRegulatory mutation
 Preaxial polydactyly type 3 (PPD3)AD174600
 Preaxial polydactyly type 4 (PPD4)AD1747007p13GLI3Gli-Kruppel family member 3
 Greig cephalopolysyndactyly syndromeAD1757007p13GLI3Gli-Kruppel family member 3
 Pallister–Hall syndromeAD1465107p13GLI3Gli-Kruppel family member 3
 Synpolydactyly (complex, fibulin1—associated)AD60818022q13.3FBLN1Fibulin 1
 SynpolydactylyAD1860002q31HOXD13Homeobox D13
 Townes–Brocks syndrome (Renal-Ear-Anal-Radial syndrome)AD10748016q12.1SALL1SAL-like 1
 Lacrimo-auriculo-dento-digital syndrome (LADD)AD14973010q26.12FGFR2Fibroblast growth factor receptor 2
 Lacrimo-auriculo-dento-digital syndrome (LADD)AD1497304p16.3FGFR3Fibroblast growth factor receptor 3
 Lacrimo-auriculo-dento-digital syndrome (LADD)AD1497305p13–p12FGF10Fibroblast growth factor 10
 Acrocallosal syndromeAR2009907p13
 Acro-pectoral syndromeAD6059677q36
 Acro-pectoro-vertebral dysplasia (F-syndrome)AD1025102q36
 Mirror-image polydactyly of hands and feet (Laurin–Sandrow syndrome)AD1357507q36SHHSonic Hedgehog
 Mirror-image polydactyly of hands and feet (Laurin–Sandrow syndrome) Unlinked to SHH
 Cenani–Lenz syndactylyAR21278011p11.2LRP4Low density lipoprotein receptor-related protein 4
 Cenani–Lenz like syndactylySP (AD?) 15q13–q14GREM1, FMN1Gremlin 1, Formin 1Monoallelic duplication of both loci (observed in one case only so far)
 Oligosyndactyly, radio-ulnar synostosis, hearing loss, and renal defects syndromeSP (AR?) 15q13–q14FMN1Formin 1Deletion
 Syndactyly, Malik–Percin typeAD60943217p13.3
 STAR syndrome (syndactyly of toes, telecanthus, ano-, and renal malformations)XL300707Xq28FAM58A
 Syndactyly type 1 (III–IV)AD1859002q34–36
 Syndactyly type 3 (IV–V)AD1859006q21–23GJA1
 Syndactyly type 4 (I–V) Haas typeAD1862007q36SHHSonic Hedgehog
 Syndactyly type 5 (syndactyly with metacarpal and metatarsal fusion)AD1863002q31HOXD13
 Syndactyly with craniosynostosis (Philadelphia type)AD6012222q35–36.3
 Syndactyly with microcephaly and mental retardation (Filippi syndrome)AR272440
 Meckel syndrome type 1AR24900017q23MKS1
 Meckel syndrome type 2AR60319411q
 Meckel syndrome type 3AR6073618q21TMEM67
 Meckel syndrome type 4AR61113412qCEP290
 Meckel syndrome type 5AR61156116q12.1RPGRIP1L
 Meckel syndrome type 6AR6122844p15CC2D2A
Note: the Smith–Lemli–Opitz syndrome can present with polydactyly and/or syndactyly. See also the SRPS group
40. Defects in joint formation and synostoses
 Multiple synostoses syndrome type 1AD18650017q22NOGNoggin
 Multiple synostoses syndrome type 2AD18650020q11.2GDF5Growth and differentiation factor 5
 Multiple synostoses syndrome type 3AD61296113q11–q12FGF9
 Proximal symphalangism type 1AD18580017q22NOGNoggin
 Proximal symphalangism type 2AD18580020q11.2GDF5Growth and differentiation factor 5
 Radio-ulnar synostosis with amegakaryocytic thrombocytopeniaAD6054327p15–14.2HOXA11Homeobox A11
See also Spondylo-Carpal-Tarsal dysplasia; mesomelic dysplasia with acral synostoses; and others

The organization of groups has been further changed in comparison to the 2006 version. Two new groups based on a common affected molecule or biochemical pathway have been created (TRPV4 group and Aggrecan group). The TRPV4 group includes disorders that are relatively common and that constitute a new prototypic spectrum ranging from mild to lethal. Aggrecan is one of the important structural molecules in cartilage and it would not be surprising if more disorders would find their way into this group in the future. Thus, groups 1–8 are based on a common underlying gene or pathway.

Groups 9–17 are based on the localization of radiographic changes to specific bone structures (vertebrae, epiphyses, metaphyses, diaphysis, or combination thereof) or of the involved segment (rhizo, meso, or acro). Groups 18–20 are defined by macroscopic criteria in combination with clinical features (bent bones, slender bones, presence of multiple dislocations). Groups 21–25 and 28 take into account features of mineralization (increased or reduced bone density, impaired mineralization, stippling, osteolysis). Group 27 encompasses the large group of lysosomal disorders with skeletal involvement. Group 29 comprises disorders with so-called abnormal (previously “anarchic”) development of skeletal components such as exostoses, ecnhondromas, and ectopic calcification. It is particularly heterogeneous and may need to be revised in the future with the help of newer molecular data.

Group 23, comprising the osteopetrosis (OP) variants and related disorders, has been expanded following the identification of distinct genetic defects in various variants of osteopetrosis. The diversity of molecular mechanisms involved and the presence of clinical, biochemical and/or histologic features that distinguish between the various OP forms justify the subdivision of the “OP phenotype” in the many subtypes.

Group 25 (Osteogenesis Imperfecta and decreased bone density group) has had special attention. The Sillence classification, published 30 years ago, provided a first systematic clinical classification and made correlations to the inheritance pattern of individual clinical types [Sillence and Rimoin, 1978; Sillence et al., 1979a,b]. Today, a surprising genetic complexity of the molecular bases of OI has been revealed, and at the same time the extensive phenotypic variation arising from single loci has been documented clearly. It seemed therefore untenable to try and maintain tight correlations between “Sillence types” and their molecular basis. It was agreed upon to retain the Sillence classification as the prototypic and universally accepted way to classify the degree of severity in OI; and to free the Sillence classification from any direct molecular reference. Thus, the many genes that may cause osteogenesis imperfecta have been listed separately. The proliferation of “OI types” to reflect each gene separately, advocated by some scholars, is more confusing than helpful in clinical practice.

Group 26 has seen the identification of several novel molecular mechanisms leading to hypophosphatemic rickets.

In Group 29 (Disorganized Development of Skeletal Components), neurofibromatosis type 1 has been included following the points made by Stevenson and others that although the main clinical features of NF1 are neurologic and cutaneous, the skeletal features are frequent, diagnostically helpful and clinically relevant [Stevenson et al., 2007].

Groups 30 (Overgrowth syndromes with significant skeletal involvement) and Group 31 (Genetic inflammatory/rheumatoid-like osteoarthropathies) have been newly added. Group 30 comprises disorders that present as overgrowth syndromes and have a significant skeletal component that is part of the diagnostic criteria for a specific condition. One condition has been tentatively included because of its conspicuous skeletal features [Nishimura et al., 2004; Schmidt et al., 2007]; however this condition remains incompletely delineated. Group 31 includes disorders with features of inflammation and skeletal involvement. The creation of these two groups has been suggested by the frequent diagnostic overlap between these disorders and primary skeletal disorders as well as by the identification of the genetic basis of such disorders in recent years, allowing for a more precise delineation of the phenotypes.

Finally, groups 32–40 are dedicated to the dysostoses and follow again anatomical criteria (cranium, face, axial skeleton, extremities) with additional criteria reflecting principles of embryonic development such as limb reduction or hypoplasia (proximal-distal growth) versus terminal differentiation and patterning of the digits or joint formation. These groups have seen a marked increase in conditions with identified molecular bases and there are indications of a much larger heterogeneity yet.

A single group, the Brachyolmias (formerly group 13), has been deleted. Following the inclusion of dominant brachyolmia in the TRPV4 group, the few remaining short-trunk disorders have been incorporated in the SED group.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Why “Groups”?

The assignment of individual disorders into groups has been practiced since the first versions of the “Nomenclature.” At that time, with little biochemical or molecular information available, the grouping of disorders reflected the belief that disorders with similar phenotypic features (e.g., dysostosis multiplex) might be caused by disturbances in related metabolic pathways or gene networks (in the case of dysostosis multiplex, lysosomal degradation). This notion has been confirmed by the identification of biochemically related groups, such as those of mineralization disorders or lysosomal disorders, and of genetic families such as the collagen 2 family, the FGFR3 family, and the DTDST family. The grouping of disorders is necessary because of the sheer number of conditions included, and can be helpful in making a differential diagnosis based on the main phenotypic findings, for example, in the mesomelic dysplasias or in chondrodysplasia punctata. Some groups are still defined by common radiographic features or by anatomical site involved. Moreover, the nosology committee recognizes that some readers may disagree with our placement of a clinical entity into one group, when it may fit equally well in another group.

Which Classification Criteria to Use?

Criticism to the previous versions of the Nosology has focused on its “hybrid” nature, in the sense that it does not stick to a single systematic approach, be it clinical or molecular. This hybrid nature is intrinsic to the process of unraveling the underlying bases of skeletal diseases; disorders are classified on phenotypic similarities first, and as their molecular bases become understood they may be reclassified based on the gene or pathway that is abnormal. The first aim of the Nosology is to provide a reference list, and only secondarily to help in the diagnostic process. It must therefore coexist with other classifications that are based either on the clinical and radiographic approach to diagnosis, or the affected molecular systems and pathways. As more and more resources are published on the World Wide Web, crosslinking between classifications and databases may facilitate their simultaneous use.

Although care has been given to apply the inclusion criteria uniformly, there are disorders without proven molecular or biochemical defect for which inclusion in the Nosology as distinct entities seem somewhat arbitrary. For these disorders, discussion within the Nosology group, where individual opinions can be harmonized and, if needed, corrected by the collective expertise, is of great importance. Moreover, there are disorders listed in MIM that have not met our 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 the demonstration of a distinct molecular basis will allow for the inclusion of many of these disorders in the future, either as separate entities or as “variants” of already existing ones.

Dysplasias Versus Dysostoses

Dysostoses are disorders affecting individual bones or group of bones. In contrast to the “dysplasias,” that arise frequently from defects in structural proteins, metabolic processes or in growth plate regulation, the dysostoses often arise from embryonic morphogenic defects and are thus more closely related to multiple malformation syndromes. Since the first inclusion of dysostoses in the 2001 revision, the number of “dysostoses” included in the Nosology has grown significantly. The present revision includes an even larger number of dysostoses reflecting the advances made in identifying their molecular basis. 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 between these subspecialty areas; the group of (cranio-)frontonasal disorders and the Franck–ter Haar syndrome can be cited as examples. The MIM catalogue contains many more entries, such as multiple malformation syndromes, that have some degree of skeletal involvement. Emphasis has been given to syndromes in which the skeletal component is prominent and/or essential to the diagnosis.

OMIM and the Nosology

Because of the importance of consistency between parallel databases, the relationship between the Nosology and the OMIM database has been reviewed. The more comprehensive nature of the data collection and filing in MIM and the different nature of its revision process can lead to a divergence between the inclusion of nosologic entities and their denomination. Thus, MIM is in general more appositional, while the Nosology tries to do some “housekeeping” of entities by regrouping them and by eliminating those that have been incorporated into others. Efforts to made to harmonize the MIM and the Nosology are underway.

Outlook

The increasing availability of massive parallel sequencing and other new sequencing technologies will likely result in a rapid identification of novel disease-causing genes, but also in novel phenotypes associated with mutations in genes already linked to other phenotypes. In the near future, the catalog of skeletal phenotypes with a genetic basis may become so large as to surpass the scope of a “Nosology” as we understand it presently, and the Nosology will transform into an annotated database.

Even in that case, the many revisions of the Nosology will hopefully have paved the way by setting standards for the recognition and definition of skeletal phenotypes. Past versions of the Nosology have been translated in different languages and have found their way into textbooks of pediatrics and genetics. At present, the Nosology may help the clinician who is struggling for a diagnosis, by providing a simple listing of disorders grouped by cardinal features. The Nosology offers a quick reminder of the many differential diagnoses for one given disorder. As an expert-reviewed list of currently recognized disorders, the Nosology also constitutes a standard against which a possible “new” disorder should be compared. Finally, the Nosology offers a catalogue of genes involved in skeletal development and homeostasis that will be of interest and of inspiration to all those who are working in skeletal biology and medicine.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

M.L.W. is an Investigator with the Howard Hughes Medical Institute, and A.S.F. is supported by the Leenaards Foundation (Lausanne, Switzerland) and by the Faculté de Biologie et Medicine of the Lausanne University.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES