American Journal of Medical Genetics 44:223-229 (1992)

International Classification of Osteochondrodysplasias International Working Group on Constitutional Diseases of Bone Cape Town, P. Beighton; Zurich, A Giedwn; Minneapolis, R . Gorlin; Vancouuer, J . Hall; Houston, B . Horton; Sydney, K . Kozlowski; Los Angeles, R . Lachman; Minneapolis, L.O. Langer; Paris, P. Maroteawc; Chicago, A Poznanski; Los Angeles, D.L. Rimoin; Sidney, D . Sillence; and Mainz, J . Spranger

INTRODUCTION At a meeting of the international working group on bone dysplasias in Bad Honnef, June 26-28,1991,the 1972 Paris classification of constitutional disorders of bone’ was subjected to its 2nd revision. There are some major changes from earlier versions. First, the present classification is exclusively based on radiodiagnostic criteria, grouping morphologically similar disorders. Most members of the working group thought that this stratification would facilitate the recognition of specific entities. The former mixture of clinical, pathogenetic, and radiological criteria led to many inconsistencies and was of lesser diagnostic assistance. Clinical criteria such as age-of-onset and natural history are no longer used because of their variability and dependence on the diagnostic acumen and therapeutic activity of the observer. In spite of rapid progress in the field of biochemistry and molecular biology, etiopathogenetic knowledge was considered too fragmen-

tary to allow for a causal classification. Information on gene localization, defective proteins, and mode of inheritance is now tabulated with each entity. Second, the present classification focuses on osteochondrodysplasias, i.e., developmental disorders of chondroosseous tissue. The section on dysostoses, i.e., developmental disorders of single bones, was judged to be too rudimentary and was disregarded. A review and classification of the dysostoses is also needed, but the working group was unable to presently engage in such an immense task. Although the list of osteochondrodysplasias has been expanded considerably, it is far from complete. Private disorders reported in a single patient or family have not been listed and in practically every category; “others” should be added. Controversies regarding the individuality of some disorders such as the Beemer-Langer type of short-rib-(polydactyly) syndrome or various forms of atelosteogenesis persist and await further analysis.

TABLE I. Classification of Osteochondrodvsdasias Osteochondrodysplasias

Inherited chromosome

A. Defects of the tubular (and flat) bones andior axial skeleton Achondroplasia group Thanatophoric dysplasia AD Thanatophoric dysplasia-straight femuriclover AD leaf skull type AD Achondroplasia Hypochondroplasia AD Achondrogenesis AR 5 P e IA AR lsTpe IB Spondylodysplastic group (Perinatally lethal) San Diego type SP Torrance type SP Luton type SP

Gene

Protein

MIM

References

187.600 187.600

Langer et al., 1969 Langer et al., 1987

100.800 146.000

Langer et al., 1967 Hall and Spranger, 1979

200.600 200.600

Houston et al., 1972 Wiedemann et al., 1974

151.210 151.210 151.210

Horton e t al., 1979 Kaibara e t al., 1983 Winter and Thompson, 1982 Lazzaroni-Fossati et al., 1978 Borochowitz et al., 1986 Beck et al., 1983

Metatropic dysplasia group Fibrochondrogenesis

AR

228.520

Schneckenbecken dysplasia Metatropic dyaplasia

AR

AD

269.250 156.530 250.600

(Continued) Received for publication February 7, 1992. Address reprint requests to J. Spranger, Universitatskinderklinik, Langenbeckstrasse 1, D-6500 Mainz, Germany. International Nomenclature of Constitutional Diseases of Bone, revision May 1983. Ann Radio1 1983; pp 26-457.

0 1992 Wiley-Liss, Inc.

224

Spranger TABLE I. Classification of Osteochondrodysplasias (continued)

Osteochondrodysplasias

Inherited chromosome

5. Short rib dysplasia group (wituwithout polydactyly) SR(P) Q p e I Saldino Koonan

Gene

Rotein

MIM

References

AR

263 530

SR(P) Q p e I1 Majewski SR(P) Type 111 Verma-Naumoff SR(P) Q p e IV Beemer-Langer Asphyxiating Thoracic Dysplasia Ellis-van Creveld Dysplasia 6. Atelosteogenesid diastrophic dysplasia group Boomerang dysplasia Atelosteogenesis type 1 Atelosteogenesis type 2 (de la Chapellel Omodysplasia I (Maroteaux) Omodysplasia I1 (Borochowitz) Oto-palato-digital syndrome type 2 Diastrophic dysplasia

AR AR AR AR AR

263.520 263.510 269.860 208.500 225.500

Pseudodiastrophic dysplasia 7. Kniest-Stickler dysplasia group Dyssegmental dysplasia-Silverman Handmaker type Dyssegmental dysplasia-Rolland-Desbuquois type Kniest dysplasia Oto-spondylo-megaepiphysealdysplasia Stickler dysplasia (heterogeneous, some not linked to Col2A1) 8. Spondyloepiphyseal dysplasia congenita group Langer-Saldino Dysplasia (Achondrogenesis tMe . - 11) ~~. ~ ~

Saldino and Nonnan, 1972 Majewski et al., 1971 Naumoff et al , 1977 Beemer et al.. 1983 Jeune et al., 1955 McKusick et al., 1964

304.120 222.600

Tenconi et al., 1983 Maroteaux et a!., 1982 Whitley et a]., 1986 Maroteaux et al., 1989 Borochowitz et al., 1991 Fitch et al., 1983 Lamy and Maroteaux,

AR AR

264.180 224.410

Eteson et al.. 1986 Fasanelli et al., 1985

AR

224.400

Aleck et al.. 1987

AD AR AD

12q13.1-q13.3

CoL2A1

Q p e I1 Collagen

156.550 215.150 108.300

Kim et al., 1975 Giedion et a1 , 1982 Herrmann et al , 1975

200.610

Saldino. 1971

AD AD AD

12q13.1-q13.3 12q13.1-q13.3 12q13.1-q13.3

CoL2A1 CoL2Al CoL2A1

Qpe I1 Collagen Type I1 Collagen Q p e I1 Collagen

SP

~

108.720 256.050

2% AD AR XLR AR

~

5q31-q34

1960

Hypochondrogenesis Spondyloepiphyseal dysplasia congenita

120 140.02

120 140 02 183 900

Maroteaux et al., 1983 Spranger and Langer, 1970

120.140.01 9. Other spondylo epi-(metal.physeal)dysplasias X.linked Spondyloepiphyseal dysplasia tarda Other late onset Spondyloepi-(metal-physeal dysplasias (i.e., Namaqualand d., Irapa D.) Progressive pseudorheumatoid dysplasia Dyggve-Melchior-Clausen dysplasia Wolcott-Rallison dysplasia Immunoosseous dysplasia Pseudachondroplasia Opsismodysplasia

XLD

Xp22

313.400

SEDL

AR AR AR AR AD

208.230 223.800 226.9RO

AR

258.480

~

177.150

Maroteaux ct al., 1957 Beighton et al., 1984 Hernandez et a]., 1980 Spranger et al.. 1983 Spranger et al.. 1975 St6s et al., 19R2 Spranger et al., 1991 Marotcaux and Lamy, 1959 Maroteaux et al., 1984a, b

10. Dysostosis multiplex group

Spranger, 1987, Hopwwd and Morris's. 89 Mucopolysaccharidww Mucopolysaccharidosix Mucopolysaccharidosis Mucopolysaccharidosis 111-B 111-c

IH 1-S

1I 111-A

111-D Mucopolysaccharidosis IV-A Mucopolysaccharidosis IV-B Mucopolysaccharidosis VI Mucopolysaccharidosis VII hcosidosis a-Mannosidosis p-Mannosidosis Aspartylglucosaminuria gM1 Gangliosidosis, several forms Sialidosis. several forms Sialic storage disease Galactosialidoais, several forms Mucosulfatidosis Mucolipidosis I1 Mucolipidosis III Mucolipidosis IV 11. Spondylometaphyseal dysplasias Spondylometaphyscal dysplasia-Kozlowski t w Spondylometaphybenl dysplaaia-corner fracture type (Sutcliffe) Spondyloenchondrodysplasia 12 Epiphyseal Dysplanias Multiple cpiphyseal dysplasia Fairbankd Ribbing 13 Chondrdysplasia punclam (stippled epiphyses) group

AR AR XLR AR AR AR

4~16.3 4~16.3 Xq27.3-q28

IDA IDA IDS

AR

12q14

GNS

3p21-p14.2 5q13.3 7q21.11 lp34 1 9 ~ 1 2-ql2 3 4 4q23-qZ'i 3 ~ 2 1 . ~ 12 4 6p21 3

GLBI ARSB GUSB FUCA MANB MNB

20

NgBE

AR AR AR AR AR AR AR AR AR AR AR AR AR AR Ar AR AD AD

%l NEU

a-Iduronidase a-Iduronidase Iduronate-2-sulfatase Heparan sulfate sulfatase N-Ac-a-D-glucosaminidase Ac-CoAa-glucosaminidaseN-acetyltransferase N-Ac-glucosamine-6-sulfate sulfatase Galactnsamine-6-sulfatase P-Galactosidase Arylsulfatase B p-Glucuronidase a-Fucwidase a-Mannosidase p-Mannosidase Aspartylglucosaminidase p-Galacto%dase a-Neuraminidase NeuriGal expression protein Multiple sulfatases N-Ac-Glue-phosphotransferase N-Ac-Glue-phosphotransferase

252.800 252.800

309.900 309.900

252 940 2.10 500 253.200 253.220 230.000 248.500 248.510 208.400 230.500 256.550 269.920 256.540

272.200 252.500 252.600 252.650 271.660

-

Kozlowski et al., 1967 Langer et a]., 1990

AR

2il.550

Schorr et al , 1976

AD

132.400

Hulvcy and Keats, 1969

:continued1

Osteochondrodysplasia Classification

225

TABLE I. Classification of Osteochondrodysplasias (continued) Inherited chromosome Gene Rotein Peroxisome AR CPXD XLD Xq28 CPXR XLR Xpte~p22.32 SP

MIM 215.100 302.950 302.940

References Spranger et al., 1971 Happle, 1979 Maroteaux, 1989 Rittler et al., 1990 Happle et al., 1980 Poznanski et al., 1970 Hall et al., 1980 Maroteaux et al., 1984 a, b

AD

156.400

Schmid type Spahr type

AD AR

156.500 250.400

McKusick type (CHH) Metaphyseal anadysplasia Shwachman type Adenosine deaminase deficiency

AR

250.250 260.400 102.700

Charrow and Poznanski, 1984 Lachman et al., 1988 Spahr and Spahr-Hartmann, 1961 McKusick et al., 1965 Maroteaux et al., 1991 Shmerling et al., 1969 Cedarbaum et al., 1976

113.500 271.530

Shohat et al., 1989 Horton et al., 1983

AD AR

127.300 249.700

AD AD

163.400 180.700

Langer, 1965 Kunze and Klemm. 1980 Hess et al., 1978 Butler and Wadlingon, 1987

% AD

102.370 231.050 101.800

Osteochondrdysplasias Rhizomelic type Conradi-Hiiunermann type X-linked recessive type MT-type Others including CHILD syndrome; Zellweger syndrome; Warfarin embryopathy, chromosomal abnormalities; fetal alcohol syndrome 14. Metaphyseal dysplasias Jansen type

XLR? AR AR

-

20q13.11

ADA

15. Brachyrachia (short spine dysplasia) Brachyolmia, several types 16. Meeamelic dysplasias Dyschondmsteosis Langer type Niwergelt type Robinow type 17. Acrolacro-mesomelic dysplasias Acromicric dysplasia Geleophysic dysplasia Acrodysostosis Richo-rhino-phalangeal dysplasia type 1 Tricho-rhino-phalangeal dysplasia type 2 Saldino-Mainer dysplasia Pseudohypoparathyroidism Several types Cranioectodermal dysplasia Acromesomelic dysplasia Grebe dysplasia 18. Dysplasias with significant (but not exclusive) membraneow bone involvement Cleidocranial dysplasia Osteodysplasty, Melnick-Needles 19. Bent bone dysplasia group Campomelic dysplasia Kyphomelic dysplasia Stiive-Wiedemanndysplasia 20 Multiple dislocations with dysplasias Larsen syndrome Desbuquois syndrome Spondy lo-epi-metaphyseal dysplasia with joint laxity 21 Osteodysplastic primordial dwarfism group -1 'be 2 22. Dysplasias with decreased bone density Osteogenesis Irnperfecta(severa1types)

Maroteaw et al.. 1986 Spranger et al., 1984 Maroteaux and Malamut, 1968 Giedion et al., 1973 Langer et al., 1984 Mainzer et al., 1970 Fitch, 1982 Levine e t al.. 1988

AR AR AR

190.350 150.230 266.920 103.580 139.320 203.330 300.800 218.330 20 1.250 200.700

AD XLD

119.600 309.350

Jensen, 1990 Melnick and Needles, 1966

211.970 211.350

Houston et al., 1983 Hall and Spranger, 1979 Stiive and Wiedemann, 1971

AD AR AR

150.250 215.200 271.640

Larsen et al., 1950 Le Merrer et al., 1991 Beighton and Kozlowski, 1980

AR

210.710

Majewski and Spranger, 1976 Majewski et al., 1982 Sillence et al., 1979

AD 8q24.12 AD 8q24.11-824.13 AR AD AR? XLD?

CMDl

AR AR AR

AR AD AD

TQPSl TQPS2

-

17q21.31q22.05 CoLlAl 7q21.3-q22.1 CollA2

Collagen type I Collagen type I

AR Osteoporosis with pseudoglioma Idiopathic juvenile osteoporosis

AR SP

Bruck syndrome Homocystinuria Singleton-Merten syndrome

AR AR SP

21q22.3

CBS

AR XLR

Xq12-ql3

MNK

AD

1~36.1~34

ALPL alkaline phosphatase

Geroderma osteodysplastica Menkes syndrome 23. Dysplasias with defective mineralization Hypophosphatasia

-

Hypophosphatemic rickets Pseudodeficiency rickets, several types

XR AR

Neonatal hyperparathyroidism

AR

Cystathionine-p-synthase

Levin et al., 1977 Langer et al., 1977 Grebe. 1952

210.720 120.150 120.160 166.210-60 259.110 259.420 Frontali et al., 1985 259.770 Dent and Friedman, 259.750 1965 Viljoen et al., 1989 259.450 Mudd et al., 1985 236.200 Singleton and Merten, 182.250 1973 Hunter e t al., 1978 231.070 Menkes, 1988 309.400 146.300 171.760 241.500 241.510 370.800 264.700 277.420 277.440 239.200

Machler et al., 1986

Liberman et al., 1983 Barsony et al., 1989 Spiegel et al., 1977 (continued)

226

Spranger TABLE I. Classification of Osteochondrodysplasias (continued)

Osteochondrodysplasias

Inherited chromosome

24. Dysplasias with increased bone density Osteopetrosis a) precocious type b) delayed type c) intermediate type d) with renal tubular acidosis Dysosteosclerosis Pycnodysostosis

AR AD AR AR AR AR

8q22

Gene

Protein

CA2 Carbonic anhydrase I1

MIM

References -.

259.700 166.600 259.710 259.730 224.300 265.800

Loria-Cortes et al., 1977 Johnston et al., 1968 Kahler e t al., 1984 Sly et al., 1985 Spranger et al., 1968 Maroteaux and Lamy, 1962 Dipieri and Gutman, 1984

AD

122.900

Axial osteosclerosis including a) Osteomesopycnosis b) with Bamboo hair (Netherton syndrome) c) Tricho-thiodystrophy Osteopoikilosis Melorheostosis Osteopathia Striata Osteopathia Striata with cranial sclerosis

AD AR AR AD SP SP AD

166.450 256.500 242.170 166.700 155.950

Diaphyseal dysplasia, Camurati-Engelmann

AD

1311.300

AD

122.860 218.300 151.050

Osteosclerosi&tanescu

type

Craniodiaphyseal dysplasia

-

166.500

AR

Leu-Majewski dysplasia

SP

Craniometadiaphyseal dysplasia Endosteal hyperostoses a) van Buchem disease b) Sclerosteosis c) Worth disease d) with cerebellar hypoplasia Pachydermoperiostosis Fronto-metaphyseal dysplasia Craniornetaphyseal dysplasia a) severe type

SP

-

AR AR AD AR AD XLR

167.100 305.620

239.100 269.500 144.750 -

AR

2 18.400

b) mild type Pyle (disease) dysplasia Osteoectasia with hyperphosphatasia Oculo-dento-osseous dysplasia a) severe type

AD AR AR

123.000 265.900 239.000

AR

257.850

b) mild type

AD

164.200

van Buchem et al., 1962 Beighton, 1988 Worth and Wollin, 1966 Charrow et al., 1991 Rimoin, 1965 Gorlin and Winter, 1980 Penchaszadeh et al., 1980 Holt, 1966 Beiehton. 1987 Fanconi et al., 1964

114.000

Traboulsi and Faris, 1986 Patton and Laurence, 1985 MacLachlan et al., 1984

127.800 133.700 166.000 166.000

Wiedemann e t al., 1981 Shapiro et al., 1979 Mainzer et al., 1971 Loewinger et al., 1977

156.250 166.250 174.800

Maroteaux, 1971 Beighton, 1989 Firat and Stutzman, 1968

AD AR

118.400 228.550

Peters, 1979 Modi. 1982

AD

102.400 102.500

Spranger et al., 1974 Udell et al., 1986

AD AR

166.300 221.800

Carnevale et al., 1987 Caputo el al., 1988

AR AR

AR

277.950 259.600 248.370

Winchester et al., 1969 Torg et al.. 1969 Tenconi et al., 1986

AD

174.810

Osterberg et al., 1988

AD Familial Infantile Cortical HyperostosisCaffey B. Disorganized development of cartilagenous and fibrous components of the skeleton Dysplasia epiphysealis hemimelica SP AD 8q23-q24.1 Multiple cartilaginous exostoses Enchondromatosis (Ollier) SP Enchondromatosis with hemangiomata SP (Maffucci) Metachondromatosis AD Osteoglophonic dysplasia SP Fibrous dysplasia (Jaffe-Lichtenstein) SP Fibrous dysplasia with pigmentary skin changes and precocious puberty (McCuneAlbright) Cherubism Myofibromatosis (generalized fibrornatosis) C. Idiopathic osteolyses 1. Predominantly phalangeal Hereditary acroosteolysis, several forms Hajdu-Cheney type 2. Predominantly carpalitarsal Carpal-tarsal osteolysis with nephropathy Francois Syndrome (dermo-chondro-corneal dystrophy) 3. Multicentric Winchester syndrome Torg type Mandibulo-acral dysplasia 4. Other Familial exuansile osteolvsis

Maroteaux, 1980 Porter and Starke, 1968 Happle et al., 1984 Melnick, 1959 Campbell et al., 1968 Gehweiler et al., 1973 Horan and Beighton, 1978 Sparkes and Graham. 1972 Schaefer et al., 1986 'hcker et al., 1976 Gorlin and Whitley, 1983 Langer et al., 1991

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