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Page 1: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

RESEARCH ARTICLE

Nosology and Classification of Genetic SkeletalDisorders: 2010 RevisionMatthew L. Warman,1 Valerie Cormier-Daire,2 Christine Hall,3 Deborah Krakow,4,5 Ralph Lachman,4

Martine LeMerrer,2 Geert Mortier,6 Stefan Mundlos,7 Gen Nishimura,8 David L. Rimoin,4

Stephen Robertson,9 Ravi Savarirayan,10 David Sillence,11 Juergen Spranger,12 Sheila Unger,12,13

Bernhard Zabel,12 and Andrea Superti-Furga12,14*1Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, The Howard Hughes Medical Institute, Children’s Hospital, Boston,

Massachusetts2Department of Genetics and INSERM U781, Paris Descartes University, Hopital Necker Enfants Malades, Paris, France3Institute of Child Health, University of London, London, UK4Medical Genetics Institute, Steven Spielberg Building, Cedars-Sinai Medical Center, Los Angeles, California5Departments of Orthopaedic Surgery and Human Genetics, UCLA, Los Angeles, California6Department of Medical Genetics, University Hospital of Antwerp, University of Antwerp, Edegem, Belgium7Institut f€ur Medizinische Genetik, Charit�e Universit€atsmedizin Berlin, Max-Planck-Institut f€ur Molekulare Genetik, Berlin, Germany8Department of Pediatric Imaging, Tokyo Metropolitan Children’s Medical Center, Fuchu, Tokyo, Japan9Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand10Murdoch Children’s Research Institute, Royal Children’s Hospital, Department of Paediatrics, University of Melbourne, Victoria, Australia11Discipline of Genetic Medicine, The Children’s Hospital at Westmead Clinical School, The University of Sydney, Westmead, Australia12Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, University of Freiburg, Freiburg, Germany13Medical Genetics Service, University of Lausanne, CHUV—Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland14Department of Pediatrics, University of Lausanne, CHUV—Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Received 16 December 2010; Accepted 30 December 2010

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 disor-

ders, and in building bridges between clinicians and scientists

interested in skeletal biology. In the 2010 revision, 456 condi-

tions were included and placed in 40 groups defined by molecu-

lar, 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 muta-

tions to ‘‘private’’ found in single families or individuals. Thus,

the Nosology is a hybrid between a list of clinically defined

The 9th ISDS meeting and the Nosology workshop were held in Boston in

July 2009 and supported by The Manton Center for Orphan Disease

Research, Children’s Hospital, Boston, Massachusetts; Children’s

Orthopaedic Surgery Foundation, Inc., Boston, Massachusetts; The

Osteogenesis Imperfecta Foundation, Gaithersburg, Maryland;

Biomarin, Novato, California; and Enobia Pharma, Montreal, Quebec,

Canada. The 2010 Nosology tables are available online at the International

Skeletal Dysplasia Society web site (www.isds.ch).

*Correspondence to:

Andrea Superti-Furga, Centre Hospitalier Universitaire Vaudois (CHUV),

Av. Decker, 2, 1011 Lausanne, Switzerland. E-mail: [email protected]

Published online 15 March 2011 in Wiley Online Library

(wileyonlinelibrary.com).

DOI 10.1002/ajmg.a.33909

How to Cite this Article:Warman ML, Cormier-Daire V, Hall C,

Krakow D, Lachman R, LeMerrer M, Mortier

G, Mundlos S, Nishimura G, Rimoin DL,

Robertson S, Savarirayan R, Sillence D,

Spranger J, Unger S, Zabel B, Superti-Furga A.

2011. Nosology and classification of genetic

skeletal disorders: 2010 revision.

Am J Med Genet Part A 155:943–968.

� 2011 Wiley-Liss, Inc. 943

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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 se-

quencing technologies; in the delineation of clinical entities and

novel disorders, by providing an overview of established noso-

logic entities; and for scientists looking for the clinical correlates

of genes, proteins and pathways involved in skeletal biology.

� 2011 Wiley-Liss, Inc.

Key words: skeletal genetics; osteochondrodysplasias; nosology;

dysostoses; molecular basis of disease

INTRODUCTION

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

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 defini-

tion of skeletal dysplasias, metabolic bone disorders, dysos-

toses, 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 anal-

ysis and/or by the presence of distinctive diagnostic features

and of observation in multiple individuals or families.

RESULTS

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.

The organization of groups has been further changed in com-

parison 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, meta-

physes, 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’’) devel-

opment 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, pub-

lished 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 refer-

ence. Thus, the many genes that may cause osteogenesis imperfecta

have been listed separately. The proliferation of ‘‘OI types’’ to reflect

944 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

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WARMAN ET AL. 945

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946 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

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Fila

min

BSp

ondy

lo-c

arp

al-t

arsa

ldy

spla

sia

AR2

72

46

0U

nlin

ked

toFL

NB

Fran

ck–

ter

Haa

rsy

ndr

ome

AR2

49

42

05

q35

.1SH

3PX

D2

BTK

S4Se

rpen

tin

efi

bula

—po

lycy

stic

kidn

eysy

ndr

ome

AD?

60

03

30

See

also

grou

p4

for

rece

ssiv

eLa

rsen

synd

rom

ean

dgr

oup

26

for

cond

itio

nsw

ith

mul

tipl

edi

sloc

atio

ns8

.TR

PV4

grou

pM

etat

ropi

cdy

spla

sia

AD1

56

53

01

2q2

4.1

TRPV

4Tr

ansi

ent

rece

pto

rpo

ten

tial

cati

onch

ann

el,

subf

amily

V,m

emb

er4

Incl

ud

esle

thal

and

non

-leth

alfo

rms

Spon

dylo

epim

etap

hyse

aldy

spla

sia,

Mar

otea

uxty

pe(P

seud

o–M

orqu

iosy

ndr

ome

type

2)

AD1

84

09

51

2q2

4.1

TRPV

4Tr

ansi

ent

rece

pto

rpo

ten

tial

cati

onch

ann

el,

subf

amily

V,m

emb

er4

Spon

dylo

met

aphy

seal

dysp

lasi

a,K

ozlo

wsk

ity

peAD

18

42

52

12

q24

.1TR

PV4

Tran

sien

tre

cep

tor

pote

nti

alca

tion

chan

nel

,su

bfam

ilyV,

mem

ber

4B

rach

yolm

ia,

auto

som

aldo

min

ant

type

AD1

13

50

01

2q2

4.1

TRPV

4Tr

ansi

ent

rece

pto

rpo

ten

tial

cati

onch

ann

el,

subf

amily

V,m

emb

er4

Fam

ilial

digi

tal

arth

ropa

thy

wit

hbr

achy

dact

yly

AD6

06

83

51

2q2

4.1

TRPV

4Tr

ansi

ent

rece

pto

rpo

ten

tial

cati

onch

ann

el,

subf

amily

V,m

emb

er4

9.

Shor

t-ri

bsdy

spla

sias

(wit

hor

wit

hout

poly

dact

yly)

grou

pCh

ondr

oect

oder

mal

dysp

lasi

a(E

llis–

van

Crev

eld)

AR2

25

50

04

p16

EVC1

EvC

gen

e1

4p1

6EV

C2Ev

Cge

ne

2Sh

ort

rib—

poly

dact

yly

syn

drom

e(S

RPS

)ty

pe1

/3(S

aldi

no-

Noo

nan

/Ve

rma-

Nau

mof

f)

AR2

63

51

01

1q2

2.3

DYN

C2H

1D

ynei

n,

cyto

pla

smic

2,

heav

ych

ain

1

SRPS

type

1/3

(Sal

din

o-N

oon

an/

Verm

a-N

aum

off)

AR2

63

51

03

q25

.33

IFT8

0In

trafl

agel

lar

tran

spor

t8

0(h

omol

ogof

)SR

PSty

pe1

/3(S

aldi

no-

Noo

nan

/Ve

rma-

Nau

mof

f)AR

26

35

10

Un

linke

dto

eith

erD

YNC2

H1

orIF

T80

SRPS

type

2(M

ajew

ski)

AR2

63

52

0N

EK1

Nim

are

late

dki

nas

e1

(Continued)

WARMAN ET AL. 947

Page 6: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

SRPS

type

4(B

eem

er)

AR2

69

86

0O

ral-f

acia

l-dig

ital

syn

drom

ety

pe4

(Moh

r–M

ajew

ski)

AR2

58

86

0

Asph

yxia

tin

gth

orac

icdy

spla

sia

(ATD

;Je

une)

AR2

08

50

03

q25

.33

IFT8

0In

trafl

agel

lar

tran

spor

t8

0(h

omol

ogof

)As

phyx

iati

ng

thor

acic

dysp

lasi

a(A

TD;

Jeun

e)AR

20

85

00

11

q22

.3D

YNC2

H1

Dyn

ein

,cy

top

lasm

ic2

,he

avy

chai

n1

Asph

yxia

tin

gth

orac

icdy

spla

sia

(ATD

;Je

une)

AR2

08

50

0U

nlin

ked

toei

ther

DYN

C2H

1or

IFT8

0Th

orac

olar

yngo

pelv

icdy

spla

sia

(Bar

nes

)AD

18

77

60

See

also

pate

rnal

UPD

14

and

cere

bro-

cost

o-m

andi

bula

rsy

ndro

me

10

.M

ulti

ple

epip

hyse

aldy

spla

sia

and

pseu

doac

hon

drop

lasi

agr

oup

Pseu

doac

hon

drop

lasi

a(P

SACH

)AD

17

71

70

19

p12–

13

.1CO

MP

COM

PM

ulti

ple

epip

hyse

aldy

spla

sia

(MED

)ty

pe1

(ED

M1

)AD

13

24

00

19

p13

.1CO

MP

COM

P

Mul

tipl

eep

iphy

seal

dysp

lasi

a(M

ED)

type

2(E

DM

2)

AD6

00

20

41

p32

.2–

33

COL9

A2Co

llage

n9

alp

ha-

2ch

ain

Mul

tipl

eep

iphy

seal

dysp

lasi

a(M

ED)

type

3(E

DM

3)

AD6

00

96

92

0q1

3.3

COL9

A3Co

llage

n9

alp

ha-

3ch

ain

Mul

tipl

eep

iphy

seal

dysp

lasi

a(M

ED)

type

5(E

DM

5)

AD6

07

07

82

p23–

24

MAT

N3

Mat

rilin

3

Mul

tipl

eep

iphy

seal

dysp

lasi

a(M

ED)

type

6(E

DM

6)

AD1

20

21

06

q13

COL9

A1Co

llage

n9

alp

ha-

1ch

ain

Mul

tipl

eep

iphy

seal

dysp

lasi

a(M

ED),

othe

rty

pes

Som

eM

ED

-like

case

su

nlin

ked

tokn

own

gen

esSt

ickl

ersy

ndr

ome,

rece

ssiv

ety

peAR

12

02

10

6q1

3CO

L9A1

Colla

gen

9al

ph

a-1

chai

nFa

mili

alhi

pdy

spla

sia

(Beu

kes)

AD1

42

66

94

q35

Mul

tipl

eep

iphy

seal

dysp

lasi

aw

ith

mic

roce

phal

yan

dn

ysta

gmus

(Low

ry-W

ood)

AR2

26

96

0

See

also

mul

tipl

eep

iphy

seal

dysp

lasi

a,re

cess

ive

type

(rM

ED;E

DM

4)

insu

lfati

ondi

sord

ers

(gro

up4

),fa

mili

alos

teoc

hond

riti

sdi

ssec

ans

inth

eag

grec

angr

oup,

asw

ella

sAS

PED

inth

eAc

rom

elic

grou

p1

1.

Met

aphy

seal

dysp

lasi

asM

etap

hyse

aldy

spla

sia,

Schm

idty

pe(M

CS)

AD1

56

50

06

q21–

22

.3CO

L10

A1Co

llage

n1

0al

ph

a-1

chai

n

Cart

ilage

-hai

rhy

popl

asia

(CH

H;

met

aphy

seal

dysp

lasi

a,M

cKus

ick

type

)

AR2

50

25

09

p13

RM

RP

RN

Aco

mpo

nen

tof

RN

Ase

HIn

clu

des

anau

xeti

cd

ysp

lasi

a

Met

aphy

seal

dysp

lasi

a,Ja

nse

nty

peAD

15

64

00

3p2

2–

21

.1PT

HR

1PT

H/P

THrP

rece

pto

r1

Acti

vati

ng

mu

tati

ons—

see

also

Blo

mst

ran

dd

ysp

lasi

a(g

rou

p2

2,

23

)Ei

ken

dysp

lasi

aAR

60

00

02

3p2

2–

21

.1PT

HR

1PT

H/P

THrP

rece

pto

r1

Acti

vati

ng

mu

tati

ons—

see

also

Blo

mst

ran

dd

ysp

lasi

a(g

rou

p2

2,

23

)

TAB

LEI(

Con

tin

ued)

Gro

up/n

ame

ofdi

sord

erIn

heri

tan

ceM

IMN

o.Lo

cus

Gen

ePr

otei

nN

otes

948 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Page 7: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Met

aphy

seal

dysp

lasi

aw

ith

pan

crea

tic

insu

ffici

ency

and

cycl

icn

eutr

open

ia(S

hwac

hman

–B

odia

n–

Dia

mon

dsy

ndr

ome,

SBD

S)

AR2

60

40

07

q11

SBD

SSB

DS

prot

ein

Met

aphy

seal

anad

yspl

asia

type

1AD

,AR

30

96

45

11

q22

.2M

MP1

3M

atri

xm

etal

lopr

otei

nas

e1

3In

clu

des

SEM

DM

isso

uri

typ

e.B

oth

dom

inan

tan

dre

cess

ive

mu

tati

ons

des

crib

edM

etap

hyse

alan

adys

plas

iaty

pe2

AR2

0q1

3.1

2M

MP9

Mat

rix

met

allo

prot

ein

ase

9M

etap

hyse

aldy

spla

sia,

Spah

rty

peAR

25

04

00

Met

aphy

seal

acro

scyp

hody

spla

sia

(var

ious

type

s)AR

25

02

15

Gen

ocho

ndr

omat

osis

(typ

e1

/typ

e2

)AD

/SP

13

73

60

Met

aphy

seal

chon

drom

atos

isw

ith

D-2

-hyd

roxy

glut

aric

acid

uria

AR/S

PSe

e2

71

55

01

2.

Spon

dylo

met

aph

ysea

ldy

spla

sias

(SM

D)

Spon

dylo

ench

ond

rody

spla

sia

(SPE

NCD

)AR

27

15

50

19

p13

.2AC

P5Ta

rtra

te-r

esis

tan

tac

idph

osp

hat

ase

(TR

AP)

Incl

ud

esco

mb

ined

imm

un

odefi

cien

cyw

ith

auto

imm

un

ity

and

spon

dy

lom

etap

hy

seal

dy

spla

sia

(MIM

60

79

44

)O

don

toch

ondr

odys

plas

ia(O

DCD

)AR

18

42

60

Spon

dylo

met

aphy

seal

dysp

lasi

a,Su

tclif

fety

peor

corn

erfr

actu

res

type

AD1

84

25

5

SMD

wit

hse

vere

gen

uva

lgum

AD1

84

25

3In

clu

des

SMD

Sch

mid

tty

pe

and

SMD

Alge

rian

typ

eSM

Dw

ith

con

e-ro

ddy

stro

phy

AR6

08

94

0SM

Dw

ith

reti

nal

dege

ner

atio

n,

axia

lty

peAR

60

22

71

Dys

spon

dylo

ench

ondr

omat

osis

SPCh

eiro

-spo

ndy

loen

chon

drom

atos

isSP

See

also

grou

p2

9Se

eal

soSM

DK

ozlo

wsk

i(gr

oup

TRPV

4)

diso

rder

sin

grou

p1

1as

wel

las

SMD

Seda

ghat

ian

type

ingr

oup

12

;the

rear

em

any

indi

vidu

alre

port

sof

SMD

vari

ants

13

.Sp

ondy

lo-e

pi-(

met

a)-p

hyse

aldy

spla

sias

(SE(

M)D

)D

yggv

e–M

elch

ior–

Clau

sen

dysp

lasi

a(D

MC)

AR2

23

80

01

8q1

2–

21

.1D

YMD

ymec

linIn

clu

des

Smit

h–

McC

ort

dy

spla

sia

Imm

uno-

osse

ous

dysp

lasi

a(S

chim

ke)

AR2

42

90

02

q34–

36

SMAR

CAL1

SWI/

SNF-

rela

ted

regu

lato

rof

chro

mat

insu

bfa

mily

A-lik

epr

otei

n1

SED

,W

olco

tt–

Ral

lison

type

AR2

26

98

02

p12

EIF2

AK3

Tran

slat

ion

init

iati

onfa

ctor

2-a

lpha

kin

ase-

3SE

MD

,M

atri

linty

peAR

60

87

28

2p2

3–

p24

MAT

N3

Mat

rilin

3Se

eal

som

atri

lin-r

elat

edM

ED

ingr

oup

8SE

MD

,sh

ort

limb—

abn

orm

alca

lcifi

cati

onty

peAR

27

16

65

1q2

3D

DR

2D

isco

idin

dom

ain

rece

pto

rfa

mily

,m

emb

er2

See

also

oth

erd

ysp

lasi

asw

ith

stip

plin

gin

grou

p2

0SE

Dta

rda,

X-lin

ked

(SED

-XL)

XLR

31

34

00

Xp2

2SE

DL

Sedl

inSp

ondy

lo-m

egae

piph

ysea

l-m

etap

hyse

aldy

spla

sia

(SM

MD

)AR

61

33

30

4p1

6.1

NK

X3-2

NK

3H

omeo

box

2

(Continued)

WARMAN ET AL. 949

Page 8: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Spon

dylo

dysp

last

icEh

lers

–D

anlo

ssy

ndr

ome

AR6

12

35

01

1p1

1.2

SLC3

9A1

3Zi

nc

tran

spor

ter

ZIP

13

SPO

NAS

TRIM

Edy

spla

sia

AR2

71

51

0SE

MD

wit

hjo

int

laxi

ty(S

EMD

-JL)

lept

odac

tylic

orH

all

type

AD6

03

54

6

SEM

Dw

ith

join

tla

xity

(SEM

D-J

L)B

eigh

ton

type

AR2

71

64

0

Plat

yspo

ndy

ly(b

rach

yolm

ia)

wit

ham

elog

enes

isim

perf

ecta

AR6

01

21

6

Late

onse

tSE

D,

auto

som

alre

cess

ive

type

AR6

09

22

3

Bra

chyo

lmia

,H

obae

k,an

dTo

ledo

type

sAR

27

15

30

,2

71

63

0N

osol

ogic

rela

tion

ship

bet

wee

nth

eTo

lead

oan

dH

obae

kty

pes

ofb

rach

yol

mia

and

rece

ssiv

ela

te-o

nse

tSE

Dar

eu

ncl

ear,

dis

tin

ctiv

ecr

iter

iala

ckin

gso

far

See

also

Bra

chyo

lmia

(gro

up8

),O

psis

mod

yspl

asia

(gro

up1

4),

SEM

Ds

(gro

up1

1),

muc

opol

ysac

char

idos

isty

pe4

(Mor

quio

synd

rom

e)an

dot

her

cond

itio

nsin

grou

p2

6,

asw

ell

asPP

RD

(SED

wit

hpr

ogre

ssiv

ear

thro

path

y)in

grou

p3

11

4.

Seve

resp

ondy

lody

spla

stic

dysp

lasi

asAc

hon

drog

enes

isty

pe1

A(A

CG1

A)AR

20

06

00

14

q32

.12

TRIP

11

Gol

gi-m

icro

tub

ule

-ass

ocia

ted

prot

ein

,2

10

-kD

a;G

MAP

21

0Sc

hnec

ken

beck

endy

spla

sia

AR2

69

25

01

p31

.3SL

C35

D1

Solu

teca

rrie

rfa

mily

35

mem

ber

D1

;U

DP-

glu

curo

nic

acid

/U

DP-

N-a

cety

lgal

acto

sam

ine

dual

tran

spor

ter

Spon

dylo

met

aphy

seal

dysp

lasi

a,Se

dagh

atia

nty

peAR

25

02

20

Seve

resp

ondy

lom

etap

hyse

aldy

spla

sia

(SM

DSe

dagh

atia

n-l

ike)

AR7

q11

SBD

SSB

DS

gen

e,fu

nct

ion

still

uncl

ear

Ops

ism

odys

plas

iaAR

25

84

80

See

also

Than

atop

hori

cdy

spla

sia,

type

s1

and

2(g

roup

1);

ACG

2an

dTo

rran

cedy

spla

sia

(gro

up2

);Fi

broc

hond

roge

nesi

s(g

roup

3);

Acho

ndro

gene

sis

type

1B

(ACG

1B

,gro

up4

);an

dM

etat

ropi

cdy

spla

sia

(TR

PV4

grou

p)1

5.

Acro

mel

icdy

spla

sias

Tric

horh

inop

hala

nge

aldy

spla

sia

type

s1

/3AD

19

03

50

8q2

4TR

PS1

Zin

cfi

nge

rtr

ansc

ript

ion

fact

orTr

icho

rhin

opha

lan

geal

dysp

lasi

aty

pe2

(Lan

ger–

Gie

dion

)AD

15

02

30

8q2

4TR

PS1

and

EXT1

Zin

cfi

nge

rtr

ansc

rip

tion

fact

oran

dE

xost

osin

1M

icro

del

etio

nsy

nd

rom

e;se

eal

soM

ult

iple

Cart

ilagi

neo

us

Exo

stos

esin

grou

p2

8Ac

roca

pito

fem

oral

dysp

lasi

aAR

60

77

78

2q3

3–

q35

IHH

Indi

anhe

dgeh

ogCr

anio

ecto

derm

aldy

spla

sia

(Lev

in–

Sen

sen

bren

ner

)ty

pe1

AR2

18

33

03

q21

IFT1

22

Intr

aflag

ella

rtr

ansp

ort

12

2(C

hlam

yd

omon

as,

hom

olog

of)

Cran

ioec

tode

rmal

dysp

lasi

a(L

evin

–Se

nse

nbr

enn

er)

type

2AR

61

36

10

2p2

4.1

WD

R3

5W

Dre

peat

-con

tain

ing

prot

ein

35

TAB

LEI(

Con

tin

ued)

Gro

up/n

ame

ofdi

sord

erIn

heri

tan

ceM

IMN

o.Lo

cus

Gen

ePr

otei

nN

otes

950 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Page 9: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Gel

eoph

ysic

dysp

lasi

aAR

23

10

50

9q3

4.2

ADAM

TSL2

ADAM

TS-li

kep

rote

in2

Gel

eoph

ysic

dysp

lasi

a,ot

her

type

sAR

Un

linke

dto

ADAM

TSL2

Acro

mic

ric

dysp

lasi

aAD

10

23

70

Incl

ud

esac

rola

ryn

geal

dy

spla

sia,

pre

viou

sly

know

nas

Fan

tasy

Isla

nd

dy

spla

sia

orTa

ttoo

dy

spla

sia

Acro

dyso

stos

isAD

10

18

00

Ange

l-sha

ped

phal

ango

-epi

phys

eal

dysp

lasi

a(A

SPED

)AD

10

58

35

Pos

sib

lyre

late

dor

alle

licto

Bra

chy

dac

tyly

typ

eC

Sald

ino–

Mai

nze

rdy

spla

sia

AR2

66

92

0Se

eal

sosh

ort

rib

dysp

lasi

asgr

oup

16

.Ac

rom

esom

elic

dysp

lasi

asAc

rom

esom

elic

dysp

lasi

aty

peM

arot

eaux

(AM

DM

)AR

60

28

75

9p1

3–

12

NPR

2N

atri

uret

icp

epti

de

rece

ptor

2G

rebe

dysp

lasi

aAR

20

07

00

20

q11

.2G

DF5

Gro

wth

and

diff

eren

tiat

ion

fact

or5

Incl

ud

esac

rom

esom

elic

dy

spla

sia

Hu

nte

r-Th

omp

son

typ

e;se

eal

soB

rach

yd

acty

lies

(gro

up

34

)Fi

bula

rhy

popl

asia

and

com

plex

brac

hyda

ctyl

y(D

uPa

n)

AR2

28

90

02

0q1

1.2

GD

F5G

row

than

dd

iffer

enti

atio

nfa

ctor

5Se

eal

soB

rach

yd

acty

lies

(gro

up

34

)Ac

rom

esom

elic

dysp

lasi

aw

ith

gen

ital

anom

alie

sAR

60

94

41

4q2

3–

24

BM

PR1

BB

one

mor

phog

enet

icpr

otei

nre

cep

tor

1B

Acro

mes

omel

icdy

spla

sia,

Ose

bold

-Rem

ondi

ni

type

AD1

12

91

0

17

.M

esom

elic

and

rhiz

o-m

esom

elic

dysp

lasi

asD

ysch

ondr

oste

osis

(Ler

i–W

eill)

Pseu

do-A

D1

27

30

0Xp

ter-

p22

.32

SHO

XSh

ort

stat

ure—

hom

eob

oxge

ne

Incl

ud

esR

ein

har

dt–

Pfe

iffer

dy

spla

sia,

MIM

19

14

00

Lan

ger

type

(hom

ozyg

ous

dysc

hon

dros

teos

is)

Pseu

do-A

R2

49

70

0Xp

ter-

p22

.32

SHO

XSh

ort

stat

ure—

hom

eob

oxge

ne

Om

odys

plas

iaAR

25

83

15

13

q31–

q32

GPC

6G

lypi

can

6E

xist

ence

of‘‘d

omin

ant

omod

ysp

lasi

a’’(

MIM

16

47

45

)re

mai

ns

tob

eco

nfi

rmed

Rob

inow

syn

drom

e,re

cess

ive

type

AR2

68

31

09

q22

RO

R2

Rec

epto

rty

rosi

ne

kin

ase-

like

orph

anre

cep

tor

2In

clu

des

pre

viou

sco

sto-

vert

ebra

lseg

men

tati

ond

efec

tw

ith

mes

omel

ia(C

OVE

SDE

M);

see

also

bra

chy

dac

tyly

typ

eB

Rob

inow

syn

drom

e,do

min

ant

type

AD1

80

70

0M

esom

elic

dysp

lasi

a,K

orea

nty

peAD

2q2

4–

32

Dup

licat

ion

inH

OXD

gen

ecl

ust

erM

esom

elic

dysp

lasi

a,K

anta

putr

aty

peAD

15

62

32

2q2

4–

32

Dup

licat

ion

sin

HO

XDge

ne

clu

ster

Mes

omel

icdy

spla

sia,

Nie

verg

elt

type

AD1

63

40

0M

esom

elic

dysp

lasi

a,K

ozlo

wsk

i-Rea

rdon

type

AR2

49

71

0

Mes

omel

icdy

spla

sia

wit

hac

ral

syn

osto

ses

(Ver

loes

–D

avid

–Pf

eiff

erty

pe)

AD6

00

38

38

q13

SULF

1an

dSL

CO5

A1H

epar

ansu

lfate

6-O

-en

dosu

lfata

se1

and

solu

teca

rrie

ror

gan

ican

ion

tran

s-po

rter

fam

ilym

emb

er5

A1

Mic

rod

elet

ion

syn

dro

me

invo

lvin

gtw

oad

jace

nt

gen

es

(Continued)

WARMAN ET AL. 951

Page 10: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Mes

omel

icdy

spla

sia,

Sava

rira

yan

type

(Tri

angu

lar

Tibi

a–Fi

bula

rAp

lasi

a)SP

60

52

74

Pos

sib

lyre

late

dto

Nie

verg

elt

dy

spla

sia.

On

eca

sere

por

ted

wit

h2

q1

1.2

mic

rod

elet

ion

ofu

ncl

ear

sign

ifica

nce

18

.B

ent

bon

esdy

spla

sias

Cam

pom

elic

dysp

lasi

a(C

D)

AD1

14

29

01

7q2

4.3

–2

5.1

SOX9

SRY-

box

9In

clu

des

acam

pom

elic

cam

pom

elic

dy

spla

sia

(ACD

)as

wel

las

mild

cam

pom

elic

dy

spla

sia

(MIM

60

21

96

)St€ uv

e–W

iede

man

ndy

spla

sia

AR6

01

55

95

p13

.1LI

FRLe

ukem

iain

hib

itor

yfa

ctor

rece

pto

rIn

clu

des

form

erly

neo

nat

alSc

hw

artz

–Ja

mp

elsy

nd

rom

eor

SJS

typ

e2

Kyp

hom

elic

dysp

lasi

a,se

vera

lfo

rms

21

13

50

Pro

bab

lyh

eter

ogen

eou

sB

ent

bone

sat

birt

hca

nbe

seen

ina

vari

ety

ofco

ndit

ions

,in

clud

ing

oste

ogen

esis

impe

rfec

ta,

Antl

ey–

Bix

ler

synd

rom

e,ca

rtila

ge-h

air

hypo

plas

ia,

Cum

min

gssy

ndro

me,

hypo

phos

phat

asia

,dy

sseg

men

tal

dysp

lasi

a,TD

,ATD

,and

othe

rs1

9.

Slen

der

bon

edy

spla

sia

grou

p3

-Msy

ndr

ome

(3M

1)

AR2

73

75

06

p21

.1CU

L7Cu

llin

7In

clu

des

dol

ich

osp

ond

ylic

dy

spla

sia

and

Yaku

tsh

ort

stat

ure

syn

dro

me

3-M

syn

drom

e(3

M2

)AR

61

29

21

2q3

5O

BSL

1O

bscu

rin

-like

1K

enn

y–

Caff

eydy

spla

sia

type

1AR

24

44

60

1q4

2–

q43

TBCE

Tubu

lin-s

peci

fic

chap

eron

eE

Ken

ny–

Caff

eydy

spla

sia

type

2AD

12

70

00

Mic

roce

phal

icos

teod

yspl

asti

cpr

imor

dial

dwar

fism

type

1/3

(MO

PD1

)AR

21

07

10

2q

Incl

ud

esTa

yb

i–Li

nd

erce

ph

alos

kele

tal

dy

spla

sia

Mic

roce

phal

icos

teod

yspl

asti

cpr

imor

dial

dwar

fism

type

2(M

OPD

2;

Maj

ewsk

ity

pe)

AR2

10

72

02

1q

PCN

T2Pe

rice

ntr

in2

IMAG

Esy

ndr

ome

(in

trau

teri

ne

grow

thre

tard

atio

n,

met

aphy

seal

dysp

lasi

a,ad

ren

alhy

popl

asia

,an

dge

nit

alan

omal

ies)

XL/A

D3

00

29

0P

ossi

bly

het

erog

eneo

us

Ost

eocr

anio

sten

osis

SP6

02

36

1O

ccu

rren

cein

sib

sre

por

ted

,in

her

itan

ceu

ncl

ear

Hal

lerm

ann–

Stre

iffsy

ndr

ome

AR2

34

10

0M

uta

tion

sin

GJA

1re

por

ted

inon

eca

seon

lySe

eal

soCe

rebr

o-ar

thro

-dig

ital

dysp

lasi

a2

0.

Dys

plas

ias

wit

hm

ulti

ple

join

tdi

sloc

atio

ns

Des

buqu

ois

dysp

lasi

a(w

ith

acce

ssor

yos

sifi

cati

once

nte

rin

digi

t2

)AR

25

14

50

17

q25

.3CA

NT1

Des

buqu

ois

dysp

lasi

aw

ith

shor

tm

etac

arpa

lsan

del

onga

ted

phal

ange

s(K

imty

pe)

AR2

51

45

01

7q2

5.3

CAN

T1

TAB

LEI(

Con

tin

ued)

Gro

up/n

ame

ofdi

sord

erIn

heri

tan

ceM

IMN

o.Lo

cus

Gen

ePr

otei

nN

otes

952 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Page 11: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Des

buqu

ois

dysp

lasi

a(o

ther

vari

ants

wit

hor

wit

hout

acce

ssor

yos

sifi

cati

once

nte

r)

ARP

rob

ably

gen

etic

ally

het

erog

eneo

us

Pseu

dodi

astr

oph

icdy

spla

sia

AR2

64

18

0Se

eal

soSE

Dw

ith

cong

enit

aldi

sloc

atio

ns,

CHST

3ty

pe(g

roup

4);

Atel

oste

ogen

esis

type

3an

dLa

rsen

synd

rom

e(g

roup

6);

SEM

Ds

wit

hjo

int

laxi

ty(g

roup

11

)2

1.

Chon

drod

yspl

asia

pun

ctat

a(C

DP)

grou

pCD

P,X-

linke

ddo

min

ant,

Con

radi

–H€ un

erm

ann

type

(CD

PX2

)XL

D3

02

96

0Xp

11

EBP

Emop

amil-

bin

din

gp

rote

in

CDP,

X-lin

ked

rece

ssiv

e,br

achy

tele

phal

angi

cty

pe(C

DPX

1)

XLR

30

29

50

Xp2

2.3

ARSE

Aryl

sulfa

tase

E

Con

gen

ital

hem

idys

plas

ia,

icht

hyos

is,

limb

defe

cts

(CH

ILD

)XL

D3

08

05

0Xp

11

NSD

HL

NAD

(P)H

ster

oid

dehy

drog

enas

e-lik

ep

rote

inCo

nge

nit

alhe

mid

yspl

asia

,ic

hthy

osis

,lim

bde

fect

s(C

HIL

D)

XLD

30

80

50

Xq2

8EB

PEm

opam

il-bi

nd

ing

pro

tein

Gre

enbe

rgdy

spla

sia

AR2

15

14

01

q42

.1LB

RLa

min

Bre

cep

tor,

3-b

eta-

hyd

roxy

ster

old

elta

(14

)-re

duct

ase

Incl

ud

esh

yd

rop

s-ec

top

icca

lcifi

cati

on-m

oth

-eat

enap

pea

ran

ced

ysp

lasi

a(H

EM

)an

dd

app

led

dia

ph

yse

ald

ysp

lasi

aR

hizo

mel

icCD

Pty

pe1

AR2

15

10

06

q22–

24

PEX7

Pero

xiso

mal

PTS

2re

cep

tor

Rhi

zom

elic

CDP

type

2AR

22

27

65

1q4

2D

HPA

TD

ihyd

roxy

acet

onep

hos

ph

ate

acyl

tran

sfer

ase

(DH

APAT

)R

hizo

mel

icCD

Pty

pe3

AR6

00

12

12

q31

AGPS

Alky

lgly

cero

ne-

ph

osp

hat

esy

nth

ase

(AG

PS)

CDP

tibi

al-m

etac

arpa

lty

peAD

/AR

11

86

51

Nos

olog

icst

atu

su

nce

rtai

nAs

tley

-Ken

dall

dysp

lasi

aAR

?R

elat

ion

ship

toO

Ian

dto

Gre

enb

erg

dy

spla

sia

un

clea

rN

ote

that

stip

plin

gca

noc

curi

nse

vera

lsyn

drom

essu

chas

Zellw

eger

,Sm

ith–

Lem

li–O

pitz

and

othe

rs.S

eeal

sode

smos

tero

losi

sas

wel

las

SEM

Dsh

ortl

imb—

abno

rmal

calc

ifica

tion

type

ingr

oup

11

22

.N

eon

atal

oste

oscl

erot

icdy

spla

sias

Blo

mst

ran

ddy

spla

sia

AR2

15

04

53

p22–

21

.1PT

HR

1PT

H/P

THrP

rece

pto

r1

Cau

sed

by

rece

ssiv

ein

acti

vati

ng

mu

tati

ons;

see

also

Eik

end

ysp

lasi

aan

dJa

nse

nd

ysp

lasi

aD

esm

oste

rolo

sis

AR6

02

39

81

p33–

31

.1D

HCR

24

3-b

eta-

hydr

oxy

ster

olde

lta-

24

-red

uct

ase

See

also

oth

erst

erol

-m

etab

olis

mre

late

dco

nd

itio

ns

Caff

eydi

seas

e(i

ncl

udin

gin

fan

tile

and

atte

nua

ted

form

s)AD

11

40

00

17

q21–

22

COL1

A1Co

llage

n1

,al

ph

a-1

chai

nSe

eal

soos

teog

enes

isim

per

fect

are

late

dto

colla

gen

1ge

nes

(gro

up

24

)Ca

ffey

dise

ase

(sev

ere

vari

ants

wit

hpr

enat

alon

set)

AR1

14

00

0

Rai

ne

dysp

lasi

a(l

etha

lan

dn

on-le

thal

form

s)AR

25

97

75

7p2

2FA

M2

0C

Incl

ud

esle

thal

and

non

-leth

alca

ses

See

also

Astl

ey-K

end

alld

yspl

asia

and

CDPs

ingr

oup

21

23

.In

crea

sed

bon

ede

nsi

tygr

oup

(wit

hout

mod

ifica

tion

ofbo

ne

shap

e)O

steo

petr

osis

,se

vere

neo

nat

alor

infa

nti

lefo

rms

(OPT

B1

)AR

25

97

00

11

q13

TCIR

G1

Subu

nit

ofAT

Pas

ep

roto

npu

mp

Ost

eope

tros

is,

seve

ren

eon

atal

orin

fan

tile

form

s(O

PTB

4)

AR6

11

49

01

6p1

3CL

CN7

Chlo

ride

chan

nel

7

( Continued)

WARMAN ET AL. 953

Page 12: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Ost

eope

tros

is,

infa

nti

lefo

rm,

wit

hn

ervo

ussy

stem

invo

lvem

ent

(OPT

B5

)AR

25

97

20

6q2

1O

STM

1G

ray

leth

al/o

steo

pet

rosi

sas

soci

ated

tran

smem

bra

ne

prot

ein

Ost

eope

tros

is,

inte

rmed

iate

form

,os

teoc

last

-poo

r(O

PTB

2)

AR2

59

71

01

3q1

4.1

1R

ANK

L(T

NFS

F11

)R

ecep

tor

acti

vato

rof

NF-

kap

pa-

Blig

and

(tum

orn

ecro

sis

fact

orli

gan

dsu

perf

amily

,mem

ber

11

)O

steo

petr

osis

,in

fan

tile

form

,os

teoc

last

-poo

rw

ith

imm

unog

lobu

linde

fici

ency

(OPT

B7

)

AR6

12

30

21

8q2

1.3

3R

ANK

(TN

FRSF

11

A)R

ecep

tor

acti

vato

rof

NF-

kapp

a-B

See

also

fam

ilial

exp

ansi

leos

teol

ysi

sin

Ost

eoly

sis

grou

p(g

rou

p2

8)

Ost

eope

tros

is,

inte

rmed

iate

form

(OPT

B6

)AR

61

14

97

17

q21

.3PL

EKH

M1

Plec

kstr

inho

mol

ogy

dom

ain

-con

tain

ing

pro

tein

,fa

mily

M,

mem

ber

1O

steo

petr

osis

,in

term

edia

tefo

rm(O

PTA2

)AR

25

97

10

16

p13

CLCN

7Ch

lori

dech

ann

elp

um

p

Ost

eope

tros

isw

ith

ren

altu

bula

rac

idos

is(O

PTB

3)

AR2

59

73

08

q22

CA2

Carb

onic

anh

yd

rase

2

Ost

eope

tros

is,

late

-on

set

form

type

1(O

PTA1

)AD

60

76

34

11

q13

.4LR

P5Lo

wde

nsi

tylip

opro

tein

rece

ptor

-rel

ated

pro

tein

5In

clu

des

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thty

pe

oste

oscl

eros

is(M

IM1

44

75

0)

Ost

eope

tros

is,

late

-on

set

form

type

2(O

PTA2

)AD

16

66

00

16

p13

CLCN

7Ch

lori

dech

ann

el7

Ost

eope

tros

isw

ith

ecto

derm

aldy

spla

sia

and

imm

une

defe

ct(O

LED

AID

)XL

30

03

01

Xq2

8IK

BK

G(N

EMO

)In

hibi

tor

ofka

pp

alig

ht

poly

pept

ide

gen

een

han

cer,

kin

ase

ofO

steo

petr

osis

,m

oder

ate

form

wit

hde

fect

ive

leuc

ocyt

ead

hesi

on(L

AD3

)AR

61

28

40

11

q12

FER

MT3

(KIN

D3

)Fe

rmit

in3

(Kin

dlin

3)

Ost

eope

tros

is,

mod

erat

efo

rmw

ith

defe

ctiv

ele

ucoc

yte

adhe

sion

AR6

12

84

01

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3R

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(Cal

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-GEF

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guan

yln

ucl

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asin

gp

rote

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osto

sis

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65

80

01

q21

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Cath

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55

95

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MD

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ud

esB

usc

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llen

dor

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nd

rom

e(M

IM1

66

70

0)

Mel

orhe

osto

sis

wit

hos

teop

oiki

losi

sAD

15

59

50

12

q14

LEM

D3

LEM

dom

ain

-con

tain

ing

3In

clu

des

mix

edsc

lero

sin

gb

one

dy

spla

sia

Ost

eopa

thia

stri

ata

wit

hcr

ania

lsc

lero

sis

(OSC

S)XL

D3

00

37

3Xq

11

.1W

TXFA

M1

23

B

Mel

orhe

osto

sis

SPN

oge

rmlin

eLE

MD

3m

uta

tion

sid

enti

fied

sofa

rD

ysos

teos

cler

osis

AR2

24

30

0P

ossi

bly

rela

ted

to‘‘o

steo

scle

roti

cm

etap

hy

seal

dy

spla

sia’

’O

steo

mes

opyk

nos

isAD

16

64

50

Ost

eope

tros

isw

ith

infa

nti

len

euro

axon

aldy

spla

sia

AR?

60

03

29

Sam

eas

oste

opet

rosi

sw

ith

ner

vou

ssy

stem

invo

lvem

ent

(see

abov

e)?

TAB

LEI(

Con

tin

ued

)

Gro

up/n

ame

ofdi

sord

erIn

heri

tan

ceM

IMN

o.Lo

cus

Gen

ePr

otei

nN

otes

954 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Page 13: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

24

.In

crea

sed

bon

ede

nsi

tygr

oup

wit

hm

etap

hyse

al

and/

ordi

aphy

seal

invo

lvem

ent

Cran

iom

etap

hyse

aldy

spla

sia,

auto

som

aldo

min

ant

type

AD1

23

00

05

p15

.2–

14

.2AN

KH

Hom

olog

ofm

ouse

ANK

(an

kylo

sis)

gen

eG

ain

offu

nct

ion

mu

tati

ons

Dia

phys

eal

dysp

lasi

aCa

mur

ati-E

nge

lman

nAD

13

13

00

19

q13

TGFb

eta1

Tran

sfor

min

ggr

owth

fact

orbe

ta1

Hem

atod

iaph

ysea

ldy

spla

sia

Gho

sal

AR2

31

09

57

q34

TBXA

S1Th

rom

boxa

ne

Asy

nth

ase

1H

yper

trop

hic

oste

oart

hrop

athy

AR2

59

10

04

q34–

35

HPG

D1

5-a

lpha

-hy

drox

ypro

stag

lan

din

dehy

drog

enas

e

Incl

udes

cran

io-o

steo

arth

ropa

thy

and

case

sof

rece

ssiv

ep

ach

yd

erm

oper

iost

osis

Pach

yder

mop

erio

stos

is(h

yper

trop

hic

oste

oart

hrop

ath

y,pr

imar

y,au

toso

mal

dom

inan

t)

AD1

67

10

0R

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ion

ship

tore

cess

ive

form

(MIM

25

91

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,H

PG

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efici

ency

)u

ncl

ear

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lode

nto

osse

ous

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lasi

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DO

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20

06

q22–

23

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1G

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ion

pro

tein

alph

a-1

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form

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Scle

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uche

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peAR

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91

00

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Scle

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mal

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ssiv

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peAR

21

84

00

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phys

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med

ulla

ryst

enos

isw

ith

bon

em

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11

22

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lasi

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12

28

60

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iom

etad

iap

hyse

aldy

spla

sia,

Wor

mia

nbo

ne

type

AR—

Endo

stea

lsc

lero

sis

wit

hce

rebe

llar

hypo

plas

iaAR

21

30

02

Len

z–M

ajew

ski

hype

rost

otic

dysp

lasi

aSP

15

10

50

Met

aphy

seal

dysp

lasi

a,B

raun

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nsc

hert

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94

6

Pyle

dise

ase

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65

90

02

5.

Ost

eoge

nes

isim

perf

ecta

and

decr

ease

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den

sity

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pFo

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mm

ents

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clas

sific

atio

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ogen

esis

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ta,

plea

sere

fer

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ete

xtO

steo

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esis

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ta,

non

-def

orm

ing

form

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type

1)

ADCO

L1A1

,CO

L1A2

COL1

A1:

colla

gen

1al

pha-

1ch

ain

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:co

llage

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alp

ha-

2ch

ain

,CR

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cart

ilage

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ocia

ted

prot

ein

,LE

PR

E1

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uci

ne

prol

ine-

enri

ched

pro

teog

lyca

n(l

epre

can

)1

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IB:p

epti

dy

lpro

lyl

isom

eras

eB

(cy

clop

hili

nB

),FK

BP1

0:

FK5

06

bin

din

gp

rote

in1

0,

SER

PIN

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serp

inp

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das

ein

hibi

tor

clad

eH

1,

SP7

:SP

7tr

ansc

ript

ion

fact

or(O

ster

ix)

Ost

eoge

nes

isim

perf

ecta

,pe

rin

atal

leth

alfo

rm(O

Ity

pe2

)AD

,AR

COL1

A1,

COL1

A2,

CRTA

P,LE

PRE1

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BO

steo

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esis

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ta,

prog

ress

ivel

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form

ing

type

(OI

type

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AD,

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,CO

L1A2

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SER

PIN

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See

also

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cksy

nd

rom

ety

pe

1(b

elow

)

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eoge

nes

isim

perf

ecta

,m

oder

ate

form

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type

4)

AD,

ARCO

L1A1

,CO

L1A2

,CR

TAP,

FKB

P10

,SP

7

(Continued)

WARMAN ET AL. 955

Page 14: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Ost

eoge

nes

isim

perf

ecta

wit

hca

lcifi

cati

onof

the

inte

ross

eou

sm

embr

anes

and/

orhy

pert

roph

icca

llus

(OI

type

5)

AD6

10

96

7

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eoge

nes

isim

perf

ecta

,ot

her

type

sB

ruck

syn

drom

ety

pe1

(BS1

)AR

25

94

50

17

q21

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P10

FK5

06

bin

din

gp

rote

in1

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eau

toso

mal

rece

ssiv

eO

I,ab

ove;

intr

afam

ilial

vari

abili

tyb

etw

een

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and

BS1

doc

um

ente

dB

ruck

syn

drom

ety

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(BS2

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60

92

20

3q2

3–

24

PLO

D2

Proc

olla

gen

lysy

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rosi

s-ps

eudo

glio

ma

syn

drom

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25

97

70

11

q12–

13

LRP5

LDL-

rece

ptor

rela

ted

prot

ein

5Ca

lvar

ial

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lesi

ons

wit

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ne

frag

ility

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26

55

0

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path

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ven

ileos

teop

oros

isSP

25

97

50

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ep

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nts

rep

orte

dw

ith

het

eroz

ygo

us

mu

tati

ons

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ne

Cole

-Car

pen

ter

dysp

lasi

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one

frag

ility

wit

hcr

anio

syn

osto

sis)

SP1

12

24

0Se

eal

socr

anio

syn

osto

sis

syn

dro

mes

ingr

oup

30

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dylo

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lar

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lasi

aAR

60

58

22

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linke

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1an

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llage

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wit

hra

diol

ucen

tle

sion

sof

the

man

dibl

eAD

16

62

60

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rs–

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los

syn

drom

e,pr

oger

oid

form

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30

07

05

q35

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GAL

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eras

ede

fici

ency

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oder

ma

oste

odys

plas

ticu

mAR

23

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70

1q2

4.2

GO

RAB

SCYL

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ing

pro

tein

1Cu

tis

laxa

,au

toso

mal

rece

ssiv

efo

rm,

type

2B

(AR

CL2

B)

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12

94

01

7q2

5.3

PYCR

1Py

rrol

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5-c

arb

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late

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ctas

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feat

ure

sov

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pp

ing

wit

hp

roge

roid

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San

dge

rod

erm

aos

teod

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last

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mCu

tis

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,au

toso

mal

rece

ssiv

efo

rm,

type

2A

(AR

CL2

A)(W

rin

kly

skin

syn

drom

e)

AR2

78

25

0,

21

92

00

12

q24

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spor

tin

g,ly

soso

mal

,V0

sub

un

itA2

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etal

feat

ure

sov

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pp

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wit

hp

roge

roid

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San

dge

rod

erm

aos

teod

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last

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mSi

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erte

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sia

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82

25

02

6.

Abn

orm

alm

iner

aliz

atio

ngr

oup

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opho

spha

tasi

a,pe

rin

atal

leth

alan

din

fan

tile

form

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24

15

00

1p3

6.1

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kalin

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osp

hat

ase,

tiss

uen

on-s

pec

ific

(TN

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)

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afam

ilial

vari

abili

ty

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opho

spha

tasi

a,ad

ult

form

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46

30

01

p36

.1–

p34

ALPL

Alka

line

phos

ph

atas

e,ti

ssue

non

-sp

ecifi

c(T

NSA

LP)

Incl

ud

esod

onto

hy

pop

hos

ph

atas

ia

TAB

LEI(

Con

tin

ued

)

Gro

up/n

ame

ofdi

sord

erIn

heri

tan

ceM

IMN

o.Lo

cus

Gen

ePr

otei

nN

otes

956 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Page 15: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Hyp

opho

spha

tem

icri

cket

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min

ant

XLD

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78

00

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atem

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embr

ane

pro

teas

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hosp

hate

mic

rick

ets,

auto

som

aldo

min

ant

AD1

93

10

01

2p1

3.3

FGF2

3Fi

brob

last

grow

thfa

ctor

23

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icri

cket

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toso

mal

rece

ssiv

e,ty

pe1

(AR

HR

1)

AR2

41

52

04

q21

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enti

nm

atri

xac

idic

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phop

rote

in1

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opho

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icri

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s,au

toso

mal

rece

ssiv

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pe2

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HR

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13

31

26

q23

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ucle

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roph

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ase/

phos

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eras

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tem

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sw

ith

hype

rcal

ciur

ia,

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ked

rece

ssiv

eXL

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00

55

4Xp

11

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5Ch

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dech

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el5

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tof

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t’sd

isea

seco

mp

lex

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ith

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auto

som

alre

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ive

(HH

RH

)

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41

53

99

q34

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eco

tran

spor

ter

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nat

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perp

arat

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idis

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seve

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rmAR

23

92

00

3q1

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ng

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htr

ansi

ent

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perp

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hyr

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sm

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98

03

q13

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21

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Calc

ium

-sen

sin

gre

cep

tor

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ium

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phos

phat

ede

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tion

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ase

(fam

ilial

chon

droc

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nos

is)

type

2

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18

60

05

p15

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14

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KH

Hom

olog

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ouse

ANK

(an

kylo

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ctio

nm

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tion

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eecr

anio

met

aph

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ald

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lasi

ain

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p2

4)

See

also

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endy

spla

sia

and

Eike

ndy

spla

sia

27

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soso

mal

stor

age

dise

ases

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hsk

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ysos

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sm

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p)M

ucop

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type

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/1S

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00

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uron

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char

idos

isty

pe3

AAR

25

29

00

17

q25

.3H

SSH

epar

ansu

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opol

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idos

isty

pe3

BAR

25

29

20

17

q21

NAG

LUN

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25

29

30

8p1

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ase

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char

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29

40

12

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opol

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30

00

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-su

lfate

sulfa

tase

Muc

opol

ysac

char

idos

isty

pe4

BAR

25

30

10

3p2

1.3

3G

LBI

beta

-Gal

acto

sid

ase

Muc

opol

ysac

char

idos

isty

pe6

AR2

53

20

05

q13

.3AR

SBAr

ylsu

lfata

seB

Muc

opol

ysac

char

idos

isty

pe7

AR2

53

22

07

q21

.11

GU

SBbe

ta-G

lucu

ron

idas

eFu

cosi

dosi

sAR

23

00

00

1p3

4FU

CAal

pha-

Fuco

sid

ase

alph

a-M

ann

osid

osis

AR2

48

50

01

9p1

3.2

–1

2M

ANA

alph

a-M

ann

osid

ase

beta

-Man

nos

idos

isAR

24

85

10

4q2

2–

25

MAN

Bbe

ta-M

ann

osid

ase

Aspa

rtyl

gluc

osam

inur

iaAR

20

84

00

4q2

3–

27

AGA

Aspa

rtyl

-glu

cosa

min

idas

eG

MI

Gan

glio

sido

sis,

seve

ral

form

sAR

23

05

00

3p2

1–

14

.2G

LB1

beta

-Gal

acto

sid

ase

Sial

idos

is,

seve

ral

form

sAR

25

65

50

6p2

1.3

NEU

1N

eura

min

idas

e(s

ialid

ase)

Sial

icac

idst

orag

edi

seas

e(S

IASD

)AR

26

99

20

6q1

4–

q15

SLC1

7A5

Sial

in(s

ialic

acid

tran

spor

ter)

Gal

acto

sial

idos

is,

seve

ral

form

sAR

25

65

40

20

q13

.1PP

GB

beta

-Gal

acto

sid

ase

pro

tect

ive

prot

ein

Mul

tipl

esu

lfata

sede

fici

ency

AR2

72

20

03

p26

SUM

F1Su

lfata

se-m

odify

ing

fact

or-1

Muc

olip

idos

isII

(I-c

ell

dise

ase)

,al

pha/

beta

type

AR2

52

50

04

q21–

23

GN

PTAB

N-A

cety

lglu

cosa

min

e1

-pho

spho

tran

sfer

ase,

alph

a/be

tasu

bu

nit

s

(Continued)

WARMAN ET AL. 957

Page 16: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Muc

olip

idos

isIII

(Pse

udo-

Hur

ler

poly

dyst

roph

y),

alph

a/be

taty

peAR

25

26

00

4q2

1–

23

GN

PTAB

N-A

cety

lglu

cosa

min

e1

-pho

spho

tran

sfer

ase,

alph

a/be

tasu

bu

nit

sM

ucol

ipid

osis

III(P

seud

o-H

urle

rpo

lydy

stro

phy)

,ga

mm

aty

peAR

25

26

05

4q2

1–

23

GN

PTG

N-A

cety

lglu

cosa

min

e1

-pho

spho

tran

sfer

ase,

gam

ma

sub

un

it2

8.

Ost

eoly

sis

grou

pFa

mili

alex

pan

sile

oste

olys

isAD

17

48

10

18

q22

.1R

ANK

(TN

FRSF

11

A)In

clu

des

exp

ansi

lesk

elet

alh

yp

erp

hos

ph

atas

ia(M

IM6

02

08

0)

Man

dibu

loac

ral

dysp

lasi

aty

peA

AD2

48

37

01

q21

.2LM

NA

Lam

inA/

CM

andi

bulo

acra

ldy

spla

sia

type

BAR

60

86

12

1p3

4ZM

PSTE

24

Zin

cm

etal

lop

rote

inas

ePr

oger

ia,

Hut

chin

son–

Gilf

ord

type

AD1

76

67

01

q21

.2LM

NA

Lam

inA/

CTo

rg–

Win

ches

ter

syn

drom

eAR

25

96

00

16

q13

MM

P2M

atri

xm

etal

lop

rote

inas

e2

Incl

ud

esN

odu

losi

s–Ar

thro

pat

hy–

Ost

eoly

sis

syn

dro

me

(MIM

60

51

56

)H

ajdu

–Ch

eney

syn

drom

eAD

10

25

00

Mul

tice

ntr

icca

rpal

-tar

sal

oste

olys

isw

ith

and

wit

hout

nep

hrop

athy

AD1

66

30

0

Lipo

mem

bran

eous

oste

odys

trop

hy

wit

hle

ukoe

nce

phal

opat

hy(p

rese

nile

dem

enti

aw

ith

bon

ecy

sts;

Nas

u–

Hak

ola)

AR2

21

77

06

p21

.2TR

EM2

Trig

geri

ng

rece

pto

rex

pre

ssed

onm

yelo

idce

lls2

Lipo

mem

bran

eous

oste

odys

trop

hy

wit

hle

ukoe

nce

phal

opat

hy(p

rese

nile

dem

enti

aw

ith

bon

ecy

sts;

Nas

u–

Hak

ola)

AR2

21

77

01

9q1

3.1

TYR

OB

PTy

ropr

otei

nty

rosi

ne

kin

ase-

bin

din

gp

rote

in

See

also

Pycn

odys

osto

sis,

clei

docr

ania

ldy

spla

sia,

and

Sing

leto

n–

Mer

ten

synd

rom

e.N

ote:

seve

raln

euro

logi

cco

ndit

ions

may

caus

eac

roos

teol

ysis

29

.D

isor

gan

ized

deve

lopm

ent

ofsk

elet

alco

mpo

nen

tsgr

oup

Mul

tipl

eca

rtila

gin

ous

exos

tose

s1

AD1

33

70

08

q23–

24

.1EX

T1Ex

osto

sin

-1M

ulti

ple

cart

ilagi

nou

sex

osto

ses

2AD

13

37

01

11

p12–

11

EXT2

Exos

tosi

n-2

Mul

tipl

eca

rtila

gin

ous

exos

tose

s3

AD6

00

20

91

9p

Cher

ubis

mAD

11

84

00

4p1

6SH

3B

P2SH

3do

mai

n-b

ind

ing

prot

ein

2Fi

brou

sdy

spla

sia,

poly

osto

tic

form

SP1

74

80

02

0q1

3G

NAS

1G

uan

ine

nuc

leot

ide-

bin

din

gpr

otei

n,

alp

ha-

stim

ula

tin

gac

tivi

tysu

bu

nit

1

Som

atic

mos

aici

sman

dim

pri

nti

ng

ph

enom

ena;

incl

ud

esM

cCu

ne–

Alb

righ

tsy

nd

rom

ePr

ogre

ssiv

eos

seou

she

tero

plas

iaAD

16

63

50

20

q13

GN

AS1

Gua

nin

en

ucle

otid

e-b

ind

ing

prot

ein

,al

ph

a-st

imu

lati

ng

acti

vity

sub

un

it1

Gen

esu

bje

ctto

imp

rin

tin

g

Gn

atho

diap

hyse

aldy

spla

sia

AD1

66

26

01

1p1

5.1

–1

4.3

TMEM

16

ETr

ansm

embr

ane

pro

tein

16

EM

etac

hon

drom

atos

isAD

15

62

50

12

q24

PTPN

11

Prot

ein

-tyr

osin

ep

hos

ph

atas

en

onre

cept

or-t

yp

e1

1

TAB

LEI(

Con

tin

ued

)

Gro

up/n

ame

ofdi

sord

erIn

heri

tan

ceM

IMN

o.Lo

cus

Gen

ePr

otei

nN

otes

958 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Page 17: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Ost

eogl

opho

nic

dysp

lasi

aAD

16

62

50

8p1

1FG

FR1

Fibr

obla

stgr

owth

fact

orre

cept

or1

See

also

Cran

iosy

nos

tosi

ssy

nd

rom

esin

grou

p3

0Fi

brod

yspl

asia

ossi

fica

ns

prog

ress

iva

(FO

P)AD

,SP

13

51

00

2q2

3–

24

ACVR

1Ac

tivi

nA

(BM

Pty

pe

1)

rece

pto

r

Neu

rofi

brom

atos

isty

pe1

(NF1

)AD

16

22

00

17

q11

.2N

F1N

euro

fibr

omin

Carp

otar

sal

oste

ocho

ndr

omat

osis

AD1

27

82

0Ch

erub

ism

wit

hgi

ngi

val

fibr

omat

osis

(Ram

onsy

ndr

ome)

AR2

66

27

0

Dys

plas

iaep

iphy

seal

ishe

mim

elic

a(T

revo

r)SP

12

78

00

Ench

ondr

omat

osis

(Olli

er)

SP1

66

00

0PT

HR

1an

dPT

PN1

1m

uta

tion

sfo

un

din

afe

wca

ses

only

,rol

est

illu

ncl

ear

Ench

ondr

omat

osis

wit

hhe

man

giom

ata

(Maf

fucc

i)SP

16

60

00

PTPN

11

mu

tati

ons

fou

nd

ina

few

case

son

ly,

role

un

clea

rSe

eal

soPr

oteu

ssy

ndro

me

ingr

oup

30

30

.O

verg

row

thsy

ndr

omes

wit

hsk

elet

alin

volv

emen

tW

eave

rsy

ndr

ome

SP/A

D2

77

59

0So

me

case

sre

por

ted

wit

hN

SD1

mu

tati

ons

(see

Soto

ssy

nd

rom

e)So

tos

syn

drom

eAD

11

75

50

5q3

5N

SD1

Nuc

lear

rece

pto

r-b

ind

ing

su-v

ar,

enh

ance

rof

zest

e,an

dtr

itho

rax

dom

ain

prot

ein

1

Som

eca

ses

may

hav

eN

FIX

mu

tati

ons

(see

Mar

shal

l–Sm

ith

syn

dro

me)

Mar

shal

l–Sm

ith

syn

drom

eSP

60

25

35

19

p13

.3N

FIX

Nuc

lear

fact

orI/

XSo

me

clin

ical

over

lap

wit

hSo

tos

syn

dro

me

(see

abov

e)Pr

oteu

ssy

ndr

ome

SP1

76

92

0So

me

Pro

teu

s-lik

eca

ses

hav

em

uta

tion

sin

the

PTEN

gen

eM

arfa

nsy

ndr

ome

AD1

54

70

01

5q2

1.1

FBN

1Fi

brill

in1

Con

gen

ital

con

trac

tura

lar

achn

odac

tyly

AD1

21

05

05

q23

.3FB

N2

Fibr

illin

2Lo

eys–

Die

tzsy

ndr

ome

type

s1

Aan

d2

AAD

60

91

92

,6

10

16

8,

9q2

2TG

FBR

1TG

Fbet

are

cep

tor

subu

nit

1Lo

eys–

Die

tzsy

ndr

ome

type

s1

Ban

d2

BAD

60

89

67

,6

10

38

03

p22

TGFB

R2

TGFb

eta

rece

pto

rsu

bun

it2

Ove

rgro

wth

syn

drom

ew

ith

2q3

7tr

ansl

ocat

ion

sSP

—2

q37

NPP

CN

atri

uret

icp

epti

de

prec

urso

rC

Ove

rgro

wth

pro

bab

lyca

use

db

yov

erex

pre

ssio

nof

NPP

CO

verg

row

thsy

ndr

ome

wit

hsk

elet

aldy

spla

sia

(Nis

him

ura–

Schm

idt,

endo

chon

dral

giga

nti

sm)

SP?

Nos

olog

icst

atu

su

ncl

ear

bu

tco

nsp

icu

ous

skel

etal

ph

enot

yp

e(s)

See

also

Shpr

intz

en–

Gol

dber

gsy

ndro

me

inCr

anio

syno

stos

isgr

oup

31

.G

enet

icin

flam

mat

ory/

rheu

mat

oid-

like

oste

oart

hrop

ath

ies

Prog

ress

ive

pseu

dorh

eum

atoi

ddy

spla

sia

(PPR

D;

SED

wit

hpr

ogre

ssiv

ear

thro

path

y)

AR2

08

23

06

q22–

23

WIS

P3W

NT1

-indu

cib

lesi

gnal

ing

path

way

pro

tein

3

Chro

nic

infa

nti

len

euro

logi

ccu

tan

eous

arti

cula

rsy

ndr

ome

(CIN

CA)/

neo

nat

alon

set

mul

tisy

stem

infl

amm

ator

ydi

seas

e(N

OM

ID)

AD6

07

11

51

q44

CIAS

1Cr

yopy

rin

(Continued)

WARMAN ET AL. 959

Page 18: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Ster

ilem

ulti

foca

los

teom

yelit

is,

peri

osti

tis,

and

pust

ulos

is(C

INCA

/NO

MID

-like

)

AR1

47

67

92

q14

.2IL

1R

NIn

terl

euki

n1

rece

pto

ran

tago

nis

t

Chro

nic

recu

rren

tm

ulti

foca

los

teom

yelit

isw

ith

con

gen

ital

dyse

ryth

ropo

ieti

can

emia

(CR

MO

wit

hCD

A;M

ajee

dsy

ndr

ome)

AR6

09

62

81

8p1

1.3

LPIN

2Li

pin

2

Hyp

eros

tosi

s/hy

perp

hosp

hate

mia

syn

drom

eAR

61

02

33

2q2

4–

q31

GAL

NT3

UD

P-N

-ace

tyl-

alp

ha-

D-g

alac

tosa

min

e:p

oly

pep

tid

eN

- acet

ylga

lact

osam

iny

ltra

nsf

er-

ase

3In

fan

tile

syst

emic

hyal

inos

is/J

uven

ilehy

alin

efi

brom

atos

is(I

SH/J

HF)

AR2

36

49

04

q21

ANTX

R2

Anth

rax

toxi

nre

cep

tor

2In

clu

des

Juve

nile

hy

alin

efi

bro

mat

osis

(JH

F,2

28

60

0)

and

Pu

reti

csy

nd

rom

e3

2.

Clei

docr

ania

ldy

spla

sia

and

isol

ated

cran

ial

ossi

fica

tion

defe

cts

grou

pCl

eido

cran

ial

dysp

lasi

aAD

11

96

00

6p2

1R

UN

X2R

unt

rela

ted

tran

scri

pti

onfa

ctor

2CD

AGS

syn

drom

e(c

ran

iosy

nos

tosi

s,de

laye

dfo

nta

nel

clos

ure,

pari

etal

fora

min

a,im

perf

orat

ea.

u.,

gen

ital

anom

alie

s,sk

iner

upti

on)

AR6

03

11

62

2q1

2–

q13

Yun

is–

Varo

ndy

spla

sia

AR2

16

34

0Pa

riet

alfo

ram

ina

(iso

late

d)AD

16

85

00

11

q11

.2AL

X4Ar

ista

less

-like

4Se

eal

soFr

onto

nas

ald

ysp

lasi

aty

pe

1(g

rou

p3

4)

Pari

etal

fora

min

a(i

sola

ted)

AD1

68

50

05

q34–

35

MSX

2M

uscl

ese

gmen

tho

meo

box

2Se

eal

sopy

cnod

ysos

tosi

s,w

rink

lysk

insy

ndro

me,

and

seve

ralo

ther

s3

3.

Cran

iosy

nos

tosi

ssy

ndr

omes

Pfei

ffer

syn

drom

e(F

GFR

1-r

elat

ed)

AD1

01

60

08

p12

FGFR

1Fi

brob

last

grow

thfa

ctor

rece

ptor

1M

ost

hav

eFG

FR1

P2

52

Rm

uta

tion

(ph

enot

yp

ege

ner

ally

mild

erth

anFG

FR2

-rel

ated

Pfe

iffer

)Pf

eiff

ersy

ndr

ome

(FG

FR2

-rel

ated

)AD

10

16

00

10

q26

.12

FGFR

2Fi

brob

last

grow

thfa

ctor

rece

ptor

2In

clu

des

Jack

son–

Wei

sssy

nd

rom

e(M

IM1

23

15

0)

and

Antl

ey–

Bix

lerv

aria

nts

cau

sed

by

FGFR

2m

uta

tion

s(s

eeb

elow

)Ap

ert

syn

drom

eAD

10

12

00

10

q26

.12

FGFR

2Fi

brob

last

grow

thfa

ctor

rece

ptor

2Cr

anio

syn

osto

sis

wit

hcu

tis

gyra

ta(B

eare

–St

even

son

)AD

12

37

90

10

q26

.12

FGFR

2Fi

brob

last

grow

thfa

ctor

rece

ptor

2Cr

ouzo

nsy

ndr

ome

AD1

23

50

01

0q2

6.1

2FG

FR2

Fibr

obla

stgr

owth

fact

orre

cept

or2

TAB

LEI(

Con

tin

ued

)

Gro

up/n

ame

ofdi

sord

erIn

heri

tan

ceM

IMN

o.Lo

cus

Gen

ePr

otei

nN

otes

960 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Page 19: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Crou

zon

-like

cran

iosy

nos

tosi

sw

ith

acan

thos

isn

igri

can

s(C

rouz

onod

erm

oske

leta

lsy

ndr

ome)

AD6

12

24

74

p16

.3FG

FR3

Fibr

obla

stgr

owth

fact

orre

cept

or3

Defi

ned

by

spec

ific

FGFR

3A3

91

Em

uta

tion

Cran

iosy

nos

tosi

s,M

uen

kety

peAD

60

28

49

4p1

6.3

FGFR

3Fi

brob

last

grow

thfa

ctor

rece

ptor

3D

efin

edb

ysp

ecifi

cFG

FR3

P2

50

Rm

uta

tion

Antl

ey–

Bix

ler

syn

drom

eAR

20

17

50

7q1

1.2

3PO

RCy

toch

rom

eP

45

0ox

idor

educ

tase

Sim

ilar

case

sw

ith

FGFR

2m

uta

tion

scl

assi

fied

asP

feiff

ersy

nd

rom

e(M

IM2

07

41

0)

Cran

iosy

nos

tosi

sB

osto

nty

peAD

60

47

57

5q3

5.2

MSX

2M

SX2

Het

eroz

ygo

us

P1

48

Hm

uta

tion

ina

sin

gle

fam

ilySa

ethr

e–Ch

otze

nsy

ndr

ome

AD1

01

40

07

p21

.1TW

IST1

TWIS

TSh

prin

tzen

–G

oldb

erg

syn

drom

eAD

18

22

12

Som

eca

ses

rep

orte

dw

ith

FBN

1m

uta

tion

sB

alle

r–G

erol

dsy

ndr

ome

AR2

18

60

08

q24

.3R

ECQ

L4R

ECQ

prot

ein

-like

4R

ECQ

L4m

igh

tn

otac

cou

nt

for

all

case

sof

Bal

ler–

Ger

old

Carp

ente

rsy

ndr

ome

AR2

01

00

0R

AB2

3Se

eal

soCo

le–

Carp

ente

rsy

ndro

me

ingr

oup

24

,CD

AGS

synd

rom

ein

grou

p2

9,a

ndCr

anio

fron

ton

asal

synd

rom

ein

grou

p3

43

4.

Dys

osto

ses

wit

hpr

edom

inan

tcr

anio

faci

alin

volv

emen

tM

andi

bulo

-fac

ial

dyso

stos

is(T

reac

her

Colli

ns,

Fran

cesc

hett

i-Kle

in)

AD1

54

50

05

q32

TCO

F1Tr

each

erCo

llin

s-Fr

ance

sch

etti

syn

drom

e1

Man

dibu

lo-f

acia

ldy

sost

osis

(Tre

ache

r-Co

llin

s,Fr

ance

sche

tti-

Kle

in)

AD1

54

50

01

3q1

2.2

POLR

1D

Poly

mer

ase

(RN

A)I

poly

pept

ide

DM

andi

bulo

-fac

ial

dyso

stos

is(T

reac

her-

Colli

ns,

Fran

cesc

hett

i-K

lein

)AR

15

45

00

6p2

1.1

POLR

1C

Poly

mer

ase

(RN

A)I

poly

pept

ide

CO

ral-f

acia

l-dig

ital

syn

drom

ety

peI

(OFD

1)

XLR

31

12

00

Xp2

2.3

CXO

RF5

chr.

Xop

enre

adin

gfr

ame

5W

eyer

acro

faci

al(a

crod

enta

l)dy

sost

osis

AD1

93

53

04

p16

EVC1

Ellis

–va

nCr

evel

d1

prot

ein

Endo

crin

e-ce

rebr

o-os

teod

yspl

asia

(ECO

)AR

61

26

51

6p1

2.3

ICK

Inte

stin

alce

llki

nas

e

Cran

iofr

onto

nas

alsy

ndr

ome

XLD

30

41

10

Xq1

3.1

EFN

B1

Ephr

inB

1Fr

onto

nas

aldy

spla

sia,

type

1AR

13

67

60

1p1

3.3

ALX3

Aris

tale

ss-li

ke-3

Fron

ton

asal

dysp

lasi

a,ty

pe2

AR6

13

45

11

1p1

1.2

ALX4

Aris

tale

ss-li

ke-4

Fron

ton

asal

dysp

lasi

a,ty

pe3

AR6

13

45

61

2q2

1.3

ALX1

Aris

tale

ss-li

ke1

Hem

ifaci

alm

icro

som

iaSP

/AD

16

42

10

Incl

ud

esG

old

enh

arsy

nd

rom

ean

dO

culo

-Au

ricu

lo-V

erte

bra

lsp

ectr

um

;p

rob

ably

gen

eti

cally

het

erog

eneo

us

Mill

ersy

ndr

ome

(pos

taxi

alac

rofa

cial

dyso

stos

is)

AR2

63

75

01

6q2

2D

HO

DH

Dih

ydro

orot

ate

dehy

drog

enas

eAc

rofa

cial

dyso

stos

is,

Nag

erty

peAD

/AR

15

44

00

Acro

faci

aldy

sost

osis

,R

odri

guez

type

AR2

01

17

0Se

eal

soO

ral-f

acia

l-dig

ital

synd

rom

ety

peIV

inth

eSh

ort

Rib

Dys

plas

ias

grou

p3

5.

Dys

osto

ses

wit

hpr

edom

inan

tve

rteb

ral

wit

han

dw

itho

utco

stal

invo

lvem

ent

Curr

arin

otr

iad

AD1

76

45

07

q36

HLX

B9

Hom

eobo

xge

ne

HB

9Sp

ondy

loco

stal

dyso

stos

isty

pe1

(SCD

1)

AR2

77

30

01

9q1

3D

LL3

Del

ta-li

ke3

( Continued)

WARMAN ET AL. 961

Page 20: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Spon

dylo

cost

aldy

sost

osis

type

2(S

CD2

)AR

60

86

81

15

q26

MES

P2M

esod

erm

pos

teri

or(e

xpre

ssed

in)

2Sp

ondy

loco

stal

dyso

stos

isty

pe3

(SCD

3)

AR?

60

98

13

7p2

2LF

NG

Lun

atic

frin

ge

Spon

dylo

cost

aldy

sost

osis

type

4(S

CD4

)AR

17

p13

.1H

ES7

Hai

ry-a

nd-

enh

ance

r-of

-spl

it-7

Spon

dylo

thor

acic

dyso

stos

isAR

15

q26

MES

P2M

esod

erm

pos

teri

or(e

xpre

ssed

in)

2K

lippe

l–Fe

ilan

omal

yw

ith

lary

nge

alm

alfo

rmat

ion

AD1

48

90

08

q22

.1G

DF6

Gro

wth

and

diff

eren

tiat

ion

fact

or6

Rol

eof

GD

F6m

uta

tion

sin

dom

inan

tsp

ond

ylo

thor

acic

dy

sost

osis

un

clea

rSp

ondy

loco

stal

/th

orac

icdy

sost

osis

,ot

her

form

sAD

/AR

See

also

GD

F6,

abov

e

Cere

bro-

cost

o-m

andi

bula

rsy

ndr

ome

(rib

gap

syn

drom

e)AD

/AR

11

76

50

Cere

bro-

cost

o-m

andi

bula

r-lik

esy

ndr

ome

wit

hve

rteb

ral

defe

cts

AR6

11

20

91

7q2

5CO

G1

Com

pon

ent

ofol

igom

eric

Gol

gico

mp

lex

1Al

socl

assi

fied

asCD

Gty

pe

IIg

Dia

phan

ospo

ndy

lody

sost

osis

AR6

08

02

27

p14

BM

PER

Bon

em

orph

ogen

etic

prot

ein

-bin

din

gen

dot

hel

ial

cell

prec

urso

r-d

eriv

edre

gula

tor

Pos

sib

lyov

erla

ps

wit

his

chio

spin

ald

yso

stos

is

See

also

Spon

dylo

carp

otar

sal

dysp

lasi

ain

grou

p7

and

spon

dylo

-met

aphy

seal

-meg

aepi

phys

eal

dysp

lasi

ain

grou

p1

33

6.

Pate

llar

dyso

stos

esIs

chio

pate

llar

dysp

lasi

a(s

mal

lpa

tella

syn

drom

e)AD

14

78

91

17

q21–

q22

TBX4

T-bo

xge

ne

4

Smal

lpa

tella

—lik

esy

ndr

ome

wit

hcl

ubfo

otAD

5q3

1PI

TX1

Pair

ed-li

keh

omeo

dom

ain

tran

scri

ptio

nfa

ctor

1(p

itui

tary

hom

eob

ox1

)

Incl

ud

esis

olat

edd

omin

ant

fam

ilial

clu

bfo

ot

Nai

l-pat

ella

syn

drom

eAD

16

12

00

9q3

4.1

LMX1

BLI

Mho

meo

box

tran

scri

pti

onfa

ctor

1G

enit

opat

ella

rsy

ndr

ome

AR?

60

61

70

Ear-

pate

lla-s

hort

stat

ure

syn

drom

e(M

eier

-Gor

lin)

AR2

24

69

0

See

also

MED

grou

pfo

rco

ndit

ions

wit

hpa

tella

rch

ange

sas

wel

las

isch

io-p

ubic

-pat

ella

rdy

spla

sia

asm

ildex

pres

sion

ofca

mpo

mel

icdy

spla

sia

37

.B

rach

ydac

tylie

s(w

ith

orw

itho

utex

tras

kele

tal

man

ifes

tati

ons)

Bra

chyd

acty

lyty

peA1

AD1

12

50

02

q35–

36

IHH

Indi

anH

edge

hog

Bra

chyd

acty

lyty

peA1

AD5

p31

Bra

chyd

acty

lyty

peA2

AD1

12

60

04

q23

BM

PR1

BB

one

mor

phog

enet

icp

rote

inre

cept

or,

1B

Bra

chyd

acty

lyty

peA2

AD1

12

60

0B

MP2

Bon

em

orph

ogen

etic

pro

tein

type

2B

rach

ydac

tyly

type

A2AD

11

26

00

20

q11

.2G

DF5

Gro

wth

and

diff

eren

tiat

ion

fact

or5

Bra

chyd

acty

lyty

peA3

AD1

12

70

0

TAB

LEI(

Con

tin

ued

)

Gro

up/n

ame

ofdi

sord

erIn

heri

tan

ceM

IMN

o.Lo

cus

Gen

ePr

otei

nN

otes

962 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Page 21: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Bra

chyd

acty

lyty

peB

AD1

13

00

09

q22

RO

R2

Rec

epto

rty

rosi

ne

kin

ase-

like

orph

anre

cep

tor

2Se

eal

soR

obin

owsy

nd

rom

e/CO

VESD

EM

Bra

chyd

acty

lyty

peB

2AD

61

13

77

17

qN

OG

Nog

gin

Bra

chyd

acty

lyty

peC

AD,

AR1

13

10

02

0q1

1.2

GD

F5G

row

than

dd

iffer

enti

atio

nfa

ctor

5Se

eal

soAS

PE

D(g

rou

p1

4)

and

oth

erG

DF5

dis

ord

ers

Bra

chyd

acty

lyty

peD

AD1

13

20

02

q31

HO

XD1

3H

omeo

box

D1

3B

rach

ydac

tyly

type

EAD

11

33

00

12

p11

.22

PTH

LHPa

rath

yroi

dh

orm

one-

like

horm

one

(par

ath

yro

idho

rmon

ere

late

dp

epti

de,

PTH

RP)

Bra

chyd

acty

lyty

peE

AD1

13

30

02

q31

HO

XD1

3H

omeo

box

D1

3B

rach

ydac

tyly

—m

enta

lre

tard

atio

nsy

ndr

ome

AD6

00

43

02

q37

.3H

DAC

4H

isto

ne

deac

ety

lase

4So

me

pat

ien

tsh

ave

mic

rod

elet

ion

sin

volv

ing

con

tigu

ous

gen

es(c

hr.

2q

37

del

etio

nsy

nd

rom

e)H

yper

phos

phat

asia

wit

hm

enta

lre

tard

atio

n,

brac

hyte

leph

alan

gy,

and

dist

inct

face

AR1

p36

.11

PIG

VPh

osph

atid

ylin

osit

ol-g

lyca

nbi

osyn

thes

iscl

ass

Vp

rote

in(G

PIm

ann

osy

ltra

nsf

eras

e2

)B

rach

ydac

tyly

-hy

pert

ensi

onsy

ndr

ome

(Bilg

intu

rian

)AD

11

24

10

12

p12

.2–

11

.2P

ossi

bly

PTH

LH

Bra

chyd

acty

lyw

ith

anon

ychi

a(C

ooks

syn

drom

e)AD

10

69

95

17

q24

.3SO

X9R

egu

lato

rym

uta

tion

s

Mic

roce

phal

y-oc

ulo

-dig

ito-

esop

hage

al-

duod

enal

syn

drom

e(F

ein

gold

syn

drom

e)

AD1

64

28

02

p24

.1M

YCN

nM

YCon

coge

ne

Han

d-fo

ot-g

enit

alsy

ndr

ome

AD1

40

00

07

p14

.2H

OXA

13

Hom

eobo

xA1

3B

rach

ydac

tyly

wit

hel

bow

dysp

lasi

a(L

iebe

nbe

rgsy

ndr

ome)

AD1

86

55

0

Keu

tel

syn

drom

eAR

24

51

50

12

p13

.1–

12

.3M

GP

Mat

rix

Gla

prot

ein

Albr

ight

here

dita

ryos

teod

ystr

oph

y(A

HO

)AD

10

35

80

20

q13

GN

AS1

Gua

nin

en

ucle

otid

eb

ind

ing

prot

ein

ofad

eny

late

cycl

ase—

sub

un

it

See

also

pol

yos

toti

cfi

bro

us

dy

spla

sia

and

pro

gres

sive

osse

ous

het

erop

lasi

a,gr

oup

28

Rub

inst

ein–

Tayb

isy

ndr

ome

AD1

80

84

91

6p1

3.3

CREB

BP

CREB

-bin

din

gp

rote

inR

ubin

stei

n–

Tayb

isy

ndr

ome

AD1

80

84

92

2q1

3EP

30

0E1

A-bi

ndi

ng

pro

tein

,3

00

-kD

aCa

tel–

Man

zke

syn

drom

eXL

R?

30

23

80

Bra

chyd

acty

ly,

Tem

tam

yty

peAR

60

52

82

Chri

stia

nty

pebr

achy

dact

yly

AD1

12

45

0Co

ffin–

Siri

ssy

ndr

ome

AR1

35

90

0M

onon

enty

pebr

achy

dact

yly

XLD

?3

01

94

0Po

lan

dan

omal

ySP

17

38

00

See

also

grou

p2

0fo

rot

her

cond

itio

nsw

ith

brac

hyda

ctyl

yas

wel

las

brac

hyte

leph

alan

gic

CDP

38

.Li

mb

hypo

plas

ia—

redu

ctio

nde

fect

sgr

oup

Uln

ar-m

amm

ary

syn

drom

eAD

18

14

50

TBX3

T-bo

xge

ne

3de

Lan

gesy

ndr

ome

AD1

22

47

05

p13

.1N

IPB

LN

ippe

d-B

-like

Fan

con

ian

emia

(see

not

ebe

low

)AR

22

76

50

Seve

ral

Seve

ral

Seve

ral

com

ple

men

tati

ongr

oup

san

dge

nes

(Continued)

WARMAN ET AL. 963

Page 22: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Thro

mbo

cyto

pen

ia-a

bsen

tra

dius

(TAR

)AR

?/A

D?

27

40

00

1q2

1.1

Seve

ral

Mic

rod

elet

ion

on1

q2

1.1

Thro

mbo

cyth

emia

wit

hdi

stal

limb

defe

cts

AD3

q27

THPO

Thro

mbo

poie

tin

Dis

tal

limb

def

ects

pos

tula

ted

asco

nse

qu

ence

ofva

scu

lar

occl

usi

ons

Hol

t–O

ram

syn

drom

eAD

14

29

00

12

q24

.1TB

X5T-

box

gen

e5

Oki

hiro

syn

drom

e(D

uan

e—ra

dial

ray

anom

aly)

AD6

07

32

32

0q1

3SA

LL4

SAL-

like

4

Cous

insy

ndr

ome

AR2

60

66

01

p13

TBX1

5T-

box

gen

e1

5R

ober

tssy

ndr

ome

AR2

68

30

08

p21

.1ES

CO2

Hom

olog

ofes

tab

lish

men

tof

cohe

sion

—2

Split

-han

d-fo

otm

alfo

rmat

ion

wit

hlo

ng

bon

ede

fici

ency

(SH

FLD

1)

AD1

19

10

01

q42

.2–

q43

Split

-han

d-fo

otm

alfo

rmat

ion

wit

hlo

ng

bon

ede

fici

ency

(SH

FLD

2)

AD6

10

68

56

q14

.1

Split

-han

d-fo

otm

alfo

rmat

ion

wit

hlo

ng

bon

ede

fici

ency

(SH

FLD

3)

AD6

12

57

61

7p1

3.1

Tibi

alhe

mim

elia

AR2

75

22

0Ti

bial

hem

imel

ia-p

olys

ynda

ctyl

y-tr

ipha

lan

geal

thum

bAD

18

87

70

Ache

irop

odia

AR2

00

50

07

q36

LMB

R1

Puta

tive

rece

pto

rp

rote

inP

arti

alLM

BR

1d

elet

ion

affe

ctin

gex

pre

ssio

nof

Son

icH

edge

hog

(SH

H)

gen

eTe

tra-

amel

iaXL

30

10

90

Tetr

a-am

elia

AR2

73

39

51

7q2

1W

NT3

Win

gles

s-ty

pe

MM

TVin

tegr

atio

nsi

tefa

mily

,m

emb

er3

Anky

lobl

epha

ron

-ect

oder

mal

dysp

lasi

a-cl

eft

lip/p

alat

e(A

EC)

AD1

06

26

03

q27

P63

(TP6

3)

Tum

orpr

otei

np

63

Ectr

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oder

mal

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acl

eft-

pala

tesy

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ome

Type

3(E

EC3

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60

42

92

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3(T

P63

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prot

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p6

3

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mal

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lasi

acl

eft-

pala

tesy

ndr

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type

1(E

EC1

)AD

12

99

00

7q1

1.2

–1

2.3

Ectr

odac

tyly

-ect

oder

mal

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lasi

a-m

acul

ardy

stro

phy

syn

drom

e(E

EM)

AR2

25

28

01

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2CD

H3

Cadh

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Lim

b-m

amm

ary

syn

drom

e(i

ncl

udin

gAD

ULT

syn

drom

e)AD

60

32

73

3q2

7P6

3(T

P63

)Tu

mor

prot

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p6

3

Split

han

d-fo

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alfo

rmat

ion

,is

olat

edfo

rm,

type

4(S

HFM

4)

AD6

05

28

93

q27

P63

(TP6

3)

Tum

orpr

otei

np

63

Split

han

d-fo

otm

alfo

rmat

ion

,is

olat

edfo

rm,

type

1(S

HFM

1)

AD1

83

60

07

q21

.3–

22

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Split

han

d-fo

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alfo

rmat

ion

,is

olat

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rm,

type

2(S

HFM

2)

XL3

13

35

0Xq

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Split

han

d-fo

otm

alfo

rmat

ion

,is

olat

edfo

rm,

type

3(S

HFM

3)

AD6

00

09

51

0q2

4FB

XW4

Dac

tylin

Split

han

d-fo

otm

alfo

rmat

ion

,is

olat

edfo

rm,

type

5(S

HFM

5)

AD6

06

70

82

q31

TAB

LEI(

Con

tin

ued

)

Gro

up/n

ame

ofdi

sord

erIn

heri

tan

ceM

IMN

o.Lo

cus

Gen

ePr

otei

nN

otes

964 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Page 23: Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf · Nosology and Classification of Genetic Skeletal Disorders: ... Genetic basis proven

Al-A

wad

iR

aas–

Rot

hsch

ildlim

b-pe

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plas

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sia

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76

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gles

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atio

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ann

syn

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typ

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ily,

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ber

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syn

drom

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liver

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oral

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ual

face

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pic

over

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00

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hart

syn

drom

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loss

ia–

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ulo-

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a(K

osen

ow)

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0N

ote:

the

part

icul

arly

com

plex

gene

tic

basi

sof

Fanc

onia

nem

iaan

dit

sco

mpl

emen

tati

ongr

oups

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ackn

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rlis

ted

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ogy.

The

Rea

deri

sre

ferr

edto

MIM

orto

spec

ializ

edre

view

s.Se

eal

soCH

ILD

ingr

oup

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and

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mes

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ican

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rom

esom

elic

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9.

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dact

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dact

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oup

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xial

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dact

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type

1(P

PD1

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17

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00

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xial

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)/tr

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(com

plex

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cks

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enal

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al-R

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ndr

ome)

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07

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01

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L-lik

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culo

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to-d

igit

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ome

(LAD

D)

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01

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Fibr

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fact

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to-d

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p16

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obla

stgr

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fact

orre

cept

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Lacr

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culo

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to-d

igit

alsy

ndr

ome

(LAD

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49

73

05

p13–

p12

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0Fi

brob

last

grow

thfa

ctor

10

Acro

callo

sal

syn

drom

eAR

20

09

90

7p1

3Ac

ro-p

ecto

ral

syn

drom

eAD

60

59

67

7q3

6Ac

ro-p

ecto

ro-v

erte

bral

dysp

lasi

a(F

-syn

drom

e)AD

10

25

10

2q3

6

Mir

ror-

imag

epo

lyda

ctyl

yof

han

dsan

dfe

et(L

auri

n–

San

drow

syn

drom

e)AD

13

57

50

7q3

6SH

HSo

nic

Hed

geh

og

Mir

ror-

imag

epo

lyda

ctyl

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dsan

dfe

et(L

auri

n–

San

drow

syn

drom

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nlin

ked

toSH

H

Cen

ani–

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ctyl

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wde

nsi

tylip

opro

tein

rece

ptor

-rel

ated

pro

tein

4

( Continued)

WARMAN ET AL. 965

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Cen

ani–

Len

zlik

esy

nda

ctyl

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(AD

?)

15

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EM1

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mlin

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up

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oth

loci

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serv

edin

one

case

only

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r)O

ligos

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o-ul

nar

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nal

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ion

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dact

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ik–

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94

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ome

(syn

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can

thus

,an

o-,

and

ren

alm

alfo

rmat

ion

s)

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00

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58

A

Syn

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type

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II–IV

)AD

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00

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dact

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type

3(I

V–V)

AD1

85

90

06

q21–

23

GJA

1Sy

nda

ctyl

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pe4

(I–

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type

AD1

86

20

07

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icH

edge

hog

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dact

yly

type

5(s

ynda

ctyl

yw

ith

met

acar

pal

and

met

atar

sal

fusi

on)

AD1

86

30

02

q31

HO

XD1

3

Syn

dact

yly

wit

hcr

anio

syn

osto

sis

(Phi

lade

lphi

aty

pe)

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01

22

22

q35–

36

.3

Syn

dact

yly

wit

hm

icro

ceph

aly

and

men

tal

reta

rdat

ion

(Fili

ppi

syn

drom

e)AR

27

24

40

Mec

kel

syn

drom

ety

pe1

AR2

49

00

01

7q2

3M

KS1

Mec

kel

syn

drom

ety

pe2

AR6

03

19

41

1q

Mec

kel

syn

drom

ety

pe3

AR6

07

36

18

q21

TMEM

67

Mec

kel

syn

drom

ety

pe4

AR6

11

13

41

2q

CEP2

90

Mec

kel

syn

drom

ety

pe5

AR6

11

56

11

6q1

2.1

RPG

RIP

1L

Mec

kel

syn

drom

ety

pe6

AR6

12

28

44

p15

CC2

D2

AN

ote:

the

Smit

h–Le

mli–

Opi

tzsy

ndro

me

can

pres

ent

wit

hpo

lyda

ctyl

yan

d/or

synd

acty

ly.

See

also

the

SRPS

grou

p4

0.

Def

ects

injo

int

form

atio

nan

dsy

nos

tose

sM

ulti

ple

syn

osto

ses

syn

drom

ety

pe1

AD1

86

50

01

7q2

2N

OG

Nog

gin

Mul

tipl

esy

nos

tose

ssy

ndr

ome

type

2AD

18

65

00

20

q11

.2G

DF5

Gro

wth

and

diff

eren

tiat

ion

fact

or5

Mul

tipl

esy

nos

tose

ssy

ndr

ome

type

3AD

61

29

61

13

q11–

q12

FGF9

Prox

imal

sym

phal

angi

smty

pe1

AD1

85

80

01

7q2

2N

OG

Nog

gin

Prox

imal

sym

phal

angi

smty

pe2

AD1

85

80

02

0q1

1.2

GD

F5G

row

than

dd

iffer

enti

atio

nfa

ctor

5R

adio

-uln

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nos

tosi

sw

ith

ameg

akar

yoc

ytic

thro

mbo

cyto

pen

iaAD

60

54

32

7p1

5–

14

.2H

OXA

11

Hom

eobo

xA1

1

See

also

Spon

dylo

-Car

pal-T

arsa

ldy

spla

sia;

mes

omel

icdy

spla

sia

wit

hac

ral

syno

stos

es;

and

othe

rs

TAB

LEI(

Con

tin

ued

)

Gro

up/n

ame

ofdi

sord

erIn

heri

tan

ceM

IMN

o.Lo

cus

Gen

ePr

otei

nN

otes

966 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

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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 Com-

ponents), 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 com-

prises 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 includ-

ed because of its conspicuous skeletal features [Nishimura et al.,

2004; Schmidt et al., 2007]; however this condition remains in-

completely 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 embry-

onic 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 in-

dications 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

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 com-

mon radiographic features or by anatomical site involved. More-

over, 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 bio-

chemical 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 molec-

ular 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 DysostosesDysostoses 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 mor-

phogenic 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 progressive-

ly 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.

WARMAN ET AL. 967

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OMIM and the NosologyBecause of the importance of consistency between parallel data-

bases, 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.

OutlookThe increasing availability of massive parallel sequencing and other

new sequencing technologies will likely result in a rapid identifica-

tion of novel disease-causing genes, but also in novel phenotypes

associated with mutations in genes already linked to other pheno-

types. 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 recogni-

tion 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 in-

volved in skeletal development and homeostasis that will be of

interest and of inspiration to all those who are working in skeletal

biology and medicine.

ACKNOWLEDGMENTS

M.L.W. is an Investigator with the Howard Hughes Medical Insti-

tute, and A.S.F. is supported by the Leenaards Foundation

(Lausanne, Switzerland) and by the Facult�e de Biologie et Medicine

of the Lausanne University.

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1971b. International nomenclature of constitutional bone diseases. Con-stitutional bone diseases without known pathogenesis. Arch Fr Pediatr28:553–557.

1971c. Nomenclature for constitutional (intrinsic) diseases of bones.Pediatrics 47:431–434.

1971d. Nomenclature for the constitutional (intrinsic) diseases of bone.Radiology 99:699–702.

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