Upload
ana-sandoval
View
16
Download
0
Tags:
Embed Size (px)
Citation preview
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
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
TAB
LEI.
Gro
up/n
ame
ofdi
sord
erIn
heri
tan
ceM
IMN
o.Lo
cus
Gen
ePr
otei
nN
otes
1.
FGFR
3ch
ondr
odys
plas
iagr
oup
Than
atop
hori
cdy
spla
sia
type
1(T
D1
)AD
18
76
00
4p1
6.3
FGFR
3FG
FR3
Incl
ud
esp
revi
ous
San
Die
goty
pe
Than
atop
hori
cdy
spla
sia
type
2(T
D2
)AD
18
76
01
4p1
6.3
FGFR
3FG
FR3
Seve
reac
hon
drop
lasi
aw
ith
deve
lopm
enta
lde
lay
and
acan
thos
isn
igri
can
s(S
ADD
AN)
ADSe
e1
87
60
04
p16
.3FG
FR3
FGFR
3
Acho
ndr
opla
sia
AD1
00
80
04
p16
.3FG
FR3
FGFR
3H
ypoc
hon
drop
lasi
aAD
14
60
00
4p1
6.3
FGFR
3FG
FR3
Cam
ptod
acty
ly,
tall
stat
ure,
and
hear
ing
loss
syn
drom
e(C
ATSH
L)AD
18
76
00
4p1
6.3
FGFR
3FG
FR3
Inac
tiva
tin
gm
uta
tion
Hyp
ocho
ndr
opla
sia-
like
dysp
lasi
a(s)
AD,
SPSi
mila
rto
hy
poc
hon
dro
pla
sia
bu
tu
nlin
ked
toFG
FR3
,p
rob
ably
het
erog
eneo
us;
un
cert
ain
dia
gnos
tic
crit
eria
See
also
grou
p3
3fo
rcr
anio
syno
stos
essy
ndro
mes
linke
dto
FGFR
3m
utat
ions
,as
wel
las
LAD
Dsy
ndro
me
ingr
oup
39
for
anot
her
FGFR
3-r
elat
edph
enot
ype
2.
Type
2co
llage
ngr
oup
and
sim
ilar
diso
rder
sAc
hon
drog
enes
isty
pe2
(ACG
2;
Lan
ger–
Sald
ino)
AD2
00
61
01
2q1
3.1
COL2
A1Ty
pe2
colla
gen
Plat
yspo
ndy
licdy
spla
sia,
Torr
ance
type
AD1
51
21
01
2q1
3.1
COL2
A1Ty
pe2
colla
gen
See
also
seve
resp
ond
ylo
dy
spla
stic
dy
spla
sias
(gro
up
13
)H
ypoc
hon
drog
enes
isAD
20
06
10
12
q13
.1CO
L2A1
Type
2co
llage
nSp
ondy
loep
iphy
seal
dysp
lasi
aco
nge
nit
a(S
EDC)
AD1
83
90
01
2q1
3.1
COL2
A1Ty
pe2
colla
gen
Spon
dylo
epim
etap
hyse
aldy
spla
sia
(SEM
D)
Stru
dwic
kty
peAD
18
42
50
12
q13
.1CO
L2A1
Type
2co
llage
n
Kn
iest
dysp
lasi
aAD
15
65
50
12
q13
.1CO
L2A1
Type
2co
llage
nSp
ondy
lope
riph
eral
dysp
lasi
aAD
27
17
00
12
q13
.1CO
L2A1
Type
2co
llage
nM
ildSE
Dw
ith
prem
atur
eon
set
arth
rosi
sAD
12
q13
.1CO
L2A1
Type
2co
llage
nO
ften
asso
ciat
edw
ith
p.R
71
9C
and
p.G
47
4S
mu
tati
ons
SED
wit
hm
etat
arsa
lsh
orte
nin
g(f
orm
erly
Czec
hdy
spla
sia)
AD6
09
16
21
2q1
3.1
COL2
A1Ty
pe2
colla
gen
Oft
enas
soci
ated
wit
hth
ep
.R2
75
Cm
uta
tion
Stic
kler
syn
drom
ety
pe1
AD1
08
30
01
2q1
3.1
COL2
A1Ty
pe2
colla
gen
Stic
kler
-like
syn
drom
e(s)
Un
linke
dto
eith
erCO
L2A1
,CO
L11
A1,
orCO
L11
A2.
See
also
COL9
A1fo
rre
cess
ive
form
3.
Type
11
colla
gen
grou
pSt
ickl
ersy
ndr
ome
type
2AD
60
48
41
1p2
1CO
L11
A1Ty
pe1
1co
llage
nal
ph
a-1
chai
nM
arsh
all
syn
drom
eAD
15
47
80
1p2
1CO
L11
A1Ty
pe1
1co
llage
nal
ph
a-1
chai
nFi
broc
hon
drog
enes
isAR
22
85
20
1p2
1CO
L11
A1Ty
pe1
1co
llage
nal
ph
a-1
chai
nO
tosp
ondy
lom
egae
piph
ysea
ldy
spla
sia
(OSM
ED),
rece
ssiv
ety
peAR
21
51
50
6p2
1.3
COL1
1A2
Type
11
colla
gen
alp
ha-
2ch
ain
WARMAN ET AL. 945
Oto
spon
dylo
meg
aepi
phys
eal
dysp
lasi
a(O
SMED
),do
min
ant
type
(Wei
ssen
bach
er–
Zwey
m€ ul
ler
syn
drom
e,St
ickl
ersy
ndr
ome
type
3)
AD2
15
15
06
p21
.3CO
L11
A2Ty
pe1
1co
llage
nal
ph
a-2
chai
n
See
also
Stic
kler
synd
rom
ety
pe1
ingr
oup
24
.Su
lfat
ion
diso
rder
sgr
oup
Acho
ndr
ogen
esis
type
1B
(ACG
1B
)AR
60
09
72
5q3
2–
33
DTD
STSL
C26
A2su
lfate
tran
spor
ter
Form
erly
know
nas
Frac
caro
typ
eac
hon
dro
gen
esis
Atel
oste
ogen
esis
type
2(A
O2
)AR
25
60
50
5q3
2–
33
DTD
STSL
C26
A2su
lfate
tran
spor
ter
Incl
ud
esd
ela
Chap
elle
dy
spla
sia,
McA
liste
rd
ysp
lasi
a,an
d‘‘n
eon
atal
osse
ous
dy
spla
sia’
’D
iast
roph
icdy
spla
sia
(DTD
)AR
22
26
00
5q3
2–
33
DTD
STSL
C26
A2su
lfate
tran
spor
ter
MED
,au
toso
mal
rece
ssiv
ety
pe(r
MED
;ED
M4
)AR
22
69
00
5q3
2–
33
DTD
STSL
C26
A2su
lfate
tran
spor
ter
See
also
mu
ltip
leep
iph
yse
ald
ysp
lasi
asan
dp
seu
doa
chon
dro
pla
sia
grou
p(g
rou
p9
)SE
MD
,PA
PSS2
type
AR6
03
00
51
0q2
3–
q24
PAPS
S2PA
PS-S
ynth
etas
e2
Form
erly
‘‘Pak
ista
ni
typ
e.’’
See
also
SEM
Dgr
oup
(gro
up
11
)Ch
ondr
odys
plas
iaw
ith
con
gen
ital
join
tdi
sloc
atio
ns,
CHST
3ty
pe(r
eces
sive
Lars
ensy
ndr
ome)
AR6
08
63
71
0q2
2.1
CHST
3Ca
rboh
ydra
tesu
lfotr
ansf
eras
e3
;ch
ondr
oiti
n6
-su
lfotr
ansf
eras
e
Incl
ud
esre
cess
ive
Lars
ensy
nd
rom
e,h
um
ero-
spin
ald
yso
stos
is,
and
SED
Om
ani
typ
eEh
lers
–D
anlo
ssy
ndr
ome,
CHST
14
type
(‘‘m
uscu
lo-s
kele
tal
vari
ant’’
)AR
60
17
76
15
q14
CHST
14
Carb
ohyd
rate
sulfo
tran
sfer
ase
14
;de
rmat
an4
-su
lfotr
ansf
eras
e
Incl
ud
esAd
du
cted
Thu
mb–
Clu
bfo
otsy
nd
rom
e
See
also
grou
p7
and
grou
p2
6fo
rot
her
cond
itio
nsw
ith
mul
tipl
edi
sloc
atio
ns5
.Pe
rlec
angr
oup
Dys
segm
enta
ldy
spla
sia,
Silv
erm
an-H
andm
aker
type
AR2
24
41
01
q36–
34
PLC (H
SPG
2)
Perl
ecan
Dys
segm
enta
ldy
spla
sia,
Rol
lan
d-D
esbu
quoi
sty
peAR
22
44
00
1q3
6–
34
PLC (H
SPG
2)
Perl
ecan
Schw
artz
–Ja
mpe
lsy
ndr
ome
(myo
ton
icch
ondr
odys
trop
hy)
AR2
55
80
01
q36–
34
PLC (H
SPG
2)
Perl
ecan
Mild
and
seve
refo
rms;
incl
ud
esp
revi
ous
Bu
rton
dy
spla
sia
6.
Aggr
ecan
grou
pSE
D,
Kim
berl
eyty
peAD
60
83
61
15
q26
AGC1
Aggr
ecan
SEM
D,
Aggr
ecan
type
AR6
12
81
31
5q2
6AG
C1Ag
grec
anFa
mili
alos
teoc
hon
drit
isdi
ssec
ans
AD1
65
80
01
5q2
6AG
C1Ag
grec
an7
.Fi
lam
ingr
oup
and
rela
ted
diso
rder
sFr
onto
met
aphy
seal
dysp
lasi
aXL
D3
05
62
0Xq
28
FLN
AFi
lam
inA
Som
eca
ses
app
aren
tly
lack
FLN
Am
uta
tion
sO
steo
dysp
last
yM
eln
ick–
Nee
dles
XLD
30
93
50
Xq2
8FL
NA
Fila
min
A
TAB
LEI(
Con
tin
ued)
Gro
up/n
ame
ofdi
sord
erIn
heri
tan
ceM
IMN
o.Lo
cus
Gen
ePr
otei
nN
otes
946 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Oto
pala
todi
gita
lsy
ndr
ome
type
1(O
PD1
)XL
D3
11
30
0Xq
28
FLN
AFi
lam
inA
Oto
pala
todi
gita
lsy
ndr
ome
type
2(O
PD2
)XL
D3
04
12
0Xq
28
FLN
AFi
lam
inA
Term
inal
osse
ous
dysp
lasi
aw
ith
pigm
enta
ryde
fect
s(T
OD
PD)
XLD
30
02
44
Xq2
8FL
NA
Fila
min
A
Atel
oste
ogen
esis
type
1(A
O1
)AD
10
87
20
3p1
4.3
FLN
BFi
lam
inB
Incl
ud
esB
oom
eran
gd
ysp
lasi
a,P
iep
korn
dy
spla
sia,
and
spon
dy
loh
um
erof
emor
al(g
ian
tce
ll)d
ysp
lasi
aAt
elos
teog
enes
isty
pe3
(AO
3)
AD1
08
72
13
p14
.3FL
NB
Fila
min
BLa
rsen
syn
drom
e(d
omin
ant)
AD1
50
25
03
p14
.3FL
NB
Fila
min
BSp
ondy
lo-c
arp
al-t
arsa
ldy
spla
sia
AR2
72
46
03
p14
.3FL
NB
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
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
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
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
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
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
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
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
Wor
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
1q1
3R
ASG
RP2
(Cal
DAG
-GEF
1)
Ras
guan
yln
ucl
eoti
de-
rele
asin
gp
rote
in2
Pykn
odys
osto
sis
AR2
65
80
01
q21
CTSK
Cath
epsi
nK
Ost
eopo
ikilo
sis
AD1
55
95
01
2q1
4LE
MD
3LE
Mdo
mai
n-c
onta
inin
g3
Incl
ud
esB
usc
hke
–O
llen
dor
ffsy
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
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
elat
ion
ship
tore
cess
ive
form
(MIM
25
91
00
,H
PG
Dd
efici
ency
)u
ncl
ear
Ocu
lode
nto
osse
ous
dysp
lasi
a(O
DO
D)
mild
type
AD1
64
20
06
q22–
23
GJA
1G
apju
nct
ion
pro
tein
alph
a-1
Ocu
lode
nto
osse
ous
dysp
lasi
a(O
DO
D)
seve
rety
peAR
25
78
50
Pos
sib
lyh
omoz
ygo
us
form
ofm
ildO
DO
DO
steo
ecta
sia
wit
hhy
perp
hosp
hata
sia
(juv
enile
Page
tdi
seas
e)AR
23
90
00
8q2
4O
PGO
steo
prot
eger
in
Scle
rost
eosi
sAR
26
95
00
17
q12–
21
SOST
Scle
rost
inEn
dost
eal
hype
rost
osis
,va
nB
uche
mty
peAR
23
91
00
17
q12–
21
SOST
Scle
rost
inSp
ecifi
c5
2kb
del
etio
nd
own
stre
amof
SOST
Tric
hode
nto
osse
ous
dysp
lasi
aAD
19
03
20
17
q21
DLX
3D
ista
l-les
sh
omeo
box
3Cr
anio
met
aphy
seal
dysp
lasi
a,au
toso
mal
rece
ssiv
ety
peAR
21
84
00
6q2
1–
22
Dia
phys
eal
med
ulla
ryst
enos
isw
ith
bon
em
alig
nan
cyAD
11
22
50
9p2
1–
p22
Cran
iodi
aphy
seal
dysp
lasi
aAD
12
28
60
Cran
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
–Ti
nsc
hert
type
XL6
05
94
6
Pyle
dise
ase
AR2
65
90
02
5.
Ost
eoge
nes
isim
perf
ecta
and
decr
ease
dbo
ne
den
sity
grou
pFo
rco
mm
ents
the
clas
sific
atio
nof
oste
ogen
esis
impe
rfec
ta,
plea
sere
fer
toth
ete
xtO
steo
gen
esis
impe
rfec
ta,
non
-def
orm
ing
form
(OI
type
1)
ADCO
L1A1
,CO
L1A2
COL1
A1:
colla
gen
1al
pha-
1ch
ain
,CO
L1A2
:co
llage
n1
alp
ha-
2ch
ain
,CR
TAP:
cart
ilage
-ass
ocia
ted
prot
ein
,LE
PR
E1
:le
uci
ne
prol
ine-
enri
ched
pro
teog
lyca
n(l
epre
can
)1
,PP
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
H:
serp
inp
epti
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
,PPI
BO
steo
gen
esis
impe
rfec
ta,
prog
ress
ivel
yde
form
ing
type
(OI
type
3)
AD,
ARCO
L1A1
,CO
L1A2
,CR
TAP,
LEPR
E1,
PPIB
,FK
BP1
0,
SER
PIN
H1
See
also
Bru
cksy
nd
rom
ety
pe
1(b
elow
)
Ost
eoge
nes
isim
perf
ecta
,m
oder
ate
form
(OI
type
4)
AD,
ARCO
L1A1
,CO
L1A2
,CR
TAP,
FKB
P10
,SP
7
(Continued)
WARMAN ET AL. 955
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
Ost
eoge
nes
isim
perf
ecta
,ot
her
type
sB
ruck
syn
drom
ety
pe1
(BS1
)AR
25
94
50
17
q21
FKB
P10
FK5
06
bin
din
gp
rote
in1
0Se
eau
toso
mal
rece
ssiv
eO
I,ab
ove;
intr
afam
ilial
vari
abili
tyb
etw
een
OI3
and
BS1
doc
um
ente
dB
ruck
syn
drom
ety
pe2
(BS2
)AR
60
92
20
3q2
3–
24
PLO
D2
Proc
olla
gen
lysy
lhy
drox
ylas
e2
Ost
eopo
rosi
s-ps
eudo
glio
ma
syn
drom
eAR
25
97
70
11
q12–
13
LRP5
LDL-
rece
ptor
rela
ted
prot
ein
5Ca
lvar
ial
doug
hnut
lesi
ons
wit
hbo
ne
frag
ility
AD1
26
55
0
Idio
path
icju
ven
ileos
teop
oros
isSP
25
97
50
Som
ep
atie
nts
rep
orte
dw
ith
het
eroz
ygo
us
mu
tati
ons
inth
eLR
P5ge
ne
Cole
-Car
pen
ter
dysp
lasi
a(b
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
Spon
dylo
-ocu
lar
dysp
lasi
aAR
60
58
22
Un
linke
dto
colla
gen
1an
dco
llage
n2
gen
esor
LRP5
Ost
eope
nia
wit
hra
diol
ucen
tle
sion
sof
the
man
dibl
eAD
16
62
60
Ehle
rs–
Dan
los
syn
drom
e,pr
oger
oid
form
AR1
30
07
05
q35
B4
GAL
T7Xy
losy
lpro
tein
4-b
eta-
gala
ctos
yltr
ansf
eras
ede
fici
ency
Ger
oder
ma
oste
odys
plas
ticu
mAR
23
10
70
1q2
4.2
GO
RAB
SCYL
1-b
ind
ing
pro
tein
1Cu
tis
laxa
,au
toso
mal
rece
ssiv
efo
rm,
type
2B
(AR
CL2
B)
AR6
12
94
01
7q2
5.3
PYCR
1Py
rrol
ine-
5-c
arb
oxy
late
redu
ctas
e1
Skel
etal
feat
ure
sov
erla
pp
ing
wit
hp
roge
roid
ED
San
dge
rod
erm
aos
teod
ysp
last
icu
mCu
tis
laxa
,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
.3AT
P6VO
A2AT
Pase
,Hþ
tran
spor
tin
g,ly
soso
mal
,V0
sub
un
itA2
Skel
etal
feat
ure
sov
erla
pp
ing
wit
hp
roge
roid
ED
San
dge
rod
erm
aos
teod
ysp
last
icu
mSi
ngl
eton
–M
erte
ndy
spla
sia
AD1
82
25
02
6.
Abn
orm
alm
iner
aliz
atio
ngr
oup
Hyp
opho
spha
tasi
a,pe
rin
atal
leth
alan
din
fan
tile
form
sAR
24
15
00
1p3
6.1
–p3
4AL
PLAl
kalin
eph
osp
hat
ase,
tiss
uen
on-s
pec
ific
(TN
SALP
)
Intr
afam
ilial
vari
abili
ty
Hyp
opho
spha
tasi
a,ad
ult
form
AD1
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
Hyp
opho
spha
tem
icri
cket
s,X-
linke
ddo
min
ant
XLD
30
78
00
Xp2
2PH
EXX-
linke
dhy
pop
hos
ph
atem
iam
embr
ane
pro
teas
eH
ypop
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
Hyp
opho
spha
tem
icri
cket
s,au
toso
mal
rece
ssiv
e,ty
pe1
(AR
HR
1)
AR2
41
52
04
q21
DM
P1D
enti
nm
atri
xac
idic
phos
phop
rote
in1
Hyp
opho
spha
tem
icri
cket
s,au
toso
mal
rece
ssiv
e,ty
pe2
(AR
HR
2)
AR6
13
31
26
q23
ENPP
1Ec
ton
ucle
otid
epy
roph
osp
hat
ase/
phos
phod
iest
eras
e1
Hyp
opho
spha
tem
icri
cket
sw
ith
hype
rcal
ciur
ia,
X-lin
ked
rece
ssiv
eXL
R3
00
55
4Xp
11
.22
ClCN
5Ch
lori
dech
ann
el5
Par
tof
Den
t’sd
isea
seco
mp
lex
Hyp
opho
spha
tem
icri
cket
sw
ith
hype
rcal
ciur
ia,
auto
som
alre
cess
ive
(HH
RH
)
AR2
41
53
99
q34
SLC3
4A3
Sodi
um-p
hosp
hat
eco
tran
spor
ter
Neo
nat
alhy
perp
arat
hyro
idis
m,
seve
refo
rmAR
23
92
00
3q1
3.3
–2
1CA
SRCa
lciu
m-s
ensi
ng
rece
ptor
Fam
ilial
hypo
calc
iuri
chy
perc
alce
mia
wit
htr
ansi
ent
neo
nat
alhy
perp
arat
hyr
oidi
sm
AD1
45
98
03
q13
.3–
21
CASR
Calc
ium
-sen
sin
gre
cep
tor
Calc
ium
pyro
phos
phat
ede
posi
tion
dise
ase
(fam
ilial
chon
droc
alci
nos
is)
type
2
AD1
18
60
05
p15
.2–
14
.2AN
KH
Hom
olog
ofm
ouse
ANK
(an
kylo
sis)
gen
eLo
ssof
fun
ctio
nm
uta
tion
s(s
eecr
anio
met
aph
yse
ald
ysp
lasi
ain
grou
p2
4)
See
also
Jans
endy
spla
sia
and
Eike
ndy
spla
sia
27
.Ly
soso
mal
stor
age
dise
ases
wit
hsk
elet
alin
volv
emen
t(d
ysos
tosi
sm
ulti
plex
grou
p)M
ucop
olys
acch
arid
osis
type
1H
/1S
AR6
07
01
44
p16
.3ID
AAl
pha-
1-I
dur
onid
ase
Muc
opol
ysac
char
idos
isty
pe2
XLR
30
99
00
Xq2
7.3
–2
8ID
SId
uron
ate-
2-s
ulfa
tase
Muc
opol
ysac
char
idos
isty
pe3
AAR
25
29
00
17
q25
.3H
SSH
epar
ansu
lfate
sulfa
tase
Muc
opol
ysac
char
idos
isty
pe3
BAR
25
29
20
17
q21
NAG
LUN
-Ac-
beta
-D-g
luco
sam
inid
ase
Muc
opol
ysac
char
idos
isty
pe3
CAR
25
29
30
8p1
1–
q13
HSG
NAT
Ac-C
oA:
alph
a-gl
uco
sam
inid
eN
-ace
tylt
ran
sfer
ase
Muc
opol
ysac
char
idos
isty
pe3
DAR
25
29
40
12
q14
GN
SN
-Ace
tylg
luco
sam
ine
6-s
ulfa
tase
Muc
opol
ysac
char
idos
isty
pe4
AAR
25
30
00
16
q24
.3G
ALN
SG
alac
tosa
min
e-6
-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
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
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
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
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
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
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
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
odac
tyly
-ect
oder
mal
dysp
lasi
acl
eft-
pala
tesy
ndr
ome
Type
3(E
EC3
)AD
60
42
92
3q2
7P6
3(T
P63
)Tu
mor
prot
ein
p6
3
Ectr
odac
tyly
-ect
oder
mal
dysp
lasi
acl
eft-
pala
tesy
ndr
ome
type
1(E
EC1
)AD
12
99
00
7q1
1.2
–1
2.3
Ectr
odac
tyly
-ect
oder
mal
dysp
lasi
a-m
acul
ardy
stro
phy
syn
drom
e(E
EM)
AR2
25
28
01
6q2
2CD
H3
Cadh
erin
3
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
ein
p6
3
Split
han
d-fo
otm
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
.1
Split
han
d-fo
otM
alfo
rmat
ion
,is
olat
edfo
rm,
type
2(S
HFM
2)
XL3
13
35
0Xq
26
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
Al-A
wad
iR
aas–
Rot
hsch
ildlim
b-pe
lvis
hypo
plas
ia–
apla
sia
AR2
76
82
03
p25
WN
T7A
Win
gles
s-ty
pe
MM
TVin
tegr
atio
nsi
tefa
mily
,m
emb
er7
AFu
hrm
ann
syn
drom
eAR
22
89
30
3p2
5W
NT7
AW
ingl
ess-
typ
eM
MTV
inte
grat
ion
site
fam
ily,
mem
ber
7A
RAP
ADIL
INO
syn
drom
eAR
26
62
80
8q2
4.3
REC
QL4
REC
Qpr
otei
n-li
ke4
Adam
s–O
liver
syn
drom
eAD
/AR
10
03
00
Fem
oral
hypo
plas
ia-u
nus
ual
face
syn
drom
e(F
HU
FS)
SP/A
D?
13
47
80
Som
ep
hen
oty
pic
over
lap
wit
hFF
Usy
nd
rom
e(b
elow
)Fe
mur
-fibu
la-u
lna
syn
drom
e(F
FU)
SP?
22
82
00
Han
hart
syn
drom
e(h
ypog
loss
ia–
hypo
dact
ylia
)AD
10
33
00
Scap
ulo-
iliac
dysp
lasi
a(K
osen
ow)
AD1
69
55
0N
ote:
the
part
icul
arly
com
plex
gene
tic
basi
sof
Fanc
onia
nem
iaan
dit
sco
mpl
emen
tati
ongr
oups
are
ackn
owle
dged
butn
otfu
rthe
rlis
ted
inth
isN
osol
ogy.
The
Rea
deri
sre
ferr
edto
MIM
orto
spec
ializ
edre
view
s.Se
eal
soCH
ILD
ingr
oup
20
and
the
mes
omel
ican
dac
rom
esom
elic
dysp
lasi
as3
9.
Poly
dact
yly–
Syn
dact
yly–
Trip
hala
ngi
smgr
oup
Prea
xial
poly
dact
yly
type
1(P
PD1
)AD
17
44
00
7q3
6SH
HSo
nic
Hed
geh
ogR
egu
lato
rym
uta
tion
Prea
xial
poly
dact
yly
type
1(P
PD1
)AD
17
44
00
Som
ein
stan
ces
not
linke
dto
SHH
Prea
xial
poly
dact
yly
type
2(P
PD2
)/tr
ipha
lan
geal
thum
b(T
PT)
AD1
74
50
07
q36
SHH
Son
icH
edge
hog
Reg
ula
tory
mu
tati
on
Prea
xial
poly
dact
yly
type
3(P
PD3
)AD
17
46
00
Prea
xial
poly
dact
yly
type
4(P
PD4
)AD
17
47
00
7p1
3G
LI3
Gli-
Kru
ppel
fam
ilym
emb
er3
Gre
igce
phal
opol
ysyn
dac
tyly
syn
drom
eAD
17
57
00
7p1
3G
LI3
Gli-
Kru
ppel
fam
ilym
emb
er3
Palli
ster
–H
all
syn
drom
eAD
14
65
10
7p1
3G
LI3
Gli-
Kru
ppel
fam
ilym
emb
er3
Syn
poly
dact
yly
(com
plex
,fi
bulin
1—
asso
ciat
ed)
AD6
08
18
02
2q1
3.3
FBLN
1Fi
bulin
1
Syn
poly
dact
yly
AD1
86
00
02
q31
HO
XD1
3H
omeo
box
D1
3To
wn
es–
Bro
cks
syn
drom
e(R
enal
-Ea
r-An
al-R
adia
lsy
ndr
ome)
AD1
07
48
01
6q1
2.1
SALL
1SA
L-lik
e1
Lacr
imo-
auri
culo
-den
to-d
igit
alsy
ndr
ome
(LAD
D)
AD1
49
73
01
0q2
6.1
2FG
FR2
Fibr
obla
stgr
owth
fact
orre
cept
or2
Lacr
imo-
auri
culo
-den
to-d
igit
alsy
ndr
ome
(LAD
D)
AD1
49
73
04
p16
.3FG
FR3
Fibr
obla
stgr
owth
fact
orre
cept
or3
Lacr
imo-
auri
culo
-den
to-d
igit
alsy
ndr
ome
(LAD
D)
AD1
49
73
05
p13–
p12
FGF1
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
yof
han
dsan
dfe
et(L
auri
n–
San
drow
syn
drom
e)U
nlin
ked
toSH
H
Cen
ani–
Len
zsy
nda
ctyl
yAR
21
27
80
11
p11
.2LR
P4Lo
wde
nsi
tylip
opro
tein
rece
ptor
-rel
ated
pro
tein
4
( Continued)
WARMAN ET AL. 965
Cen
ani–
Len
zlik
esy
nda
ctyl
ySP
(AD
?)
15
q13–
q14
GR
EM1
,FM
N1
Gre
mlin
1,
Form
in1
Mon
oalle
licd
up
licat
ion
ofb
oth
loci
(ob
serv
edin
one
case
only
sofa
r)O
ligos
ynda
ctyl
y,
radi
o-ul
nar
syn
osto
sis,
hear
ing
loss
,an
dre
nal
defe
cts
syn
drom
e
SP(A
R?
)1
5q1
3–
q14
FMN
1Fo
rmin
1D
elet
ion
Syn
dact
yly,
Mal
ik–
Perc
inty
peAD
60
94
32
17
p13
.3ST
ARsy
ndr
ome
(syn
dact
yly
ofto
es,
tele
can
thus
,an
o-,
and
ren
alm
alfo
rmat
ion
s)
XL3
00
70
7Xq
28
FAM
58
A
Syn
dact
yly
type
1(I
II–IV
)AD
18
59
00
2q3
4–
36
Syn
dact
yly
type
3(I
V–V)
AD1
85
90
06
q21–
23
GJA
1Sy
nda
ctyl
yty
pe4
(I–
V)H
aas
type
AD1
86
20
07
q36
SHH
Son
icH
edge
hog
Syn
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)
AD6
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
arsy
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
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
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.
REFERENCES
1970. International nomenclature of constitutional diseases of bones. AnnRadiol (Paris) 13:455–464.
1971a. A nomenclature for constitutional (intrinsic) diseases of bones.J Pediatr 78:177–179.
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.
1978. International nomenclature of constitutional diseases of bone.Revision–May, 1977. J Pediatr 93:614–616.
1979. International nomenclature of constitutional diseases of bone:Revision—May 1977. Am J Med Genet 3:21–26.
1983. International nomenclature of constitutional diseases of bone.Revision, May, 1983. Ann Radiol (Paris) 26:457–462.
1998. International nomenclature and classification of the osteochondro-dysplasias (1997). International working group on constitutional dis-eases of bone. Am J Med Genet 79:376–382.
Hall CM. 2002. International nosology and classification of constitutionaldisorders of bone (2001). Am J Med Genet 113:65–77.
Lachman RS. 1998. International nomenclature and classification of theosteochondrodysplasias (1997). Pediatr Radiol 28:737–744.
McKusick VA, Scott CI. 1971. A nomenclature for constitutional disordersof bone. J Bone Joint Surg Am 53:978–986.
Nishimura G, Hasegawa T, Kinoshita E, Tanaka Y, Kurosawa K, YoshimotoM. 2004. Newly recognized syndrome of metaphyseal undermodeling,spondylar dysplasia, and overgrowth: Report of two adolescents and achild. Am J Med Genet Part A 128A:204–208.
Rimoin DL. 1979. International nomenclature of constitutional diseases ofbone with bibliography. Birth Defects Orig Artic Ser 15:30.
Schmidt H, Kammer B, Grasser M, Enders A, Rost I, Kiess W. 2007.Endochondral gigantism: A newly recognized skeletal dysplasia with pre-and postnatal overgrowth and endocrine abnormalities. Am J Med GenetPart A 143A:1868–1875.
Sillence DO, Rimoin DL. 1978. Classification of osteogenesis imperfect.Lancet 1:1041–1042.
Sillence DO, Rimoin DL, Danks DM. 1979a. Clinical variability in osteo-genesis imperfecta-variable expressivity or genetic heterogeneity. BirthDefects Orig Artic Ser 15:113–129.
Sillence DO, Senn A, Danks DM. 1979b. Genetic heterogeneity in osteo-genesis imperfecta. J Med Genet 16:101–116.
Spranger J. 1992. International classification of osteochondrodysplasias.The international working group on constitutional diseases of bone. Eur JPediatr 151:407–415.
Stevenson DA, Viskochil DH, Carey JC. 2007. Neurofibromatosis type 1 is agenetic skeletal disorder. Am J Med Genet Part A 143A:2082–2083;authorreply 2084.
Superti-Furga A, Unger S. 2007. Nosology and classification of geneticskeletal disorders: 2006 revision. Am J Med Genet Part A 143A:1–18.
968 AMERICAN JOURNAL OF MEDICAL GENETICS PART A