RESEARCH ARTICLE

Nosology and Classication of Genetic Skeletal

Disorders: 2010 Revision
Matthew 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-Furga
12,14
*
1
Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, The Howard Hughes Medical Institute, Childrens Hospital, Boston,
Massachusetts
2
Department of Genetics and INSERM U781, Paris Descartes University, H^opital Necker Enfants Malades, Paris, France
3
Institute of Child Health, University of London, London, UK
4
Medical Genetics Institute, Steven Spielberg Building, Cedars-Sinai Medical Center, Los Angeles, California
5
Departments of Orthopaedic Surgery and Human Genetics, UCLA, Los Angeles, California
6
Department of Medical Genetics, University Hospital of Antwerp, University of Antwerp, Edegem, Belgium
7
Institut fur Medizinische Genetik, Charite Universitatsmedizin Berlin, Max-Planck-Institut fur Molekulare Genetik, Berlin, Germany
8
Department of Pediatric Imaging, Tokyo Metropolitan Childrens Medical Center, Fuchu, Tokyo, Japan
9
Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand
10
Murdoch Childrens Research Institute, Royal Childrens Hospital, Department of Paediatrics, University of Melbourne, Victoria, Australia
11
Discipline of Genetic Medicine, The Childrens Hospital at Westmead Clinical School, The University of Sydney, Westmead, Australia
12
Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, University of Freiburg, Freiburg, Germany
13
Medical Genetics Service, University of Lausanne, CHUVCentre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
14
Department of Pediatrics, University of Lausanne, CHUVCentre 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 Classication of
Genetic Skeletal Disorders provides an overview of recognized
diagnostic entities and groups themby 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 dened 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 dened
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, Childrens Hospital, Boston, Massachusetts; Childrens
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: asuperti@unil.ch
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 classication of genetic
skeletal disorders: 2010 revision.
Am J Med Genet Part A 155:943968.
2011 Wiley-Liss, Inc. 943
disorders, waiting for molecular clarication, 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 ood 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 classication of skeletal disorders, syndromes
and metabolic diseases that were being newly described. Revisions
have beenpreparedin1977, 1983, 1992, and1997[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) Signicant skeletal involvement, corresponding to the deni-
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 ndtheir 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 conrmed 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 fty-six different conditions were included and
placed in 40 groups dened 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 spectrumranging frommildtolethal. Aggrecanis one of
the important structural molecules in cartilage and it would not be
surprising if more disorders would nd their way into this group in
the future. Thus, groups 18 are based on a common underlying
gene or pathway.
Groups 917 are based on the localization of radiographic
changes to specic bone structures (vertebrae, epiphyses, meta-
physes, diaphysis, or combination thereof) or of the involved
segment (rhizo, meso, or acro). Groups 1820 are dened by
macroscopic criteria in combination with clinical features (bent
bones, slender bones, presence of multiple dislocations). Groups
2125 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 withskeletal involvement. Group29 comprises
disorders with so-called abnormal (previously anarchic) devel-
opment of skeletal components such as exostoses, ecnhondromas,
and ectopic calcication. 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 identication
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 classication, pub-
lished 30 years ago, provided a rst systematic clinical classication
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 classication as the prototypic and
universally accepted way to classify the degree of severity in OI; and
to free the Sillence classication from any direct molecular refer-
ence. Thus, the many genes that may cause osteogenesis imperfecta
have beenlistedseparately. The proliferationof OI types toreect
944 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
T
A
B
L
E
I
.
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
1
.
F
G
F
R
3
c
h
o
n
d
r
o
d
y
s
p
l
a
s
i
a
g
r
o
u
p
T
h
a
n
a
t
o
p
h
o
r
i
c
d
y
s
p
l
a
s
i
a
t
y
p
e
1
(
T
D
1
)
A
D
1
8
7
6
0
0
4
p
1
6
.
3
F
G
F
R
3
F
G
F
R
3
I
n
c
l
u
d
e
s
p
r
e
v
i
o
u
s
S
a
n
D
i
e
g
o
t
y
p
e
T
h
a
n
a
t
o
p
h
o
r
i
c
d
y
s
p
l
a
s
i
a
t
y
p
e
2
(
T
D
2
)
A
D
1
8
7
6
0
1
4
p
1
6
.
3
F
G
F
R
3
F
G
F
R
3
S
e
v
e
r
e
a
c
h
o
n
d
r
o
p
l
a
s
i
a
w
i
t
h
d
e
v
e
l
o
p
m
e
n
t
a
l
d
e
l
a
y
a
n
d
a
c
a
n
t
h
o
s
i
s
n
i
g
r
i
c
a
n
s
(
S
A
D
D
A
N
)
A
D
S
e
e
1
8
7
6
0
0
4
p
1
6
.
3
F
G
F
R
3
F
G
F
R
3
A
c
h
o
n
d
r
o
p
l
a
s
i
a
A
D
1
0
0
8
0
0
4
p
1
6
.
3
F
G
F
R
3
F
G
F
R
3
H
y
p
o
c
h
o
n
d
r
o
p
l
a
s
i
a
A
D
1
4
6
0
0
0
4
p
1
6
.
3
F
G
F
R
3
F
G
F
R
3
C
a
m
p
t
o
d
a
c
t
y
l
y
,
t
a
l
l
s
t
a
t
u
r
e
,
a
n
d
h
e
a
r
i
n
g
l
o
s
s
s
y
n
d
r
o
m
e
(
C
A
T
S
H
L
)
A
D
1
8
7
6
0
0
4
p
1
6
.
3
F
G
F
R
3
F
G
F
R
3
I
n
a
c
t
i
v
a
t
i
n
g
m
u
t
a
t
i
o
n
H
y
p
o
c
h
o
n
d
r
o
p
l
a
s
i
a
-
l
i
k
e
d
y
s
p
l
a
s
i
a
(
s
)
A
D
,
S
P
S
i
m
i
l
a
r
t
o
h
y
p
o
c
h
o
n
d
r
o
p
l
a
s
i
a
b
u
t
u
n
l
i
n
k
e
d
t
o
F
G
F
R
3
,
p
r
o
b
a
b
l
y
h
e
t
e
r
o
g
e
n
e
o
u
s
;
u
n
c
e
r
t
a
i
n
d
i
a
g
n
o
s
t
i
c
c
r
i
t
e
r
i
a
S
e
e
a
l
s
o
g
r
o
u
p
3
3
f
o
r
c
r
a
n
i
o
s
y
n
o
s
t
o
s
e
s
s
y
n
d
r
o
m
e
s
l
i
n
k
e
d
t
o
F
G
F
R
3
m
u
t
a
t
i
o
n
s
,
a
s
w
e
l
l
a
s
L
A
D
D
s
y
n
d
r
o
m
e
i
n
g
r
o
u
p
3
9
f
o
r
a
n
o
t
h
e
r
F
G
F
R
3
-
r
e
l
a
t
e
d
p
h
e
n
o
t
y
p
e
2
.
T
y
p
e
2
c
o
l
l
a
g
e
n
g
r
o
u
p
a
n
d
s
i
m
i
l
a
r
d
i
s
o
r
d
e
r
s
A
c
h
o
n
d
r
o
g
e
n
e
s
i
s
t
y
p
e
2
(
A
C
G
2
;
L
a
n
g
e
r

S
a
l
d
i
n
o
)
A
D
2
0
0
6
1
0
1
2
q
1
3
.
1
C
O
L
2
A
1
T
y
p
e
2
c
o
l
l
a
g
e
n
P
l
a
t
y
s
p
o
n
d
y
l
i
c
d
y
s
p
l
a
s
i
a
,
T
o
r
r
a
n
c
e
t
y
p
e
A
D
1
5
1
2
1
0
1
2
q
1
3
.
1
C
O
L
2
A
1
T
y
p
e
2
c
o
l
l
a
g
e
n
S
e
e
a
l
s
o
s
e
v
e
r
e
s
p
o
n
d
y
l
o
d
y
s
p
l
a
s
t
i
c
d
y
s
p
l
a
s
i
a
s
(
g
r
o
u
p
1
3
)
H
y
p
o
c
h
o
n
d
r
o
g
e
n
e
s
i
s
A
D
2
0
0
6
1
0
1
2
q
1
3
.
1
C
O
L
2
A
1
T
y
p
e
2
c
o
l
l
a
g
e
n
S
p
o
n
d
y
l
o
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
c
o
n
g
e
n
i
t
a
(
S
E
D
C
)
A
D
1
8
3
9
0
0
1
2
q
1
3
.
1
C
O
L
2
A
1
T
y
p
e
2
c
o
l
l
a
g
e
n
S
p
o
n
d
y
l
o
e
p
i
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
S
E
M
D
)
S
t
r
u
d
w
i
c
k
t
y
p
e
A
D
1
8
4
2
5
0
1
2
q
1
3
.
1
C
O
L
2
A
1
T
y
p
e
2
c
o
l
l
a
g
e
n
K
n
i
e
s
t
d
y
s
p
l
a
s
i
a
A
D
1
5
6
5
5
0
1
2
q
1
3
.
1
C
O
L
2
A
1
T
y
p
e
2
c
o
l
l
a
g
e
n
S
p
o
n
d
y
l
o
p
e
r
i
p
h
e
r
a
l
d
y
s
p
l
a
s
i
a
A
D
2
7
1
7
0
0
1
2
q
1
3
.
1
C
O
L
2
A
1
T
y
p
e
2
c
o
l
l
a
g
e
n
M
i
l
d
S
E
D
w
i
t
h
p
r
e
m
a
t
u
r
e
o
n
s
e
t
a
r
t
h
r
o
s
i
s
A
D
1
2
q
1
3
.
1
C
O
L
2
A
1
T
y
p
e
2
c
o
l
l
a
g
e
n
O
f
t
e
n
a
s
s
o
c
i
a
t
e
d
w
i
t
h
p
.
R
7
1
9
C
a
n
d
p
.
G
4
7
4
S
m
u
t
a
t
i
o
n
s
S
E
D
w
i
t
h
m
e
t
a
t
a
r
s
a
l
s
h
o
r
t
e
n
i
n
g
(
f
o
r
m
e
r
l
y
C
z
e
c
h
d
y
s
p
l
a
s
i
a
)
A
D
6
0
9
1
6
2
1
2
q
1
3
.
1
C
O
L
2
A
1
T
y
p
e
2
c
o
l
l
a
g
e
n
O
f
t
e
n
a
s
s
o
c
i
a
t
e
d
w
i
t
h
t
h
e
p
.
R
2
7
5
C
m
u
t
a
t
i
o
n
S
t
i
c
k
l
e
r
s
y
n
d
r
o
m
e
t
y
p
e
1
A
D
1
0
8
3
0
0
1
2
q
1
3
.
1
C
O
L
2
A
1
T
y
p
e
2
c
o
l
l
a
g
e
n
S
t
i
c
k
l
e
r
-
l
i
k
e
s
y
n
d
r
o
m
e
(
s
)
U
n
l
i
n
k
e
d
t
o
e
i
t
h
e
r
C
O
L
2
A
1
,
C
O
L
1
1
A
1
,
o
r
C
O
L
1
1
A
2
.
S
e
e
a
l
s
o
C
O
L
9
A
1
f
o
r
r
e
c
e
s
s
i
v
e
f
o
r
m
3
.
T
y
p
e
1
1
c
o
l
l
a
g
e
n
g
r
o
u
p
S
t
i
c
k
l
e
r
s
y
n
d
r
o
m
e
t
y
p
e
2
A
D
6
0
4
8
4
1
1
p
2
1
C
O
L
1
1
A
1
T
y
p
e
1
1
c
o
l
l
a
g
e
n
a
l
p
h
a
-
1
c
h
a
i
n
M
a
r
s
h
a
l
l
s
y
n
d
r
o
m
e
A
D
1
5
4
7
8
0
1
p
2
1
C
O
L
1
1
A
1
T
y
p
e
1
1
c
o
l
l
a
g
e
n
a
l
p
h
a
-
1
c
h
a
i
n
F
i
b
r
o
c
h
o
n
d
r
o
g
e
n
e
s
i
s
A
R
2
2
8
5
2
0
1
p
2
1
C
O
L
1
1
A
1
T
y
p
e
1
1
c
o
l
l
a
g
e
n
a
l
p
h
a
-
1
c
h
a
i
n
O
t
o
s
p
o
n
d
y
l
o
m
e
g
a
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
O
S
M
E
D
)
,
r
e
c
e
s
s
i
v
e
t
y
p
e
A
R
2
1
5
1
5
0
6
p
2
1
.
3
C
O
L
1
1
A
2
T
y
p
e
1
1
c
o
l
l
a
g
e
n
a
l
p
h
a
-
2
c
h
a
i
n
WARMAN ET AL. 945
O
t
o
s
p
o
n
d
y
l
o
m
e
g
a
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
O
S
M
E
D
)
,
d
o
m
i
n
a
n
t
t
y
p
e
(
W
e
i
s
s
e
n
b
a
c
h
e
r

Z
w
e
y
m
u
l
l
e
r
s
y
n
d
r
o
m
e
,
S
t
i
c
k
l
e
r
s
y
n
d
r
o
m
e
t
y
p
e
3
)
A
D
2
1
5
1
5
0
6
p
2
1
.
3
C
O
L
1
1
A
2
T
y
p
e
1
1
c
o
l
l
a
g
e
n
a
l
p
h
a
-
2
c
h
a
i
n
S
e
e
a
l
s
o
S
t
i
c
k
l
e
r
s
y
n
d
r
o
m
e
t
y
p
e
1
i
n
g
r
o
u
p
2
4
.
S
u
l
f
a
t
i
o
n
d
i
s
o
r
d
e
r
s
g
r
o
u
p
A
c
h
o
n
d
r
o
g
e
n
e
s
i
s
t
y
p
e
1
B
(
A
C
G
1
B
)
A
R
6
0
0
9
7
2
5
q
3
2

3
3
D
T
D
S
T
S
L
C
2
6
A
2
s
u
l
f
a
t
e
t
r
a
n
s
p
o
r
t
e
r
F
o
r
m
e
r
l
y
k
n
o
w
n
a
s
F
r
a
c
c
a
r
o
t
y
p
e
a
c
h
o
n
d
r
o
g
e
n
e
s
i
s
A
t
e
l
o
s
t
e
o
g
e
n
e
s
i
s
t
y
p
e
2
(
A
O
2
)
A
R
2
5
6
0
5
0
5
q
3
2

3
3
D
T
D
S
T
S
L
C
2
6
A
2
s
u
l
f
a
t
e
t
r
a
n
s
p
o
r
t
e
r
I
n
c
l
u
d
e
s
d
e
l
a
C
h
a
p
e
l
l
e
d
y
s
p
l
a
s
i
a
,
M
c
A
l
i
s
t
e
r
d
y
s
p
l
a
s
i
a
,
a
n
d

n
e
o
n
a
t
a
l
o
s
s
e
o
u
s
d
y
s
p
l
a
s
i
a

D
i
a
s
t
r
o
p
h
i
c
d
y
s
p
l
a
s
i
a
(
D
T
D
)
A
R
2
2
2
6
0
0
5
q
3
2

3
3
D
T
D
S
T
S
L
C
2
6
A
2
s
u
l
f
a
t
e
t
r
a
n
s
p
o
r
t
e
r
M
E
D
,
a
u
t
o
s
o
m
a
l
r
e
c
e
s
s
i
v
e
t
y
p
e
(
r
M
E
D
;
E
D
M
4
)
A
R
2
2
6
9
0
0
5
q
3
2

3
3
D
T
D
S
T
S
L
C
2
6
A
2
s
u
l
f
a
t
e
t
r
a
n
s
p
o
r
t
e
r
S
e
e
a
l
s
o
m
u
l
t
i
p
l
e
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
s
a
n
d
p
s
e
u
d
o
a
c
h
o
n
d
r
o
p
l
a
s
i
a
g
r
o
u
p
(
g
r
o
u
p
9
)
S
E
M
D
,
P
A
P
S
S
2
t
y
p
e
A
R
6
0
3
0
0
5
1
0
q
2
3

q
2
4
P
A
P
S
S
2
P
A
P
S
-
S
y
n
t
h
e
t
a
s
e
2
F
o
r
m
e
r
l
y

P
a
k
i
s
t
a
n
i
t
y
p
e
.

S
e
e
a
l
s
o
S
E
M
D
g
r
o
u
p
(
g
r
o
u
p
1
1
)
C
h
o
n
d
r
o
d
y
s
p
l
a
s
i
a
w
i
t
h
c
o
n
g
e
n
i
t
a
l
j
o
i
n
t
d
i
s
l
o
c
a
t
i
o
n
s
,
C
H
S
T
3
t
y
p
e
(
r
e
c
e
s
s
i
v
e
L
a
r
s
e
n
s
y
n
d
r
o
m
e
)
A
R
6
0
8
6
3
7
1
0
q
2
2
.
1
C
H
S
T
3
C
a
r
b
o
h
y
d
r
a
t
e
s
u
l
f
o
t
r
a
n
s
f
e
r
a
s
e
3
;
c
h
o
n
d
r
o
i
t
i
n
6
-
s
u
l
f
o
t
r
a
n
s
f
e
r
a
s
e
I
n
c
l
u
d
e
s
r
e
c
e
s
s
i
v
e
L
a
r
s
e
n
s
y
n
d
r
o
m
e
,
h
u
m
e
r
o
-
s
p
i
n
a
l
d
y
s
o
s
t
o
s
i
s
,
a
n
d
S
E
D
O
m
a
n
i
t
y
p
e
E
h
l
e
r
s

D
a
n
l
o
s
s
y
n
d
r
o
m
e
,
C
H
S
T
1
4
t
y
p
e
(

m
u
s
c
u
l
o
-
s
k
e
l
e
t
a
l
v
a
r
i
a
n
t

)
A
R
6
0
1
7
7
6
1
5
q
1
4
C
H
S
T
1
4
C
a
r
b
o
h
y
d
r
a
t
e
s
u
l
f
o
t
r
a
n
s
f
e
r
a
s
e
1
4
;
d
e
r
m
a
t
a
n
4
-
s
u
l
f
o
t
r
a
n
s
f
e
r
a
s
e
I
n
c
l
u
d
e
s
A
d
d
u
c
t
e
d
T
h
u
m
b

C
l
u
b
f
o
o
t
s
y
n
d
r
o
m
e
S
e
e
a
l
s
o
g
r
o
u
p
7
a
n
d
g
r
o
u
p
2
6
f
o
r
o
t
h
e
r
c
o
n
d
i
t
i
o
n
s
w
i
t
h
m
u
l
t
i
p
l
e
d
i
s
l
o
c
a
t
i
o
n
s
5
.
P
e
r
l
e
c
a
n
g
r
o
u
p
D
y
s
s
e
g
m
e
n
t
a
l
d
y
s
p
l
a
s
i
a
,
S
i
l
v
e
r
m
a
n
-
H
a
n
d
m
a
k
e
r
t
y
p
e
A
R
2
2
4
4
1
0
1
q
3
6

3
4
P
L
C
(
H
S
P
G
2
)
P
e
r
l
e
c
a
n
D
y
s
s
e
g
m
e
n
t
a
l
d
y
s
p
l
a
s
i
a
,
R
o
l
l
a
n
d
-
D
e
s
b
u
q
u
o
i
s
t
y
p
e
A
R
2
2
4
4
0
0
1
q
3
6

3
4
P
L
C
(
H
S
P
G
2
)
P
e
r
l
e
c
a
n
S
c
h
w
a
r
t
z

J
a
m
p
e
l
s
y
n
d
r
o
m
e
(
m
y
o
t
o
n
i
c
c
h
o
n
d
r
o
d
y
s
t
r
o
p
h
y
)
A
R
2
5
5
8
0
0
1
q
3
6

3
4
P
L
C
(
H
S
P
G
2
)
P
e
r
l
e
c
a
n
M
i
l
d
a
n
d
s
e
v
e
r
e
f
o
r
m
s
;
i
n
c
l
u
d
e
s
p
r
e
v
i
o
u
s
B
u
r
t
o
n
d
y
s
p
l
a
s
i
a
6
.
A
g
g
r
e
c
a
n
g
r
o
u
p
S
E
D
,
K
i
m
b
e
r
l
e
y
t
y
p
e
A
D
6
0
8
3
6
1
1
5
q
2
6
A
G
C
1
A
g
g
r
e
c
a
n
S
E
M
D
,
A
g
g
r
e
c
a
n
t
y
p
e
A
R
6
1
2
8
1
3
1
5
q
2
6
A
G
C
1
A
g
g
r
e
c
a
n
F
a
m
i
l
i
a
l
o
s
t
e
o
c
h
o
n
d
r
i
t
i
s
d
i
s
s
e
c
a
n
s
A
D
1
6
5
8
0
0
1
5
q
2
6
A
G
C
1
A
g
g
r
e
c
a
n
7
.
F
i
l
a
m
i
n
g
r
o
u
p
a
n
d
r
e
l
a
t
e
d
d
i
s
o
r
d
e
r
s
F
r
o
n
t
o
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
X
L
D
3
0
5
6
2
0
X
q
2
8
F
L
N
A
F
i
l
a
m
i
n
A
S
o
m
e
c
a
s
e
s
a
p
p
a
r
e
n
t
l
y
l
a
c
k
F
L
N
A
m
u
t
a
t
i
o
n
s
O
s
t
e
o
d
y
s
p
l
a
s
t
y
M
e
l
n
i
c
k

N
e
e
d
l
e
s
X
L
D
3
0
9
3
5
0
X
q
2
8
F
L
N
A
F
i
l
a
m
i
n
A
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
946 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
O
t
o
p
a
l
a
t
o
d
i
g
i
t
a
l
s
y
n
d
r
o
m
e
t
y
p
e
1
(
O
P
D
1
)
X
L
D
3
1
1
3
0
0
X
q
2
8
F
L
N
A
F
i
l
a
m
i
n
A
O
t
o
p
a
l
a
t
o
d
i
g
i
t
a
l
s
y
n
d
r
o
m
e
t
y
p
e
2
(
O
P
D
2
)
X
L
D
3
0
4
1
2
0
X
q
2
8
F
L
N
A
F
i
l
a
m
i
n
A
T
e
r
m
i
n
a
l
o
s
s
e
o
u
s
d
y
s
p
l
a
s
i
a
w
i
t
h
p
i
g
m
e
n
t
a
r
y
d
e
f
e
c
t
s
(
T
O
D
P
D
)
X
L
D
3
0
0
2
4
4
X
q
2
8
F
L
N
A
F
i
l
a
m
i
n
A
A
t
e
l
o
s
t
e
o
g
e
n
e
s
i
s
t
y
p
e
1
(
A
O
1
)
A
D
1
0
8
7
2
0
3
p
1
4
.
3
F
L
N
B
F
i
l
a
m
i
n
B
I
n
c
l
u
d
e
s
B
o
o
m
e
r
a
n
g
d
y
s
p
l
a
s
i
a
,
P
i
e
p
k
o
r
n
d
y
s
p
l
a
s
i
a
,
a
n
d
s
p
o
n
d
y
l
o
h
u
m
e
r
o
f
e
m
o
r
a
l
(
g
i
a
n
t
c
e
l
l
)
d
y
s
p
l
a
s
i
a
A
t
e
l
o
s
t
e
o
g
e
n
e
s
i
s
t
y
p
e
3
(
A
O
3
)
A
D
1
0
8
7
2
1
3
p
1
4
.
3
F
L
N
B
F
i
l
a
m
i
n
B
L
a
r
s
e
n
s
y
n
d
r
o
m
e
(
d
o
m
i
n
a
n
t
)
A
D
1
5
0
2
5
0
3
p
1
4
.
3
F
L
N
B
F
i
l
a
m
i
n
B
S
p
o
n
d
y
l
o
-
c
a
r
p
a
l
-
t
a
r
s
a
l
d
y
s
p
l
a
s
i
a
A
R
2
7
2
4
6
0
3
p
1
4
.
3
F
L
N
B
F
i
l
a
m
i
n
B
S
p
o
n
d
y
l
o
-
c
a
r
p
a
l
-
t
a
r
s
a
l
d
y
s
p
l
a
s
i
a
A
R
2
7
2
4
6
0
U
n
l
i
n
k
e
d
t
o
F
L
N
B
F
r
a
n
c
k

t
e
r
H
a
a
r
s
y
n
d
r
o
m
e
A
R
2
4
9
4
2
0
5
q
3
5
.
1
S
H
3
P
X
D
2
B
T
K
S
4
S
e
r
p
e
n
t
i
n
e

b
u
l
a

p
o
l
y
c
y
s
t
i
c
k
i
d
n
e
y
s
y
n
d
r
o
m
e
A
D
?
6
0
0
3
3
0
S
e
e
a
l
s
o
g
r
o
u
p
4
f
o
r
r
e
c
e
s
s
i
v
e
L
a
r
s
e
n
s
y
n
d
r
o
m
e
a
n
d
g
r
o
u
p
2
6
f
o
r
c
o
n
d
i
t
i
o
n
s
w
i
t
h
m
u
l
t
i
p
l
e
d
i
s
l
o
c
a
t
i
o
n
s
8
.
T
R
P
V
4
g
r
o
u
p
M
e
t
a
t
r
o
p
i
c
d
y
s
p
l
a
s
i
a
A
D
1
5
6
5
3
0
1
2
q
2
4
.
1
T
R
P
V
4
T
r
a
n
s
i
e
n
t
r
e
c
e
p
t
o
r
p
o
t
e
n
t
i
a
l
c
a
t
i
o
n
c
h
a
n
n
e
l
,
s
u
b
f
a
m
i
l
y
V
,
m
e
m
b
e
r
4
I
n
c
l
u
d
e
s
l
e
t
h
a
l
a
n
d
n
o
n
-
l
e
t
h
a
l
f
o
r
m
s
S
p
o
n
d
y
l
o
e
p
i
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
M
a
r
o
t
e
a
u
x
t
y
p
e
(
P
s
e
u
d
o

M
o
r
q
u
i
o
s
y
n
d
r
o
m
e
t
y
p
e
2
)
A
D
1
8
4
0
9
5
1
2
q
2
4
.
1
T
R
P
V
4
T
r
a
n
s
i
e
n
t
r
e
c
e
p
t
o
r
p
o
t
e
n
t
i
a
l
c
a
t
i
o
n
c
h
a
n
n
e
l
,
s
u
b
f
a
m
i
l
y
V
,
m
e
m
b
e
r
4
S
p
o
n
d
y
l
o
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
K
o
z
l
o
w
s
k
i
t
y
p
e
A
D
1
8
4
2
5
2
1
2
q
2
4
.
1
T
R
P
V
4
T
r
a
n
s
i
e
n
t
r
e
c
e
p
t
o
r
p
o
t
e
n
t
i
a
l
c
a
t
i
o
n
c
h
a
n
n
e
l
,
s
u
b
f
a
m
i
l
y
V
,
m
e
m
b
e
r
4
B
r
a
c
h
y
o
l
m
i
a
,
a
u
t
o
s
o
m
a
l
d
o
m
i
n
a
n
t
t
y
p
e
A
D
1
1
3
5
0
0
1
2
q
2
4
.
1
T
R
P
V
4
T
r
a
n
s
i
e
n
t
r
e
c
e
p
t
o
r
p
o
t
e
n
t
i
a
l
c
a
t
i
o
n
c
h
a
n
n
e
l
,
s
u
b
f
a
m
i
l
y
V
,
m
e
m
b
e
r
4
F
a
m
i
l
i
a
l
d
i
g
i
t
a
l
a
r
t
h
r
o
p
a
t
h
y
w
i
t
h
b
r
a
c
h
y
d
a
c
t
y
l
y
A
D
6
0
6
8
3
5
1
2
q
2
4
.
1
T
R
P
V
4
T
r
a
n
s
i
e
n
t
r
e
c
e
p
t
o
r
p
o
t
e
n
t
i
a
l
c
a
t
i
o
n
c
h
a
n
n
e
l
,
s
u
b
f
a
m
i
l
y
V
,
m
e
m
b
e
r
4
9
.
S
h
o
r
t
-
r
i
b
s
d
y
s
p
l
a
s
i
a
s
(
w
i
t
h
o
r
w
i
t
h
o
u
t
p
o
l
y
d
a
c
t
y
l
y
)
g
r
o
u
p
C
h
o
n
d
r
o
e
c
t
o
d
e
r
m
a
l
d
y
s
p
l
a
s
i
a
(
E
l
l
i
s

v
a
n
C
r
e
v
e
l
d
)
A
R
2
2
5
5
0
0
4
p
1
6
E
V
C
1
E
v
C
g
e
n
e
1
4
p
1
6
E
V
C
2
E
v
C
g
e
n
e
2
S
h
o
r
t
r
i
b

p
o
l
y
d
a
c
t
y
l
y
s
y
n
d
r
o
m
e
(
S
R
P
S
)
t
y
p
e
1
/
3
(
S
a
l
d
i
n
o
-
N
o
o
n
a
n
/
V
e
r
m
a
-
N
a
u
m
o
f
f
)
A
R
2
6
3
5
1
0
1
1
q
2
2
.
3
D
Y
N
C
2
H
1
D
y
n
e
i
n
,
c
y
t
o
p
l
a
s
m
i
c
2
,
h
e
a
v
y
c
h
a
i
n
1
S
R
P
S
t
y
p
e
1
/
3
(
S
a
l
d
i
n
o
-
N
o
o
n
a
n
/
V
e
r
m
a
-
N
a
u
m
o
f
f
)
A
R
2
6
3
5
1
0
3
q
2
5
.
3
3
I
F
T
8
0
I
n
t
r
a

a
g
e
l
l
a
r
t
r
a
n
s
p
o
r
t
8
0
(
h
o
m
o
l
o
g
o
f
)
S
R
P
S
t
y
p
e
1
/
3
(
S
a
l
d
i
n
o
-
N
o
o
n
a
n
/
V
e
r
m
a
-
N
a
u
m
o
f
f
)
A
R
2
6
3
5
1
0
U
n
l
i
n
k
e
d
t
o
e
i
t
h
e
r
D
Y
N
C
2
H
1
o
r
I
F
T
8
0
S
R
P
S
t
y
p
e
2
(
M
a
j
e
w
s
k
i
)
A
R
2
6
3
5
2
0
N
E
K
1
N
i
m
a
r
e
l
a
t
e
d
k
i
n
a
s
e
1
(
C
o
n
t
i
n
u
e
d
)
WARMAN ET AL. 947
S
R
P
S
t
y
p
e
4
(
B
e
e
m
e
r
)
A
R
2
6
9
8
6
0
O
r
a
l
-
f
a
c
i
a
l
-
d
i
g
i
t
a
l
s
y
n
d
r
o
m
e
t
y
p
e
4
(
M
o
h
r

M
a
j
e
w
s
k
i
)
A
R
2
5
8
8
6
0
A
s
p
h
y
x
i
a
t
i
n
g
t
h
o
r
a
c
i
c
d
y
s
p
l
a
s
i
a
(
A
T
D
;
J
e
u
n
e
)
A
R
2
0
8
5
0
0
3
q
2
5
.
3
3
I
F
T
8
0
I
n
t
r
a

a
g
e
l
l
a
r
t
r
a
n
s
p
o
r
t
8
0
(
h
o
m
o
l
o
g
o
f
)
A
s
p
h
y
x
i
a
t
i
n
g
t
h
o
r
a
c
i
c
d
y
s
p
l
a
s
i
a
(
A
T
D
;
J
e
u
n
e
)
A
R
2
0
8
5
0
0
1
1
q
2
2
.
3
D
Y
N
C
2
H
1
D
y
n
e
i
n
,
c
y
t
o
p
l
a
s
m
i
c
2
,
h
e
a
v
y
c
h
a
i
n
1
A
s
p
h
y
x
i
a
t
i
n
g
t
h
o
r
a
c
i
c
d
y
s
p
l
a
s
i
a
(
A
T
D
;
J
e
u
n
e
)
A
R
2
0
8
5
0
0
U
n
l
i
n
k
e
d
t
o
e
i
t
h
e
r
D
Y
N
C
2
H
1
o
r
I
F
T
8
0
T
h
o
r
a
c
o
l
a
r
y
n
g
o
p
e
l
v
i
c
d
y
s
p
l
a
s
i
a
(
B
a
r
n
e
s
)
A
D
1
8
7
7
6
0
S
e
e
a
l
s
o
p
a
t
e
r
n
a
l
U
P
D
1
4
a
n
d
c
e
r
e
b
r
o
-
c
o
s
t
o
-
m
a
n
d
i
b
u
l
a
r
s
y
n
d
r
o
m
e
1
0
.
M
u
l
t
i
p
l
e
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
a
n
d
p
s
e
u
d
o
a
c
h
o
n
d
r
o
p
l
a
s
i
a
g
r
o
u
p
P
s
e
u
d
o
a
c
h
o
n
d
r
o
p
l
a
s
i
a
(
P
S
A
C
H
)
A
D
1
7
7
1
7
0
1
9
p
1
2

1
3
.
1
C
O
M
P
C
O
M
P
M
u
l
t
i
p
l
e
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
M
E
D
)
t
y
p
e
1
(
E
D
M
1
)
A
D
1
3
2
4
0
0
1
9
p
1
3
.
1
C
O
M
P
C
O
M
P
M
u
l
t
i
p
l
e
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
M
E
D
)
t
y
p
e
2
(
E
D
M
2
)
A
D
6
0
0
2
0
4
1
p
3
2
.
2

3
3
C
O
L
9
A
2
C
o
l
l
a
g
e
n
9
a
l
p
h
a
-
2
c
h
a
i
n
M
u
l
t
i
p
l
e
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
M
E
D
)
t
y
p
e
3
(
E
D
M
3
)
A
D
6
0
0
9
6
9
2
0
q
1
3
.
3
C
O
L
9
A
3
C
o
l
l
a
g
e
n
9
a
l
p
h
a
-
3
c
h
a
i
n
M
u
l
t
i
p
l
e
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
M
E
D
)
t
y
p
e
5
(
E
D
M
5
)
A
D
6
0
7
0
7
8
2
p
2
3

2
4
M
A
T
N
3
M
a
t
r
i
l
i
n
3
M
u
l
t
i
p
l
e
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
M
E
D
)
t
y
p
e
6
(
E
D
M
6
)
A
D
1
2
0
2
1
0
6
q
1
3
C
O
L
9
A
1
C
o
l
l
a
g
e
n
9
a
l
p
h
a
-
1
c
h
a
i
n
M
u
l
t
i
p
l
e
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
M
E
D
)
,
o
t
h
e
r
t
y
p
e
s
S
o
m
e
M
E
D
-
l
i
k
e
c
a
s
e
s
u
n
l
i
n
k
e
d
t
o
k
n
o
w
n
g
e
n
e
s
S
t
i
c
k
l
e
r
s
y
n
d
r
o
m
e
,
r
e
c
e
s
s
i
v
e
t
y
p
e
A
R
1
2
0
2
1
0
6
q
1
3
C
O
L
9
A
1
C
o
l
l
a
g
e
n
9
a
l
p
h
a
-
1
c
h
a
i
n
F
a
m
i
l
i
a
l
h
i
p
d
y
s
p
l
a
s
i
a
(
B
e
u
k
e
s
)
A
D
1
4
2
6
6
9
4
q
3
5
M
u
l
t
i
p
l
e
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
w
i
t
h
m
i
c
r
o
c
e
p
h
a
l
y
a
n
d
n
y
s
t
a
g
m
u
s
(
L
o
w
r
y
-
W
o
o
d
)
A
R
2
2
6
9
6
0
S
e
e
a
l
s
o
m
u
l
t
i
p
l
e
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
r
e
c
e
s
s
i
v
e
t
y
p
e
(
r
M
E
D
;
E
D
M
4
)
i
n
s
u
l
f
a
t
i
o
n
d
i
s
o
r
d
e
r
s
(
g
r
o
u
p
4
)
,
f
a
m
i
l
i
a
l
o
s
t
e
o
c
h
o
n
d
r
i
t
i
s
d
i
s
s
e
c
a
n
s
i
n
t
h
e
a
g
g
r
e
c
a
n
g
r
o
u
p
,
a
s
w
e
l
l
a
s
A
S
P
E
D
i
n
t
h
e
A
c
r
o
m
e
l
i
c
g
r
o
u
p
1
1
.
M
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
s
M
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
S
c
h
m
i
d
t
y
p
e
(
M
C
S
)
A
D
1
5
6
5
0
0
6
q
2
1

2
2
.
3
C
O
L
1
0
A
1
C
o
l
l
a
g
e
n
1
0
a
l
p
h
a
-
1
c
h
a
i
n
C
a
r
t
i
l
a
g
e
-
h
a
i
r
h
y
p
o
p
l
a
s
i
a
(
C
H
H
;
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
M
c
K
u
s
i
c
k
t
y
p
e
)
A
R
2
5
0
2
5
0
9
p
1
3
R
M
R
P
R
N
A
c
o
m
p
o
n
e
n
t
o
f
R
N
A
s
e
H
I
n
c
l
u
d
e
s
a
n
a
u
x
e
t
i
c
d
y
s
p
l
a
s
i
a
M
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
J
a
n
s
e
n
t
y
p
e
A
D
1
5
6
4
0
0
3
p
2
2

2
1
.
1
P
T
H
R
1
P
T
H
/
P
T
H
r
P
r
e
c
e
p
t
o
r
1
A
c
t
i
v
a
t
i
n
g
m
u
t
a
t
i
o
n
s

s
e
e
a
l
s
o
B
l
o
m
s
t
r
a
n
d
d
y
s
p
l
a
s
i
a
(
g
r
o
u
p
2
2
,
2
3
)
E
i
k
e
n
d
y
s
p
l
a
s
i
a
A
R
6
0
0
0
0
2
3
p
2
2

2
1
.
1
P
T
H
R
1
P
T
H
/
P
T
H
r
P
r
e
c
e
p
t
o
r
1
A
c
t
i
v
a
t
i
n
g
m
u
t
a
t
i
o
n
s

s
e
e
a
l
s
o
B
l
o
m
s
t
r
a
n
d
d
y
s
p
l
a
s
i
a
(
g
r
o
u
p
2
2
,
2
3
)
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
948 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
M
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
w
i
t
h
p
a
n
c
r
e
a
t
i
c
i
n
s
u
f

c
i
e
n
c
y
a
n
d
c
y
c
l
i
c
n
e
u
t
r
o
p
e
n
i
a
(
S
h
w
a
c
h
m
a
n

B
o
d
i
a
n

D
i
a
m
o
n
d
s
y
n
d
r
o
m
e
,
S
B
D
S
)
A
R
2
6
0
4
0
0
7
q
1
1
S
B
D
S
S
B
D
S
p
r
o
t
e
i
n
M
e
t
a
p
h
y
s
e
a
l
a
n
a
d
y
s
p
l
a
s
i
a
t
y
p
e
1
A
D
,
A
R
3
0
9
6
4
5
1
1
q
2
2
.
2
M
M
P
1
3
M
a
t
r
i
x
m
e
t
a
l
l
o
p
r
o
t
e
i
n
a
s
e
1
3
I
n
c
l
u
d
e
s
S
E
M
D
M
i
s
s
o
u
r
i
t
y
p
e
.
B
o
t
h
d
o
m
i
n
a
n
t
a
n
d
r
e
c
e
s
s
i
v
e
m
u
t
a
t
i
o
n
s
d
e
s
c
r
i
b
e
d
M
e
t
a
p
h
y
s
e
a
l
a
n
a
d
y
s
p
l
a
s
i
a
t
y
p
e
2
A
R
2
0
q
1
3
.
1
2
M
M
P
9
M
a
t
r
i
x
m
e
t
a
l
l
o
p
r
o
t
e
i
n
a
s
e
9
M
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
S
p
a
h
r
t
y
p
e
A
R
2
5
0
4
0
0
M
e
t
a
p
h
y
s
e
a
l
a
c
r
o
s
c
y
p
h
o
d
y
s
p
l
a
s
i
a
(
v
a
r
i
o
u
s
t
y
p
e
s
)
A
R
2
5
0
2
1
5
G
e
n
o
c
h
o
n
d
r
o
m
a
t
o
s
i
s
(
t
y
p
e
1
/
t
y
p
e
2
)
A
D
/
S
P
1
3
7
3
6
0
M
e
t
a
p
h
y
s
e
a
l
c
h
o
n
d
r
o
m
a
t
o
s
i
s
w
i
t
h
D
-
2
-
h
y
d
r
o
x
y
g
l
u
t
a
r
i
c
a
c
i
d
u
r
i
a
A
R
/
S
P
S
e
e
2
7
1
5
5
0
1
2
.
S
p
o
n
d
y
l
o
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
s
(
S
M
D
)
S
p
o
n
d
y
l
o
e
n
c
h
o
n
d
r
o
d
y
s
p
l
a
s
i
a
(
S
P
E
N
C
D
)
A
R
2
7
1
5
5
0
1
9
p
1
3
.
2
A
C
P
5
T
a
r
t
r
a
t
e
-
r
e
s
i
s
t
a
n
t
a
c
i
d
p
h
o
s
p
h
a
t
a
s
e
(
T
R
A
P
)
I
n
c
l
u
d
e
s
c
o
m
b
i
n
e
d
i
m
m
u
n
o
d
e

c
i
e
n
c
y
w
i
t
h
a
u
t
o
i
m
m
u
n
i
t
y
a
n
d
s
p
o
n
d
y
l
o
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
M
I
M
6
0
7
9
4
4
)
O
d
o
n
t
o
c
h
o
n
d
r
o
d
y
s
p
l
a
s
i
a
(
O
D
C
D
)
A
R
1
8
4
2
6
0
S
p
o
n
d
y
l
o
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
S
u
t
c
l
i
f
f
e
t
y
p
e
o
r
c
o
r
n
e
r
f
r
a
c
t
u
r
e
s
t
y
p
e
A
D
1
8
4
2
5
5
S
M
D
w
i
t
h
s
e
v
e
r
e
g
e
n
u
v
a
l
g
u
m
A
D
1
8
4
2
5
3
I
n
c
l
u
d
e
s
S
M
D
S
c
h
m
i
d
t
t
y
p
e
a
n
d
S
M
D
A
l
g
e
r
i
a
n
t
y
p
e
S
M
D
w
i
t
h
c
o
n
e
-
r
o
d
d
y
s
t
r
o
p
h
y
A
R
6
0
8
9
4
0
S
M
D
w
i
t
h
r
e
t
i
n
a
l
d
e
g
e
n
e
r
a
t
i
o
n
,
a
x
i
a
l
t
y
p
e
A
R
6
0
2
2
7
1
D
y
s
s
p
o
n
d
y
l
o
e
n
c
h
o
n
d
r
o
m
a
t
o
s
i
s
S
P
C
h
e
i
r
o
-
s
p
o
n
d
y
l
o
e
n
c
h
o
n
d
r
o
m
a
t
o
s
i
s
S
P
S
e
e
a
l
s
o
g
r
o
u
p
2
9
S
e
e
a
l
s
o
S
M
D
K
o
z
l
o
w
s
k
i
(
g
r
o
u
p
T
R
P
V
4
)
d
i
s
o
r
d
e
r
s
i
n
g
r
o
u
p
1
1
a
s
w
e
l
l
a
s
S
M
D
S
e
d
a
g
h
a
t
i
a
n
t
y
p
e
i
n
g
r
o
u
p
1
2
;
t
h
e
r
e
a
r
e
m
a
n
y
i
n
d
i
v
i
d
u
a
l
r
e
p
o
r
t
s
o
f
S
M
D
v
a
r
i
a
n
t
s
1
3
.
S
p
o
n
d
y
l
o
-
e
p
i
-
(
m
e
t
a
)
-
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
s
(
S
E
(
M
)
D
)
D
y
g
g
v
e

M
e
l
c
h
i
o
r

C
l
a
u
s
e
n
d
y
s
p
l
a
s
i
a
(
D
M
C
)
A
R
2
2
3
8
0
0
1
8
q
1
2

2
1
.
1
D
Y
M
D
y
m
e
c
l
i
n
I
n
c
l
u
d
e
s
S
m
i
t
h

M
c
C
o
r
t
d
y
s
p
l
a
s
i
a
I
m
m
u
n
o
-
o
s
s
e
o
u
s
d
y
s
p
l
a
s
i
a
(
S
c
h
i
m
k
e
)
A
R
2
4
2
9
0
0
2
q
3
4

3
6
S
M
A
R
C
A
L
1
S
W
I
/
S
N
F
-
r
e
l
a
t
e
d
r
e
g
u
l
a
t
o
r
o
f
c
h
r
o
m
a
t
i
n
s
u
b
f
a
m
i
l
y
A
-
l
i
k
e
p
r
o
t
e
i
n
1
S
E
D
,
W
o
l
c
o
t
t

R
a
l
l
i
s
o
n
t
y
p
e
A
R
2
2
6
9
8
0
2
p
1
2
E
I
F
2
A
K
3
T
r
a
n
s
l
a
t
i
o
n
i
n
i
t
i
a
t
i
o
n
f
a
c
t
o
r
2
-
a
l
p
h
a
k
i
n
a
s
e
-
3
S
E
M
D
,
M
a
t
r
i
l
i
n
t
y
p
e
A
R
6
0
8
7
2
8
2
p
2
3

p
2
4
M
A
T
N
3
M
a
t
r
i
l
i
n
3
S
e
e
a
l
s
o
m
a
t
r
i
l
i
n
-
r
e
l
a
t
e
d
M
E
D
i
n
g
r
o
u
p
8
S
E
M
D
,
s
h
o
r
t
l
i
m
b

a
b
n
o
r
m
a
l
c
a
l
c
i

c
a
t
i
o
n
t
y
p
e
A
R
2
7
1
6
6
5
1
q
2
3
D
D
R
2
D
i
s
c
o
i
d
i
n
d
o
m
a
i
n
r
e
c
e
p
t
o
r
f
a
m
i
l
y
,
m
e
m
b
e
r
2
S
e
e
a
l
s
o
o
t
h
e
r
d
y
s
p
l
a
s
i
a
s
w
i
t
h
s
t
i
p
p
l
i
n
g
i
n
g
r
o
u
p
2
0
S
E
D
t
a
r
d
a
,
X
-
l
i
n
k
e
d
(
S
E
D
-
X
L
)
X
L
R
3
1
3
4
0
0
X
p
2
2
S
E
D
L
S
e
d
l
i
n
S
p
o
n
d
y
l
o
-
m
e
g
a
e
p
i
p
h
y
s
e
a
l
-
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
S
M
M
D
)
A
R
6
1
3
3
3
0
4
p
1
6
.
1
N
K
X
3
-
2
N
K
3
H
o
m
e
o
b
o
x
2
(
C
o
n
t
i
n
u
e
d
)
WARMAN ET AL. 949
S
p
o
n
d
y
l
o
d
y
s
p
l
a
s
t
i
c
E
h
l
e
r
s

D
a
n
l
o
s
s
y
n
d
r
o
m
e
A
R
6
1
2
3
5
0
1
1
p
1
1
.
2
S
L
C
3
9
A
1
3
Z
i
n
c
t
r
a
n
s
p
o
r
t
e
r
Z
I
P
1
3
S
P
O
N
A
S
T
R
I
M
E
d
y
s
p
l
a
s
i
a
A
R
2
7
1
5
1
0
S
E
M
D
w
i
t
h
j
o
i
n
t
l
a
x
i
t
y
(
S
E
M
D
-
J
L
)
l
e
p
t
o
d
a
c
t
y
l
i
c
o
r
H
a
l
l
t
y
p
e
A
D
6
0
3
5
4
6
S
E
M
D
w
i
t
h
j
o
i
n
t
l
a
x
i
t
y
(
S
E
M
D
-
J
L
)
B
e
i
g
h
t
o
n
t
y
p
e
A
R
2
7
1
6
4
0
P
l
a
t
y
s
p
o
n
d
y
l
y
(
b
r
a
c
h
y
o
l
m
i
a
)
w
i
t
h
a
m
e
l
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
A
R
6
0
1
2
1
6
L
a
t
e
o
n
s
e
t
S
E
D
,
a
u
t
o
s
o
m
a
l
r
e
c
e
s
s
i
v
e
t
y
p
e
A
R
6
0
9
2
2
3
B
r
a
c
h
y
o
l
m
i
a
,
H
o
b
a
e
k
,
a
n
d
T
o
l
e
d
o
t
y
p
e
s
A
R
2
7
1
5
3
0
,
2
7
1
6
3
0
N
o
s
o
l
o
g
i
c
r
e
l
a
t
i
o
n
s
h
i
p
b
e
t
w
e
e
n
t
h
e
T
o
l
e
a
d
o
a
n
d
H
o
b
a
e
k
t
y
p
e
s
o
f
b
r
a
c
h
y
o
l
m
i
a
a
n
d
r
e
c
e
s
s
i
v
e
l
a
t
e
-
o
n
s
e
t
S
E
D
a
r
e
u
n
c
l
e
a
r
,
d
i
s
t
i
n
c
t
i
v
e
c
r
i
t
e
r
i
a
l
a
c
k
i
n
g
s
o
f
a
r
S
e
e
a
l
s
o
B
r
a
c
h
y
o
l
m
i
a
(
g
r
o
u
p
8
)
,
O
p
s
i
s
m
o
d
y
s
p
l
a
s
i
a
(
g
r
o
u
p
1
4
)
,
S
E
M
D
s
(
g
r
o
u
p
1
1
)
,
m
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
4
(
M
o
r
q
u
i
o
s
y
n
d
r
o
m
e
)
a
n
d
o
t
h
e
r
c
o
n
d
i
t
i
o
n
s
i
n
g
r
o
u
p
2
6
,
a
s
w
e
l
l
a
s
P
P
R
D
(
S
E
D
w
i
t
h
p
r
o
g
r
e
s
s
i
v
e
a
r
t
h
r
o
p
a
t
h
y
)
i
n
g
r
o
u
p
3
1
1
4
.
S
e
v
e
r
e
s
p
o
n
d
y
l
o
d
y
s
p
l
a
s
t
i
c
d
y
s
p
l
a
s
i
a
s
A
c
h
o
n
d
r
o
g
e
n
e
s
i
s
t
y
p
e
1
A
(
A
C
G
1
A
)
A
R
2
0
0
6
0
0
1
4
q
3
2
.
1
2
T
R
I
P
1
1
G
o
l
g
i
-
m
i
c
r
o
t
u
b
u
l
e
-
a
s
s
o
c
i
a
t
e
d
p
r
o
t
e
i
n
,
2
1
0
-
k
D
a
;
G
M
A
P
2
1
0
S
c
h
n
e
c
k
e
n
b
e
c
k
e
n
d
y
s
p
l
a
s
i
a
A
R
2
6
9
2
5
0
1
p
3
1
.
3
S
L
C
3
5
D
1
S
o
l
u
t
e
c
a
r
r
i
e
r
f
a
m
i
l
y
3
5
m
e
m
b
e
r
D
1
;
U
D
P
-
g
l
u
c
u
r
o
n
i
c
a
c
i
d
/
U
D
P
-
N
-
a
c
e
t
y
l
g
a
l
a
c
t
o
s
a
m
i
n
e
d
u
a
l
t
r
a
n
s
p
o
r
t
e
r
S
p
o
n
d
y
l
o
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
S
e
d
a
g
h
a
t
i
a
n
t
y
p
e
A
R
2
5
0
2
2
0
S
e
v
e
r
e
s
p
o
n
d
y
l
o
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
S
M
D
S
e
d
a
g
h
a
t
i
a
n
-
l
i
k
e
)
A
R
7
q
1
1
S
B
D
S
S
B
D
S
g
e
n
e
,
f
u
n
c
t
i
o
n
s
t
i
l
l
u
n
c
l
e
a
r
O
p
s
i
s
m
o
d
y
s
p
l
a
s
i
a
A
R
2
5
8
4
8
0
S
e
e
a
l
s
o
T
h
a
n
a
t
o
p
h
o
r
i
c
d
y
s
p
l
a
s
i
a
,
t
y
p
e
s
1
a
n
d
2
(
g
r
o
u
p
1
)
;
A
C
G
2
a
n
d
T
o
r
r
a
n
c
e
d
y
s
p
l
a
s
i
a
(
g
r
o
u
p
2
)
;
F
i
b
r
o
c
h
o
n
d
r
o
g
e
n
e
s
i
s
(
g
r
o
u
p
3
)
;
A
c
h
o
n
d
r
o
g
e
n
e
s
i
s
t
y
p
e
1
B
(
A
C
G
1
B
,
g
r
o
u
p
4
)
;
a
n
d
M
e
t
a
t
r
o
p
i
c
d
y
s
p
l
a
s
i
a
(
T
R
P
V
4
g
r
o
u
p
)
1
5
.
A
c
r
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
s
T
r
i
c
h
o
r
h
i
n
o
p
h
a
l
a
n
g
e
a
l
d
y
s
p
l
a
s
i
a
t
y
p
e
s
1
/
3
A
D
1
9
0
3
5
0
8
q
2
4
T
R
P
S
1
Z
i
n
c

n
g
e
r
t
r
a
n
s
c
r
i
p
t
i
o
n
f
a
c
t
o
r
T
r
i
c
h
o
r
h
i
n
o
p
h
a
l
a
n
g
e
a
l
d
y
s
p
l
a
s
i
a
t
y
p
e
2
(
L
a
n
g
e
r

G
i
e
d
i
o
n
)
A
D
1
5
0
2
3
0
8
q
2
4
T
R
P
S
1
a
n
d
E
X
T
1
Z
i
n
c

n
g
e
r
t
r
a
n
s
c
r
i
p
t
i
o
n
f
a
c
t
o
r
a
n
d
E
x
o
s
t
o
s
i
n
1
M
i
c
r
o
d
e
l
e
t
i
o
n
s
y
n
d
r
o
m
e
;
s
e
e
a
l
s
o
M
u
l
t
i
p
l
e
C
a
r
t
i
l
a
g
i
n
e
o
u
s
E
x
o
s
t
o
s
e
s
i
n
g
r
o
u
p
2
8
A
c
r
o
c
a
p
i
t
o
f
e
m
o
r
a
l
d
y
s
p
l
a
s
i
a
A
R
6
0
7
7
7
8
2
q
3
3

q
3
5
I
H
H
I
n
d
i
a
n
h
e
d
g
e
h
o
g
C
r
a
n
i
o
e
c
t
o
d
e
r
m
a
l
d
y
s
p
l
a
s
i
a
(
L
e
v
i
n

S
e
n
s
e
n
b
r
e
n
n
e
r
)
t
y
p
e
1
A
R
2
1
8
3
3
0
3
q
2
1
I
F
T
1
2
2
I
n
t
r
a

a
g
e
l
l
a
r
t
r
a
n
s
p
o
r
t
1
2
2
(
C
h
l
a
m
y
d
o
m
o
n
a
s
,
h
o
m
o
l
o
g
o
f
)
C
r
a
n
i
o
e
c
t
o
d
e
r
m
a
l
d
y
s
p
l
a
s
i
a
(
L
e
v
i
n

S
e
n
s
e
n
b
r
e
n
n
e
r
)
t
y
p
e
2
A
R
6
1
3
6
1
0
2
p
2
4
.
1
W
D
R
3
5
W
D
r
e
p
e
a
t
-
c
o
n
t
a
i
n
i
n
g
p
r
o
t
e
i
n
3
5
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
950 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
G
e
l
e
o
p
h
y
s
i
c
d
y
s
p
l
a
s
i
a
A
R
2
3
1
0
5
0
9
q
3
4
.
2
A
D
A
M
T
S
L
2
A
D
A
M
T
S
-
l
i
k
e
p
r
o
t
e
i
n
2
G
e
l
e
o
p
h
y
s
i
c
d
y
s
p
l
a
s
i
a
,
o
t
h
e
r
t
y
p
e
s
A
R
U
n
l
i
n
k
e
d
t
o
A
D
A
M
T
S
L
2
A
c
r
o
m
i
c
r
i
c
d
y
s
p
l
a
s
i
a
A
D
1
0
2
3
7
0
I
n
c
l
u
d
e
s
a
c
r
o
l
a
r
y
n
g
e
a
l
d
y
s
p
l
a
s
i
a
,
p
r
e
v
i
o
u
s
l
y
k
n
o
w
n
a
s
F
a
n
t
a
s
y
I
s
l
a
n
d
d
y
s
p
l
a
s
i
a
o
r
T
a
t
t
o
o
d
y
s
p
l
a
s
i
a
A
c
r
o
d
y
s
o
s
t
o
s
i
s
A
D
1
0
1
8
0
0
A
n
g
e
l
-
s
h
a
p
e
d
p
h
a
l
a
n
g
o
-
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
(
A
S
P
E
D
)
A
D
1
0
5
8
3
5
P
o
s
s
i
b
l
y
r
e
l
a
t
e
d
o
r
a
l
l
e
l
i
c
t
o
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
C
S
a
l
d
i
n
o

M
a
i
n
z
e
r
d
y
s
p
l
a
s
i
a
A
R
2
6
6
9
2
0
S
e
e
a
l
s
o
s
h
o
r
t
r
i
b
d
y
s
p
l
a
s
i
a
s
g
r
o
u
p
1
6
.
A
c
r
o
m
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
s
A
c
r
o
m
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
t
y
p
e
M
a
r
o
t
e
a
u
x
(
A
M
D
M
)
A
R
6
0
2
8
7
5
9
p
1
3

1
2
N
P
R
2
N
a
t
r
i
u
r
e
t
i
c
p
e
p
t
i
d
e
r
e
c
e
p
t
o
r
2
G
r
e
b
e
d
y
s
p
l
a
s
i
a
A
R
2
0
0
7
0
0
2
0
q
1
1
.
2
G
D
F
5
G
r
o
w
t
h
a
n
d
d
i
f
f
e
r
e
n
t
i
a
t
i
o
n
f
a
c
t
o
r
5
I
n
c
l
u
d
e
s
a
c
r
o
m
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
H
u
n
t
e
r
-
T
h
o
m
p
s
o
n
t
y
p
e
;
s
e
e
a
l
s
o
B
r
a
c
h
y
d
a
c
t
y
l
i
e
s
(
g
r
o
u
p
3
4
)
F
i
b
u
l
a
r
h
y
p
o
p
l
a
s
i
a
a
n
d
c
o
m
p
l
e
x
b
r
a
c
h
y
d
a
c
t
y
l
y
(
D
u
P
a
n
)
A
R
2
2
8
9
0
0
2
0
q
1
1
.
2
G
D
F
5
G
r
o
w
t
h
a
n
d
d
i
f
f
e
r
e
n
t
i
a
t
i
o
n
f
a
c
t
o
r
5
S
e
e
a
l
s
o
B
r
a
c
h
y
d
a
c
t
y
l
i
e
s
(
g
r
o
u
p
3
4
)
A
c
r
o
m
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
w
i
t
h
g
e
n
i
t
a
l
a
n
o
m
a
l
i
e
s
A
R
6
0
9
4
4
1
4
q
2
3

2
4
B
M
P
R
1
B
B
o
n
e
m
o
r
p
h
o
g
e
n
e
t
i
c
p
r
o
t
e
i
n
r
e
c
e
p
t
o
r
1
B
A
c
r
o
m
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
,
O
s
e
b
o
l
d
-
R
e
m
o
n
d
i
n
i
t
y
p
e
A
D
1
1
2
9
1
0
1
7
.
M
e
s
o
m
e
l
i
c
a
n
d
r
h
i
z
o
-
m
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
s
D
y
s
c
h
o
n
d
r
o
s
t
e
o
s
i
s
(
L
e
r
i

W
e
i
l
l
)
P
s
e
u
d
o
-
A
D
1
2
7
3
0
0
X
p
t
e
r
-
p
2
2
.
3
2
S
H
O
X
S
h
o
r
t
s
t
a
t
u
r
e

h
o
m
e
o
b
o
x
g
e
n
e
I
n
c
l
u
d
e
s
R
e
i
n
h
a
r
d
t

P
f
e
i
f
f
e
r
d
y
s
p
l
a
s
i
a
,
M
I
M
1
9
1
4
0
0
L
a
n
g
e
r
t
y
p
e
(
h
o
m
o
z
y
g
o
u
s
d
y
s
c
h
o
n
d
r
o
s
t
e
o
s
i
s
)
P
s
e
u
d
o
-
A
R
2
4
9
7
0
0
X
p
t
e
r
-
p
2
2
.
3
2
S
H
O
X
S
h
o
r
t
s
t
a
t
u
r
e

h
o
m
e
o
b
o
x
g
e
n
e
O
m
o
d
y
s
p
l
a
s
i
a
A
R
2
5
8
3
1
5
1
3
q
3
1

q
3
2
G
P
C
6
G
l
y
p
i
c
a
n
6
E
x
i
s
t
e
n
c
e
o
f

d
o
m
i
n
a
n
t
o
m
o
d
y
s
p
l
a
s
i
a

(
M
I
M
1
6
4
7
4
5
)
r
e
m
a
i
n
s
t
o
b
e
c
o
n

r
m
e
d
R
o
b
i
n
o
w
s
y
n
d
r
o
m
e
,
r
e
c
e
s
s
i
v
e
t
y
p
e
A
R
2
6
8
3
1
0
9
q
2
2
R
O
R
2
R
e
c
e
p
t
o
r
t
y
r
o
s
i
n
e
k
i
n
a
s
e
-
l
i
k
e
o
r
p
h
a
n
r
e
c
e
p
t
o
r
2
I
n
c
l
u
d
e
s
p
r
e
v
i
o
u
s
c
o
s
t
o
-
v
e
r
t
e
b
r
a
l
s
e
g
m
e
n
t
a
t
i
o
n
d
e
f
e
c
t
w
i
t
h
m
e
s
o
m
e
l
i
a
(
C
O
V
E
S
D
E
M
)
;
s
e
e
a
l
s
o
b
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
B
R
o
b
i
n
o
w
s
y
n
d
r
o
m
e
,
d
o
m
i
n
a
n
t
t
y
p
e
A
D
1
8
0
7
0
0
M
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
,
K
o
r
e
a
n
t
y
p
e
A
D
2
q
2
4

3
2
D
u
p
l
i
c
a
t
i
o
n
i
n
H
O
X
D
g
e
n
e
c
l
u
s
t
e
r
M
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
,
K
a
n
t
a
p
u
t
r
a
t
y
p
e
A
D
1
5
6
2
3
2
2
q
2
4

3
2
D
u
p
l
i
c
a
t
i
o
n
s
i
n
H
O
X
D
g
e
n
e
c
l
u
s
t
e
r
M
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
,
N
i
e
v
e
r
g
e
l
t
t
y
p
e
A
D
1
6
3
4
0
0
M
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
,
K
o
z
l
o
w
s
k
i
-
R
e
a
r
d
o
n
t
y
p
e
A
R
2
4
9
7
1
0
M
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
w
i
t
h
a
c
r
a
l
s
y
n
o
s
t
o
s
e
s
(
V
e
r
l
o
e
s

D
a
v
i
d

P
f
e
i
f
f
e
r
t
y
p
e
)
A
D
6
0
0
3
8
3
8
q
1
3
S
U
L
F
1
a
n
d
S
L
C
O
5
A
1
H
e
p
a
r
a
n
s
u
l
f
a
t
e
6
-
O
-
e
n
d
o
s
u
l
f
a
t
a
s
e
1
a
n
d
s
o
l
u
t
e
c
a
r
r
i
e
r
o
r
g
a
n
i
c
a
n
i
o
n
t
r
a
n
s
-
p
o
r
t
e
r
f
a
m
i
l
y
m
e
m
b
e
r
5
A
1
M
i
c
r
o
d
e
l
e
t
i
o
n
s
y
n
d
r
o
m
e
i
n
v
o
l
v
i
n
g
t
w
o
a
d
j
a
c
e
n
t
g
e
n
e
s
(
C
o
n
t
i
n
u
e
d
)
WARMAN ET AL. 951
M
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
,
S
a
v
a
r
i
r
a
y
a
n
t
y
p
e
(
T
r
i
a
n
g
u
l
a
r
T
i
b
i
a

F
i
b
u
l
a
r
A
p
l
a
s
i
a
)
S
P
6
0
5
2
7
4
P
o
s
s
i
b
l
y
r
e
l
a
t
e
d
t
o
N
i
e
v
e
r
g
e
l
t
d
y
s
p
l
a
s
i
a
.
O
n
e
c
a
s
e
r
e
p
o
r
t
e
d
w
i
t
h
2
q
1
1
.
2
m
i
c
r
o
d
e
l
e
t
i
o
n
o
f
u
n
c
l
e
a
r
s
i
g
n
i

c
a
n
c
e
1
8
.
B
e
n
t
b
o
n
e
s
d
y
s
p
l
a
s
i
a
s
C
a
m
p
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
(
C
D
)
A
D
1
1
4
2
9
0
1
7
q
2
4
.
3

2
5
.
1
S
O
X
9
S
R
Y
-
b
o
x
9
I
n
c
l
u
d
e
s
a
c
a
m
p
o
m
e
l
i
c
c
a
m
p
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
(
A
C
D
)
a
s
w
e
l
l
a
s
m
i
l
d
c
a
m
p
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
(
M
I
M
6
0
2
1
9
6
)
S
t
u
v
e

W
i
e
d
e
m
a
n
n
d
y
s
p
l
a
s
i
a
A
R
6
0
1
5
5
9
5
p
1
3
.
1
L
I
F
R
L
e
u
k
e
m
i
a
i
n
h
i
b
i
t
o
r
y
f
a
c
t
o
r
r
e
c
e
p
t
o
r
I
n
c
l
u
d
e
s
f
o
r
m
e
r
l
y
n
e
o
n
a
t
a
l
S
c
h
w
a
r
t
z

J
a
m
p
e
l
s
y
n
d
r
o
m
e
o
r
S
J
S
t
y
p
e
2
K
y
p
h
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
,
s
e
v
e
r
a
l
f
o
r
m
s
2
1
1
3
5
0
P
r
o
b
a
b
l
y
h
e
t
e
r
o
g
e
n
e
o
u
s
B
e
n
t
b
o
n
e
s
a
t
b
i
r
t
h
c
a
n
b
e
s
e
e
n
i
n
a
v
a
r
i
e
t
y
o
f
c
o
n
d
i
t
i
o
n
s
,
i
n
c
l
u
d
i
n
g
o
s
t
e
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
,
A
n
t
l
e
y

B
i
x
l
e
r
s
y
n
d
r
o
m
e
,
c
a
r
t
i
l
a
g
e
-
h
a
i
r
h
y
p
o
p
l
a
s
i
a
,
C
u
m
m
i
n
g
s
s
y
n
d
r
o
m
e
,
h
y
p
o
p
h
o
s
p
h
a
t
a
s
i
a
,
d
y
s
s
e
g
m
e
n
t
a
l
d
y
s
p
l
a
s
i
a
,
T
D
,
A
T
D
,
a
n
d
o
t
h
e
r
s
1
9
.
S
l
e
n
d
e
r
b
o
n
e
d
y
s
p
l
a
s
i
a
g
r
o
u
p
3
-
M
s
y
n
d
r
o
m
e
(
3
M
1
)
A
R
2
7
3
7
5
0
6
p
2
1
.
1
C
U
L
7
C
u
l
l
i
n
7
I
n
c
l
u
d
e
s
d
o
l
i
c
h
o
s
p
o
n
d
y
l
i
c
d
y
s
p
l
a
s
i
a
a
n
d
Y
a
k
u
t
s
h
o
r
t
s
t
a
t
u
r
e
s
y
n
d
r
o
m
e
3
-
M
s
y
n
d
r
o
m
e
(
3
M
2
)
A
R
6
1
2
9
2
1
2
q
3
5
O
B
S
L
1
O
b
s
c
u
r
i
n
-
l
i
k
e
1
K
e
n
n
y

C
a
f
f
e
y
d
y
s
p
l
a
s
i
a
t
y
p
e
1
A
R
2
4
4
4
6
0
1
q
4
2

q
4
3
T
B
C
E
T
u
b
u
l
i
n
-
s
p
e
c
i

c
c
h
a
p
e
r
o
n
e
E
K
e
n
n
y

C
a
f
f
e
y
d
y
s
p
l
a
s
i
a
t
y
p
e
2
A
D
1
2
7
0
0
0
M
i
c
r
o
c
e
p
h
a
l
i
c
o
s
t
e
o
d
y
s
p
l
a
s
t
i
c
p
r
i
m
o
r
d
i
a
l
d
w
a
r

s
m
t
y
p
e
1
/
3
(
M
O
P
D
1
)
A
R
2
1
0
7
1
0
2
q
I
n
c
l
u
d
e
s
T
a
y
b
i

L
i
n
d
e
r
c
e
p
h
a
l
o
s
k
e
l
e
t
a
l
d
y
s
p
l
a
s
i
a
M
i
c
r
o
c
e
p
h
a
l
i
c
o
s
t
e
o
d
y
s
p
l
a
s
t
i
c
p
r
i
m
o
r
d
i
a
l
d
w
a
r

s
m
t
y
p
e
2
(
M
O
P
D
2
;
M
a
j
e
w
s
k
i
t
y
p
e
)
A
R
2
1
0
7
2
0
2
1
q
P
C
N
T
2
P
e
r
i
c
e
n
t
r
i
n
2
I
M
A
G
E
s
y
n
d
r
o
m
e
(
i
n
t
r
a
u
t
e
r
i
n
e
g
r
o
w
t
h
r
e
t
a
r
d
a
t
i
o
n
,
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
a
d
r
e
n
a
l
h
y
p
o
p
l
a
s
i
a
,
a
n
d
g
e
n
i
t
a
l
a
n
o
m
a
l
i
e
s
)
X
L
/
A
D
3
0
0
2
9
0
P
o
s
s
i
b
l
y
h
e
t
e
r
o
g
e
n
e
o
u
s
O
s
t
e
o
c
r
a
n
i
o
s
t
e
n
o
s
i
s
S
P
6
0
2
3
6
1
O
c
c
u
r
r
e
n
c
e
i
n
s
i
b
s
r
e
p
o
r
t
e
d
,
i
n
h
e
r
i
t
a
n
c
e
u
n
c
l
e
a
r
H
a
l
l
e
r
m
a
n
n

S
t
r
e
i
f
f
s
y
n
d
r
o
m
e
A
R
2
3
4
1
0
0
M
u
t
a
t
i
o
n
s
i
n
G
J
A
1
r
e
p
o
r
t
e
d
i
n
o
n
e
c
a
s
e
o
n
l
y
S
e
e
a
l
s
o
C
e
r
e
b
r
o
-
a
r
t
h
r
o
-
d
i
g
i
t
a
l
d
y
s
p
l
a
s
i
a
2
0
.
D
y
s
p
l
a
s
i
a
s
w
i
t
h
m
u
l
t
i
p
l
e
j
o
i
n
t
d
i
s
l
o
c
a
t
i
o
n
s
D
e
s
b
u
q
u
o
i
s
d
y
s
p
l
a
s
i
a
(
w
i
t
h
a
c
c
e
s
s
o
r
y
o
s
s
i

c
a
t
i
o
n
c
e
n
t
e
r
i
n
d
i
g
i
t
2
)
A
R
2
5
1
4
5
0
1
7
q
2
5
.
3
C
A
N
T
1
D
e
s
b
u
q
u
o
i
s
d
y
s
p
l
a
s
i
a
w
i
t
h
s
h
o
r
t
m
e
t
a
c
a
r
p
a
l
s
a
n
d
e
l
o
n
g
a
t
e
d
p
h
a
l
a
n
g
e
s
(
K
i
m
t
y
p
e
)
A
R
2
5
1
4
5
0
1
7
q
2
5
.
3
C
A
N
T
1
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
952 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
D
e
s
b
u
q
u
o
i
s
d
y
s
p
l
a
s
i
a
(
o
t
h
e
r
v
a
r
i
a
n
t
s
w
i
t
h
o
r
w
i
t
h
o
u
t
a
c
c
e
s
s
o
r
y
o
s
s
i

c
a
t
i
o
n
c
e
n
t
e
r
)
A
R
P
r
o
b
a
b
l
y
g
e
n
e
t
i
c
a
l
l
y
h
e
t
e
r
o
g
e
n
e
o
u
s
P
s
e
u
d
o
d
i
a
s
t
r
o
p
h
i
c
d
y
s
p
l
a
s
i
a
A
R
2
6
4
1
8
0
S
e
e
a
l
s
o
S
E
D
w
i
t
h
c
o
n
g
e
n
i
t
a
l
d
i
s
l
o
c
a
t
i
o
n
s
,
C
H
S
T
3
t
y
p
e
(
g
r
o
u
p
4
)
;
A
t
e
l
o
s
t
e
o
g
e
n
e
s
i
s
t
y
p
e
3
a
n
d
L
a
r
s
e
n
s
y
n
d
r
o
m
e
(
g
r
o
u
p
6
)
;
S
E
M
D
s
w
i
t
h
j
o
i
n
t
l
a
x
i
t
y
(
g
r
o
u
p
1
1
)
2
1
.
C
h
o
n
d
r
o
d
y
s
p
l
a
s
i
a
p
u
n
c
t
a
t
a
(
C
D
P
)
g
r
o
u
p
C
D
P
,
X
-
l
i
n
k
e
d
d
o
m
i
n
a
n
t
,
C
o
n
r
a
d
i

H
u
n
e
r
m
a
n
n
t
y
p
e
(
C
D
P
X
2
)
X
L
D
3
0
2
9
6
0
X
p
1
1
E
B
P
E
m
o
p
a
m
i
l
-
b
i
n
d
i
n
g
p
r
o
t
e
i
n
C
D
P
,
X
-
l
i
n
k
e
d
r
e
c
e
s
s
i
v
e
,
b
r
a
c
h
y
t
e
l
e
p
h
a
l
a
n
g
i
c
t
y
p
e
(
C
D
P
X
1
)
X
L
R
3
0
2
9
5
0
X
p
2
2
.
3
A
R
S
E
A
r
y
l
s
u
l
f
a
t
a
s
e
E
C
o
n
g
e
n
i
t
a
l
h
e
m
i
d
y
s
p
l
a
s
i
a
,
i
c
h
t
h
y
o
s
i
s
,
l
i
m
b
d
e
f
e
c
t
s
(
C
H
I
L
D
)
X
L
D
3
0
8
0
5
0
X
p
1
1
N
S
D
H
L
N
A
D
(
P
)
H
s
t
e
r
o
i
d
d
e
h
y
d
r
o
g
e
n
a
s
e
-
l
i
k
e
p
r
o
t
e
i
n
C
o
n
g
e
n
i
t
a
l
h
e
m
i
d
y
s
p
l
a
s
i
a
,
i
c
h
t
h
y
o
s
i
s
,
l
i
m
b
d
e
f
e
c
t
s
(
C
H
I
L
D
)
X
L
D
3
0
8
0
5
0
X
q
2
8
E
B
P
E
m
o
p
a
m
i
l
-
b
i
n
d
i
n
g
p
r
o
t
e
i
n
G
r
e
e
n
b
e
r
g
d
y
s
p
l
a
s
i
a
A
R
2
1
5
1
4
0
1
q
4
2
.
1
L
B
R
L
a
m
i
n
B
r
e
c
e
p
t
o
r
,
3
-
b
e
t
a
-
h
y
d
r
o
x
y
s
t
e
r
o
l
d
e
l
t
a
(
1
4
)
-
r
e
d
u
c
t
a
s
e
I
n
c
l
u
d
e
s
h
y
d
r
o
p
s
-
e
c
t
o
p
i
c
c
a
l
c
i

c
a
t
i
o
n
-
m
o
t
h
-
e
a
t
e
n
a
p
p
e
a
r
a
n
c
e
d
y
s
p
l
a
s
i
a
(
H
E
M
)
a
n
d
d
a
p
p
l
e
d
d
i
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
R
h
i
z
o
m
e
l
i
c
C
D
P
t
y
p
e
1
A
R
2
1
5
1
0
0
6
q
2
2

2
4
P
E
X
7
P
e
r
o
x
i
s
o
m
a
l
P
T
S
2
r
e
c
e
p
t
o
r
R
h
i
z
o
m
e
l
i
c
C
D
P
t
y
p
e
2
A
R
2
2
2
7
6
5
1
q
4
2
D
H
P
A
T
D
i
h
y
d
r
o
x
y
a
c
e
t
o
n
e
p
h
o
s
p
h
a
t
e
a
c
y
l
t
r
a
n
s
f
e
r
a
s
e
(
D
H
A
P
A
T
)
R
h
i
z
o
m
e
l
i
c
C
D
P
t
y
p
e
3
A
R
6
0
0
1
2
1
2
q
3
1
A
G
P
S
A
l
k
y
l
g
l
y
c
e
r
o
n
e
-
p
h
o
s
p
h
a
t
e
s
y
n
t
h
a
s
e
(
A
G
P
S
)
C
D
P
t
i
b
i
a
l
-
m
e
t
a
c
a
r
p
a
l
t
y
p
e
A
D
/
A
R
1
1
8
6
5
1
N
o
s
o
l
o
g
i
c
s
t
a
t
u
s
u
n
c
e
r
t
a
i
n
A
s
t
l
e
y
-
K
e
n
d
a
l
l
d
y
s
p
l
a
s
i
a
A
R
?
R
e
l
a
t
i
o
n
s
h
i
p
t
o
O
I
a
n
d
t
o
G
r
e
e
n
b
e
r
g
d
y
s
p
l
a
s
i
a
u
n
c
l
e
a
r
N
o
t
e
t
h
a
t
s
t
i
p
p
l
i
n
g
c
a
n
o
c
c
u
r
i
n
s
e
v
e
r
a
l
s
y
n
d
r
o
m
e
s
s
u
c
h
a
s
Z
e
l
l
w
e
g
e
r
,
S
m
i
t
h

L
e
m
l
i

O
p
i
t
z
a
n
d
o
t
h
e
r
s
.
S
e
e
a
l
s
o
d
e
s
m
o
s
t
e
r
o
l
o
s
i
s
a
s
w
e
l
l
a
s
S
E
M
D
s
h
o
r
t
l
i
m
b

a
b
n
o
r
m
a
l
c
a
l
c
i

c
a
t
i
o
n
t
y
p
e
i
n
g
r
o
u
p
1
1
2
2
.
N
e
o
n
a
t
a
l
o
s
t
e
o
s
c
l
e
r
o
t
i
c
d
y
s
p
l
a
s
i
a
s
B
l
o
m
s
t
r
a
n
d
d
y
s
p
l
a
s
i
a
A
R
2
1
5
0
4
5
3
p
2
2

2
1
.
1
P
T
H
R
1
P
T
H
/
P
T
H
r
P
r
e
c
e
p
t
o
r
1
C
a
u
s
e
d
b
y
r
e
c
e
s
s
i
v
e
i
n
a
c
t
i
v
a
t
i
n
g
m
u
t
a
t
i
o
n
s
;
s
e
e
a
l
s
o
E
i
k
e
n
d
y
s
p
l
a
s
i
a
a
n
d
J
a
n
s
e
n
d
y
s
p
l
a
s
i
a
D
e
s
m
o
s
t
e
r
o
l
o
s
i
s
A
R
6
0
2
3
9
8
1
p
3
3

3
1
.
1
D
H
C
R
2
4
3
-
b
e
t
a
-
h
y
d
r
o
x
y
s
t
e
r
o
l
d
e
l
t
a
-
2
4
-
r
e
d
u
c
t
a
s
e
S
e
e
a
l
s
o
o
t
h
e
r
s
t
e
r
o
l
-
m
e
t
a
b
o
l
i
s
m
r
e
l
a
t
e
d
c
o
n
d
i
t
i
o
n
s
C
a
f
f
e
y
d
i
s
e
a
s
e
(
i
n
c
l
u
d
i
n
g
i
n
f
a
n
t
i
l
e
a
n
d
a
t
t
e
n
u
a
t
e
d
f
o
r
m
s
)
A
D
1
1
4
0
0
0
1
7
q
2
1

2
2
C
O
L
1
A
1
C
o
l
l
a
g
e
n
1
,
a
l
p
h
a
-
1
c
h
a
i
n
S
e
e
a
l
s
o
o
s
t
e
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
r
e
l
a
t
e
d
t
o
c
o
l
l
a
g
e
n
1
g
e
n
e
s
(
g
r
o
u
p
2
4
)
C
a
f
f
e
y
d
i
s
e
a
s
e
(
s
e
v
e
r
e
v
a
r
i
a
n
t
s
w
i
t
h
p
r
e
n
a
t
a
l
o
n
s
e
t
)
A
R
1
1
4
0
0
0
R
a
i
n
e
d
y
s
p
l
a
s
i
a
(
l
e
t
h
a
l
a
n
d
n
o
n
-
l
e
t
h
a
l
f
o
r
m
s
)
A
R
2
5
9
7
7
5
7
p
2
2
F
A
M
2
0
C
I
n
c
l
u
d
e
s
l
e
t
h
a
l
a
n
d
n
o
n
-
l
e
t
h
a
l
c
a
s
e
s
S
e
e
a
l
s
o
A
s
t
l
e
y
-
K
e
n
d
a
l
l
d
y
s
p
l
a
s
i
a
a
n
d
C
D
P
s
i
n
g
r
o
u
p
2
1
2
3
.
I
n
c
r
e
a
s
e
d
b
o
n
e
d
e
n
s
i
t
y
g
r
o
u
p
(
w
i
t
h
o
u
t
m
o
d
i

c
a
t
i
o
n
o
f
b
o
n
e
s
h
a
p
e
)
O
s
t
e
o
p
e
t
r
o
s
i
s
,
s
e
v
e
r
e
n
e
o
n
a
t
a
l
o
r
i
n
f
a
n
t
i
l
e
f
o
r
m
s
(
O
P
T
B
1
)
A
R
2
5
9
7
0
0
1
1
q
1
3
T
C
I
R
G
1
S
u
b
u
n
i
t
o
f
A
T
P
a
s
e
p
r
o
t
o
n
p
u
m
p
O
s
t
e
o
p
e
t
r
o
s
i
s
,
s
e
v
e
r
e
n
e
o
n
a
t
a
l
o
r
i
n
f
a
n
t
i
l
e
f
o
r
m
s
(
O
P
T
B
4
)
A
R
6
1
1
4
9
0
1
6
p
1
3
C
L
C
N
7
C
h
l
o
r
i
d
e
c
h
a
n
n
e
l
7
(
C
o
n
t
i
n
u
e
d
)
WARMAN ET AL. 953
O
s
t
e
o
p
e
t
r
o
s
i
s
,
i
n
f
a
n
t
i
l
e
f
o
r
m
,
w
i
t
h
n
e
r
v
o
u
s
s
y
s
t
e
m
i
n
v
o
l
v
e
m
e
n
t
(
O
P
T
B
5
)
A
R
2
5
9
7
2
0
6
q
2
1
O
S
T
M
1
G
r
a
y
l
e
t
h
a
l
/
o
s
t
e
o
p
e
t
r
o
s
i
s
a
s
s
o
c
i
a
t
e
d
t
r
a
n
s
m
e
m
b
r
a
n
e
p
r
o
t
e
i
n
O
s
t
e
o
p
e
t
r
o
s
i
s
,
i
n
t
e
r
m
e
d
i
a
t
e
f
o
r
m
,
o
s
t
e
o
c
l
a
s
t
-
p
o
o
r
(
O
P
T
B
2
)
A
R
2
5
9
7
1
0
1
3
q
1
4
.
1
1
R
A
N
K
L
(
T
N
F
S
F
1
1
)
R
e
c
e
p
t
o
r
a
c
t
i
v
a
t
o
r
o
f
N
F
-
k
a
p
p
a
-
B
l
i
g
a
n
d
(
t
u
m
o
r
n
e
c
r
o
s
i
s
f
a
c
t
o
r
l
i
g
a
n
d
s
u
p
e
r
f
a
m
i
l
y
,
m
e
m
b
e
r
1
1
)
O
s
t
e
o
p
e
t
r
o
s
i
s
,
i
n
f
a
n
t
i
l
e
f
o
r
m
,
o
s
t
e
o
c
l
a
s
t
-
p
o
o
r
w
i
t
h
i
m
m
u
n
o
g
l
o
b
u
l
i
n
d
e

c
i
e
n
c
y
(
O
P
T
B
7
)
A
R
6
1
2
3
0
2
1
8
q
2
1
.
3
3
R
A
N
K
(
T
N
F
R
S
F
1
1
A
)
R
e
c
e
p
t
o
r
a
c
t
i
v
a
t
o
r
o
f
N
F
-
k
a
p
p
a
-
B
S
e
e
a
l
s
o
f
a
m
i
l
i
a
l
e
x
p
a
n
s
i
l
e
o
s
t
e
o
l
y
s
i
s
i
n
O
s
t
e
o
l
y
s
i
s
g
r
o
u
p
(
g
r
o
u
p
2
8
)
O
s
t
e
o
p
e
t
r
o
s
i
s
,
i
n
t
e
r
m
e
d
i
a
t
e
f
o
r
m
(
O
P
T
B
6
)
A
R
6
1
1
4
9
7
1
7
q
2
1
.
3
P
L
E
K
H
M
1
P
l
e
c
k
s
t
r
i
n
h
o
m
o
l
o
g
y
d
o
m
a
i
n
-
c
o
n
t
a
i
n
i
n
g
p
r
o
t
e
i
n
,
f
a
m
i
l
y
M
,
m
e
m
b
e
r
1
O
s
t
e
o
p
e
t
r
o
s
i
s
,
i
n
t
e
r
m
e
d
i
a
t
e
f
o
r
m
(
O
P
T
A
2
)
A
R
2
5
9
7
1
0
1
6
p
1
3
C
L
C
N
7
C
h
l
o
r
i
d
e
c
h
a
n
n
e
l
p
u
m
p
O
s
t
e
o
p
e
t
r
o
s
i
s
w
i
t
h
r
e
n
a
l
t
u
b
u
l
a
r
a
c
i
d
o
s
i
s
(
O
P
T
B
3
)
A
R
2
5
9
7
3
0
8
q
2
2
C
A
2
C
a
r
b
o
n
i
c
a
n
h
y
d
r
a
s
e
2
O
s
t
e
o
p
e
t
r
o
s
i
s
,
l
a
t
e
-
o
n
s
e
t
f
o
r
m
t
y
p
e
1
(
O
P
T
A
1
)
A
D
6
0
7
6
3
4
1
1
q
1
3
.
4
L
R
P
5
L
o
w
d
e
n
s
i
t
y
l
i
p
o
p
r
o
t
e
i
n
r
e
c
e
p
t
o
r
-
r
e
l
a
t
e
d
p
r
o
t
e
i
n
5
I
n
c
l
u
d
e
s
W
o
r
t
h
t
y
p
e
o
s
t
e
o
s
c
l
e
r
o
s
i
s
(
M
I
M
1
4
4
7
5
0
)
O
s
t
e
o
p
e
t
r
o
s
i
s
,
l
a
t
e
-
o
n
s
e
t
f
o
r
m
t
y
p
e
2
(
O
P
T
A
2
)
A
D
1
6
6
6
0
0
1
6
p
1
3
C
L
C
N
7
C
h
l
o
r
i
d
e
c
h
a
n
n
e
l
7
O
s
t
e
o
p
e
t
r
o
s
i
s
w
i
t
h
e
c
t
o
d
e
r
m
a
l
d
y
s
p
l
a
s
i
a
a
n
d
i
m
m
u
n
e
d
e
f
e
c
t
(
O
L
E
D
A
I
D
)
X
L
3
0
0
3
0
1
X
q
2
8
I
K
B
K
G
(
N
E
M
O
)
I
n
h
i
b
i
t
o
r
o
f
k
a
p
p
a
l
i
g
h
t
p
o
l
y
p
e
p
t
i
d
e
g
e
n
e
e
n
h
a
n
c
e
r
,
k
i
n
a
s
e
o
f
O
s
t
e
o
p
e
t
r
o
s
i
s
,
m
o
d
e
r
a
t
e
f
o
r
m
w
i
t
h
d
e
f
e
c
t
i
v
e
l
e
u
c
o
c
y
t
e
a
d
h
e
s
i
o
n
(
L
A
D
3
)
A
R
6
1
2
8
4
0
1
1
q
1
2
F
E
R
M
T
3
(
K
I
N
D
3
)
F
e
r
m
i
t
i
n
3
(
K
i
n
d
l
i
n
3
)
O
s
t
e
o
p
e
t
r
o
s
i
s
,
m
o
d
e
r
a
t
e
f
o
r
m
w
i
t
h
d
e
f
e
c
t
i
v
e
l
e
u
c
o
c
y
t
e
a
d
h
e
s
i
o
n
A
R
6
1
2
8
4
0
1
1
q
1
3
R
A
S
G
R
P
2
(
C
a
l
D
A
G
-
G
E
F
1
)
R
a
s
g
u
a
n
y
l
n
u
c
l
e
o
t
i
d
e
-
r
e
l
e
a
s
i
n
g
p
r
o
t
e
i
n
2
P
y
k
n
o
d
y
s
o
s
t
o
s
i
s
A
R
2
6
5
8
0
0
1
q
2
1
C
T
S
K
C
a
t
h
e
p
s
i
n
K
O
s
t
e
o
p
o
i
k
i
l
o
s
i
s
A
D
1
5
5
9
5
0
1
2
q
1
4
L
E
M
D
3
L
E
M
d
o
m
a
i
n
-
c
o
n
t
a
i
n
i
n
g
3
I
n
c
l
u
d
e
s
B
u
s
c
h
k
e

O
l
l
e
n
d
o
r
f
f
s
y
n
d
r
o
m
e
(
M
I
M
1
6
6
7
0
0
)
M
e
l
o
r
h
e
o
s
t
o
s
i
s
w
i
t
h
o
s
t
e
o
p
o
i
k
i
l
o
s
i
s
A
D
1
5
5
9
5
0
1
2
q
1
4
L
E
M
D
3
L
E
M
d
o
m
a
i
n
-
c
o
n
t
a
i
n
i
n
g
3
I
n
c
l
u
d
e
s
m
i
x
e
d
s
c
l
e
r
o
s
i
n
g
b
o
n
e
d
y
s
p
l
a
s
i
a
O
s
t
e
o
p
a
t
h
i
a
s
t
r
i
a
t
a
w
i
t
h
c
r
a
n
i
a
l
s
c
l
e
r
o
s
i
s
(
O
S
C
S
)
X
L
D
3
0
0
3
7
3
X
q
1
1
.
1
W
T
X
F
A
M
1
2
3
B
M
e
l
o
r
h
e
o
s
t
o
s
i
s
S
P
N
o
g
e
r
m
l
i
n
e
L
E
M
D
3
m
u
t
a
t
i
o
n
s
i
d
e
n
t
i

e
d
s
o
f
a
r
D
y
s
o
s
t
e
o
s
c
l
e
r
o
s
i
s
A
R
2
2
4
3
0
0
P
o
s
s
i
b
l
y
r
e
l
a
t
e
d
t
o

o
s
t
e
o
s
c
l
e
r
o
t
i
c
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a

O
s
t
e
o
m
e
s
o
p
y
k
n
o
s
i
s
A
D
1
6
6
4
5
0
O
s
t
e
o
p
e
t
r
o
s
i
s
w
i
t
h
i
n
f
a
n
t
i
l
e
n
e
u
r
o
a
x
o
n
a
l
d
y
s
p
l
a
s
i
a
A
R
?
6
0
0
3
2
9
S
a
m
e
a
s
o
s
t
e
o
p
e
t
r
o
s
i
s
w
i
t
h
n
e
r
v
o
u
s
s
y
s
t
e
m
i
n
v
o
l
v
e
m
e
n
t
(
s
e
e
a
b
o
v
e
)
?
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
954 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2
4
.
I
n
c
r
e
a
s
e
d
b
o
n
e
d
e
n
s
i
t
y
g
r
o
u
p
w
i
t
h
m
e
t
a
p
h
y
s
e
a
l
a
n
d
/
o
r
d
i
a
p
h
y
s
e
a
l
i
n
v
o
l
v
e
m
e
n
t
C
r
a
n
i
o
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
a
u
t
o
s
o
m
a
l
d
o
m
i
n
a
n
t
t
y
p
e
A
D
1
2
3
0
0
0
5
p
1
5
.
2

1
4
.
2
A
N
K
H
H
o
m
o
l
o
g
o
f
m
o
u
s
e
A
N
K
(
a
n
k
y
l
o
s
i
s
)
g
e
n
e
G
a
i
n
o
f
f
u
n
c
t
i
o
n
m
u
t
a
t
i
o
n
s
D
i
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
C
a
m
u
r
a
t
i
-
E
n
g
e
l
m
a
n
n
A
D
1
3
1
3
0
0
1
9
q
1
3
T
G
F
b
e
t
a
1
T
r
a
n
s
f
o
r
m
i
n
g
g
r
o
w
t
h
f
a
c
t
o
r
b
e
t
a
1
H
e
m
a
t
o
d
i
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
G
h
o
s
a
l
A
R
2
3
1
0
9
5
7
q
3
4
T
B
X
A
S
1
T
h
r
o
m
b
o
x
a
n
e
A
s
y
n
t
h
a
s
e
1
H
y
p
e
r
t
r
o
p
h
i
c
o
s
t
e
o
a
r
t
h
r
o
p
a
t
h
y
A
R
2
5
9
1
0
0
4
q
3
4

3
5
H
P
G
D
1
5
-
a
l
p
h
a
-
h
y
d
r
o
x
y
p
r
o
s
t
a
g
l
a
n
d
i
n
d
e
h
y
d
r
o
g
e
n
a
s
e
I
n
c
l
u
d
e
s
c
r
a
n
i
o
-
o
s
t
e
o
a
r
t
h
r
o
p
a
t
h
y
a
n
d
c
a
s
e
s
o
f
r
e
c
e
s
s
i
v
e
p
a
c
h
y
d
e
r
m
o
p
e
r
i
o
s
t
o
s
i
s
P
a
c
h
y
d
e
r
m
o
p
e
r
i
o
s
t
o
s
i
s
(
h
y
p
e
r
t
r
o
p
h
i
c
o
s
t
e
o
a
r
t
h
r
o
p
a
t
h
y
,
p
r
i
m
a
r
y
,
a
u
t
o
s
o
m
a
l
d
o
m
i
n
a
n
t
)
A
D
1
6
7
1
0
0
R
e
l
a
t
i
o
n
s
h
i
p
t
o
r
e
c
e
s
s
i
v
e
f
o
r
m
(
M
I
M
2
5
9
1
0
0
,
H
P
G
D
d
e

c
i
e
n
c
y
)
u
n
c
l
e
a
r
O
c
u
l
o
d
e
n
t
o
o
s
s
e
o
u
s
d
y
s
p
l
a
s
i
a
(
O
D
O
D
)
m
i
l
d
t
y
p
e
A
D
1
6
4
2
0
0
6
q
2
2

2
3
G
J
A
1
G
a
p
j
u
n
c
t
i
o
n
p
r
o
t
e
i
n
a
l
p
h
a
-
1
O
c
u
l
o
d
e
n
t
o
o
s
s
e
o
u
s
d
y
s
p
l
a
s
i
a
(
O
D
O
D
)
s
e
v
e
r
e
t
y
p
e
A
R
2
5
7
8
5
0
P
o
s
s
i
b
l
y
h
o
m
o
z
y
g
o
u
s
f
o
r
m
o
f
m
i
l
d
O
D
O
D
O
s
t
e
o
e
c
t
a
s
i
a
w
i
t
h
h
y
p
e
r
p
h
o
s
p
h
a
t
a
s
i
a
(
j
u
v
e
n
i
l
e
P
a
g
e
t
d
i
s
e
a
s
e
)
A
R
2
3
9
0
0
0
8
q
2
4
O
P
G
O
s
t
e
o
p
r
o
t
e
g
e
r
i
n
S
c
l
e
r
o
s
t
e
o
s
i
s
A
R
2
6
9
5
0
0
1
7
q
1
2

2
1
S
O
S
T
S
c
l
e
r
o
s
t
i
n
E
n
d
o
s
t
e
a
l
h
y
p
e
r
o
s
t
o
s
i
s
,
v
a
n
B
u
c
h
e
m
t
y
p
e
A
R
2
3
9
1
0
0
1
7
q
1
2

2
1
S
O
S
T
S
c
l
e
r
o
s
t
i
n
S
p
e
c
i

c
5
2
k
b
d
e
l
e
t
i
o
n
d
o
w
n
s
t
r
e
a
m
o
f
S
O
S
T
T
r
i
c
h
o
d
e
n
t
o
o
s
s
e
o
u
s
d
y
s
p
l
a
s
i
a
A
D
1
9
0
3
2
0
1
7
q
2
1
D
L
X
3
D
i
s
t
a
l
-
l
e
s
s
h
o
m
e
o
b
o
x
3
C
r
a
n
i
o
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
a
u
t
o
s
o
m
a
l
r
e
c
e
s
s
i
v
e
t
y
p
e
A
R
2
1
8
4
0
0
6
q
2
1

2
2
D
i
a
p
h
y
s
e
a
l
m
e
d
u
l
l
a
r
y
s
t
e
n
o
s
i
s
w
i
t
h
b
o
n
e
m
a
l
i
g
n
a
n
c
y
A
D
1
1
2
2
5
0
9
p
2
1

p
2
2
C
r
a
n
i
o
d
i
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
A
D
1
2
2
8
6
0
C
r
a
n
i
o
m
e
t
a
d
i
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
W
o
r
m
i
a
n
b
o
n
e
t
y
p
e
A
R

E
n
d
o
s
t
e
a
l
s
c
l
e
r
o
s
i
s
w
i
t
h
c
e
r
e
b
e
l
l
a
r
h
y
p
o
p
l
a
s
i
a
A
R
2
1
3
0
0
2
L
e
n
z

M
a
j
e
w
s
k
i
h
y
p
e
r
o
s
t
o
t
i
c
d
y
s
p
l
a
s
i
a
S
P
1
5
1
0
5
0
M
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
,
B
r
a
u
n

T
i
n
s
c
h
e
r
t
t
y
p
e
X
L
6
0
5
9
4
6
P
y
l
e
d
i
s
e
a
s
e
A
R
2
6
5
9
0
0
2
5
.
O
s
t
e
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
a
n
d
d
e
c
r
e
a
s
e
d
b
o
n
e
d
e
n
s
i
t
y
g
r
o
u
p
F
o
r
c
o
m
m
e
n
t
s
t
h
e
c
l
a
s
s
i

c
a
t
i
o
n
o
f
o
s
t
e
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
,
p
l
e
a
s
e
r
e
f
e
r
t
o
t
h
e
t
e
x
t
O
s
t
e
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
,
n
o
n
-
d
e
f
o
r
m
i
n
g
f
o
r
m
(
O
I
t
y
p
e
1
)
A
D
C
O
L
1
A
1
,
C
O
L
1
A
2
C
O
L
1
A
1
:
c
o
l
l
a
g
e
n
1
a
l
p
h
a
-
1
c
h
a
i
n
,
C
O
L
1
A
2
:
c
o
l
l
a
g
e
n
1
a
l
p
h
a
-
2
c
h
a
i
n
,
C
R
T
A
P
:
c
a
r
t
i
l
a
g
e
-
a
s
s
o
c
i
a
t
e
d
p
r
o
t
e
i
n
,
L
E
P
R
E
1
:
l
e
u
c
i
n
e
p
r
o
l
i
n
e
-
e
n
r
i
c
h
e
d
p
r
o
t
e
o
g
l
y
c
a
n
(
l
e
p
r
e
c
a
n
)
1
,
P
P
I
B
:
p
e
p
t
i
d
y
l
p
r
o
l
y
l
i
s
o
m
e
r
a
s
e
B
(
c
y
c
l
o
p
h
i
l
i
n
B
)
,
F
K
B
P
1
0
:
F
K
5
0
6
b
i
n
d
i
n
g
p
r
o
t
e
i
n
1
0
,
S
E
R
P
I
N
H
:
s
e
r
p
i
n
p
e
p
t
i
d
a
s
e
i
n
h
i
b
i
t
o
r
c
l
a
d
e
H
1
,
S
P
7
:
S
P
7
t
r
a
n
s
c
r
i
p
t
i
o
n
f
a
c
t
o
r
(
O
s
t
e
r
i
x
)
O
s
t
e
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
,
p
e
r
i
n
a
t
a
l
l
e
t
h
a
l
f
o
r
m
(
O
I
t
y
p
e
2
)
A
D
,
A
R
C
O
L
1
A
1
,
C
O
L
1
A
2
,
C
R
T
A
P
,
L
E
P
R
E
1
,
P
P
I
B
O
s
t
e
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
,
p
r
o
g
r
e
s
s
i
v
e
l
y
d
e
f
o
r
m
i
n
g
t
y
p
e
(
O
I
t
y
p
e
3
)
A
D
,
A
R
C
O
L
1
A
1
,
C
O
L
1
A
2
,
C
R
T
A
P
,
L
E
P
R
E
1
,
P
P
I
B
,
F
K
B
P
1
0
,
S
E
R
P
I
N
H
1
S
e
e
a
l
s
o
B
r
u
c
k
s
y
n
d
r
o
m
e
t
y
p
e
1
(
b
e
l
o
w
)
O
s
t
e
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
,
m
o
d
e
r
a
t
e
f
o
r
m
(
O
I
t
y
p
e
4
)
A
D
,
A
R
C
O
L
1
A
1
,
C
O
L
1
A
2
,
C
R
T
A
P
,
F
K
B
P
1
0
,
S
P
7
(
C
o
n
t
i
n
u
e
d
)
WARMAN ET AL. 955
O
s
t
e
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
w
i
t
h
c
a
l
c
i

c
a
t
i
o
n
o
f
t
h
e
i
n
t
e
r
o
s
s
e
o
u
s
m
e
m
b
r
a
n
e
s
a
n
d
/
o
r
h
y
p
e
r
t
r
o
p
h
i
c
c
a
l
l
u
s
(
O
I
t
y
p
e
5
)
A
D
6
1
0
9
6
7
O
s
t
e
o
g
e
n
e
s
i
s
i
m
p
e
r
f
e
c
t
a
,
o
t
h
e
r
t
y
p
e
s
B
r
u
c
k
s
y
n
d
r
o
m
e
t
y
p
e
1
(
B
S
1
)
A
R
2
5
9
4
5
0
1
7
q
2
1
F
K
B
P
1
0
F
K
5
0
6
b
i
n
d
i
n
g
p
r
o
t
e
i
n
1
0
S
e
e
a
u
t
o
s
o
m
a
l
r
e
c
e
s
s
i
v
e
O
I
,
a
b
o
v
e
;
i
n
t
r
a
f
a
m
i
l
i
a
l
v
a
r
i
a
b
i
l
i
t
y
b
e
t
w
e
e
n
O
I
3
a
n
d
B
S
1
d
o
c
u
m
e
n
t
e
d
B
r
u
c
k
s
y
n
d
r
o
m
e
t
y
p
e
2
(
B
S
2
)
A
R
6
0
9
2
2
0
3
q
2
3

2
4
P
L
O
D
2
P
r
o
c
o
l
l
a
g
e
n
l
y
s
y
l
h
y
d
r
o
x
y
l
a
s
e
2
O
s
t
e
o
p
o
r
o
s
i
s
-
p
s
e
u
d
o
g
l
i
o
m
a
s
y
n
d
r
o
m
e
A
R
2
5
9
7
7
0
1
1
q
1
2

1
3
L
R
P
5
L
D
L
-
r
e
c
e
p
t
o
r
r
e
l
a
t
e
d
p
r
o
t
e
i
n
5
C
a
l
v
a
r
i
a
l
d
o
u
g
h
n
u
t
l
e
s
i
o
n
s
w
i
t
h
b
o
n
e
f
r
a
g
i
l
i
t
y
A
D
1
2
6
5
5
0
I
d
i
o
p
a
t
h
i
c
j
u
v
e
n
i
l
e
o
s
t
e
o
p
o
r
o
s
i
s
S
P
2
5
9
7
5
0
S
o
m
e
p
a
t
i
e
n
t
s
r
e
p
o
r
t
e
d
w
i
t
h
h
e
t
e
r
o
z
y
g
o
u
s
m
u
t
a
t
i
o
n
s
i
n
t
h
e
L
R
P
5
g
e
n
e
C
o
l
e
-
C
a
r
p
e
n
t
e
r
d
y
s
p
l
a
s
i
a
(
b
o
n
e
f
r
a
g
i
l
i
t
y
w
i
t
h
c
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
)
S
P
1
1
2
2
4
0
S
e
e
a
l
s
o
c
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
s
y
n
d
r
o
m
e
s
i
n
g
r
o
u
p
3
0
S
p
o
n
d
y
l
o
-
o
c
u
l
a
r
d
y
s
p
l
a
s
i
a
A
R
6
0
5
8
2
2
U
n
l
i
n
k
e
d
t
o
c
o
l
l
a
g
e
n
1
a
n
d
c
o
l
l
a
g
e
n
2
g
e
n
e
s
o
r
L
R
P
5
O
s
t
e
o
p
e
n
i
a
w
i
t
h
r
a
d
i
o
l
u
c
e
n
t
l
e
s
i
o
n
s
o
f
t
h
e
m
a
n
d
i
b
l
e
A
D
1
6
6
2
6
0
E
h
l
e
r
s

D
a
n
l
o
s
s
y
n
d
r
o
m
e
,
p
r
o
g
e
r
o
i
d
f
o
r
m
A
R
1
3
0
0
7
0
5
q
3
5
B
4
G
A
L
T
7
X
y
l
o
s
y
l
p
r
o
t
e
i
n
4
-
b
e
t
a
-
g
a
l
a
c
t
o
s
y
l
t
r
a
n
s
f
e
r
a
s
e
d
e

c
i
e
n
c
y
G
e
r
o
d
e
r
m
a
o
s
t
e
o
d
y
s
p
l
a
s
t
i
c
u
m
A
R
2
3
1
0
7
0
1
q
2
4
.
2
G
O
R
A
B
S
C
Y
L
1
-
b
i
n
d
i
n
g
p
r
o
t
e
i
n
1
C
u
t
i
s
l
a
x
a
,
a
u
t
o
s
o
m
a
l
r
e
c
e
s
s
i
v
e
f
o
r
m
,
t
y
p
e
2
B
(
A
R
C
L
2
B
)
A
R
6
1
2
9
4
0
1
7
q
2
5
.
3
P
Y
C
R
1
P
y
r
r
o
l
i
n
e
-
5
-
c
a
r
b
o
x
y
l
a
t
e
r
e
d
u
c
t
a
s
e
1
S
k
e
l
e
t
a
l
f
e
a
t
u
r
e
s
o
v
e
r
l
a
p
p
i
n
g
w
i
t
h
p
r
o
g
e
r
o
i
d
E
D
S
a
n
d
g
e
r
o
d
e
r
m
a
o
s
t
e
o
d
y
s
p
l
a
s
t
i
c
u
m
C
u
t
i
s
l
a
x
a
,
a
u
t
o
s
o
m
a
l
r
e
c
e
s
s
i
v
e
f
o
r
m
,
t
y
p
e
2
A
(
A
R
C
L
2
A
)
(
W
r
i
n
k
l
y
s
k
i
n
s
y
n
d
r
o
m
e
)
A
R
2
7
8
2
5
0
,
2
1
9
2
0
0
1
2
q
2
4
.
3
A
T
P
6
V
O
A
2
A
T
P
a
s
e
,
H

t
r
a
n
s
p
o
r
t
i
n
g
,
l
y
s
o
s
o
m
a
l
,
V
0
s
u
b
u
n
i
t
A
2
S
k
e
l
e
t
a
l
f
e
a
t
u
r
e
s
o
v
e
r
l
a
p
p
i
n
g
w
i
t
h
p
r
o
g
e
r
o
i
d
E
D
S
a
n
d
g
e
r
o
d
e
r
m
a
o
s
t
e
o
d
y
s
p
l
a
s
t
i
c
u
m
S
i
n
g
l
e
t
o
n

M
e
r
t
e
n
d
y
s
p
l
a
s
i
a
A
D
1
8
2
2
5
0
2
6
.
A
b
n
o
r
m
a
l
m
i
n
e
r
a
l
i
z
a
t
i
o
n
g
r
o
u
p
H
y
p
o
p
h
o
s
p
h
a
t
a
s
i
a
,
p
e
r
i
n
a
t
a
l
l
e
t
h
a
l
a
n
d
i
n
f
a
n
t
i
l
e
f
o
r
m
s
A
R
2
4
1
5
0
0
1
p
3
6
.
1

p
3
4
A
L
P
L
A
l
k
a
l
i
n
e
p
h
o
s
p
h
a
t
a
s
e
,
t
i
s
s
u
e
n
o
n
-
s
p
e
c
i

c
(
T
N
S
A
L
P
)
I
n
t
r
a
f
a
m
i
l
i
a
l
v
a
r
i
a
b
i
l
i
t
y
H
y
p
o
p
h
o
s
p
h
a
t
a
s
i
a
,
a
d
u
l
t
f
o
r
m
A
D
1
4
6
3
0
0
1
p
3
6
.
1

p
3
4
A
L
P
L
A
l
k
a
l
i
n
e
p
h
o
s
p
h
a
t
a
s
e
,
t
i
s
s
u
e
n
o
n
-
s
p
e
c
i

c
(
T
N
S
A
L
P
)
I
n
c
l
u
d
e
s
o
d
o
n
t
o
h
y
p
o
p
h
o
s
p
h
a
t
a
s
i
a
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
956 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
H
y
p
o
p
h
o
s
p
h
a
t
e
m
i
c
r
i
c
k
e
t
s
,
X
-
l
i
n
k
e
d
d
o
m
i
n
a
n
t
X
L
D
3
0
7
8
0
0
X
p
2
2
P
H
E
X
X
-
l
i
n
k
e
d
h
y
p
o
p
h
o
s
p
h
a
t
e
m
i
a
m
e
m
b
r
a
n
e
p
r
o
t
e
a
s
e
H
y
p
o
p
h
o
s
p
h
a
t
e
m
i
c
r
i
c
k
e
t
s
,
a
u
t
o
s
o
m
a
l
d
o
m
i
n
a
n
t
A
D
1
9
3
1
0
0
1
2
p
1
3
.
3
F
G
F
2
3
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
2
3
H
y
p
o
p
h
o
s
p
h
a
t
e
m
i
c
r
i
c
k
e
t
s
,
a
u
t
o
s
o
m
a
l
r
e
c
e
s
s
i
v
e
,
t
y
p
e
1
(
A
R
H
R
1
)
A
R
2
4
1
5
2
0
4
q
2
1
D
M
P
1
D
e
n
t
i
n
m
a
t
r
i
x
a
c
i
d
i
c
p
h
o
s
p
h
o
p
r
o
t
e
i
n
1
H
y
p
o
p
h
o
s
p
h
a
t
e
m
i
c
r
i
c
k
e
t
s
,
a
u
t
o
s
o
m
a
l
r
e
c
e
s
s
i
v
e
,
t
y
p
e
2
(
A
R
H
R
2
)
A
R
6
1
3
3
1
2
6
q
2
3
E
N
P
P
1
E
c
t
o
n
u
c
l
e
o
t
i
d
e
p
y
r
o
p
h
o
s
p
h
a
t
a
s
e
/
p
h
o
s
p
h
o
d
i
e
s
t
e
r
a
s
e
1
H
y
p
o
p
h
o
s
p
h
a
t
e
m
i
c
r
i
c
k
e
t
s
w
i
t
h
h
y
p
e
r
c
a
l
c
i
u
r
i
a
,
X
-
l
i
n
k
e
d
r
e
c
e
s
s
i
v
e
X
L
R
3
0
0
5
5
4
X
p
1
1
.
2
2
C
l
C
N
5
C
h
l
o
r
i
d
e
c
h
a
n
n
e
l
5
P
a
r
t
o
f
D
e
n
t

s
d
i
s
e
a
s
e
c
o
m
p
l
e
x
H
y
p
o
p
h
o
s
p
h
a
t
e
m
i
c
r
i
c
k
e
t
s
w
i
t
h
h
y
p
e
r
c
a
l
c
i
u
r
i
a
,
a
u
t
o
s
o
m
a
l
r
e
c
e
s
s
i
v
e
(
H
H
R
H
)
A
R
2
4
1
5
3
9
9
q
3
4
S
L
C
3
4
A
3
S
o
d
i
u
m
-
p
h
o
s
p
h
a
t
e
c
o
t
r
a
n
s
p
o
r
t
e
r
N
e
o
n
a
t
a
l
h
y
p
e
r
p
a
r
a
t
h
y
r
o
i
d
i
s
m
,
s
e
v
e
r
e
f
o
r
m
A
R
2
3
9
2
0
0
3
q
1
3
.
3

2
1
C
A
S
R
C
a
l
c
i
u
m
-
s
e
n
s
i
n
g
r
e
c
e
p
t
o
r
F
a
m
i
l
i
a
l
h
y
p
o
c
a
l
c
i
u
r
i
c
h
y
p
e
r
c
a
l
c
e
m
i
a
w
i
t
h
t
r
a
n
s
i
e
n
t
n
e
o
n
a
t
a
l
h
y
p
e
r
p
a
r
a
t
h
y
r
o
i
d
i
s
m
A
D
1
4
5
9
8
0
3
q
1
3
.
3

2
1
C
A
S
R
C
a
l
c
i
u
m
-
s
e
n
s
i
n
g
r
e
c
e
p
t
o
r
C
a
l
c
i
u
m
p
y
r
o
p
h
o
s
p
h
a
t
e
d
e
p
o
s
i
t
i
o
n
d
i
s
e
a
s
e
(
f
a
m
i
l
i
a
l
c
h
o
n
d
r
o
c
a
l
c
i
n
o
s
i
s
)
t
y
p
e
2
A
D
1
1
8
6
0
0
5
p
1
5
.
2

1
4
.
2
A
N
K
H
H
o
m
o
l
o
g
o
f
m
o
u
s
e
A
N
K
(
a
n
k
y
l
o
s
i
s
)
g
e
n
e
L
o
s
s
o
f
f
u
n
c
t
i
o
n
m
u
t
a
t
i
o
n
s
(
s
e
e
c
r
a
n
i
o
m
e
t
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
i
n
g
r
o
u
p
2
4
)
S
e
e
a
l
s
o
J
a
n
s
e
n
d
y
s
p
l
a
s
i
a
a
n
d
E
i
k
e
n
d
y
s
p
l
a
s
i
a
2
7
.
L
y
s
o
s
o
m
a
l
s
t
o
r
a
g
e
d
i
s
e
a
s
e
s
w
i
t
h
s
k
e
l
e
t
a
l
i
n
v
o
l
v
e
m
e
n
t
(
d
y
s
o
s
t
o
s
i
s
m
u
l
t
i
p
l
e
x
g
r
o
u
p
)
M
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
1
H
/
1
S
A
R
6
0
7
0
1
4
4
p
1
6
.
3
I
D
A
A
l
p
h
a
-
1
-
I
d
u
r
o
n
i
d
a
s
e
M
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
2
X
L
R
3
0
9
9
0
0
X
q
2
7
.
3

2
8
I
D
S
I
d
u
r
o
n
a
t
e
-
2
-
s
u
l
f
a
t
a
s
e
M
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
3
A
A
R
2
5
2
9
0
0
1
7
q
2
5
.
3
H
S
S
H
e
p
a
r
a
n
s
u
l
f
a
t
e
s
u
l
f
a
t
a
s
e
M
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
3
B
A
R
2
5
2
9
2
0
1
7
q
2
1
N
A
G
L
U
N
-
A
c
-
b
e
t
a
-
D
-
g
l
u
c
o
s
a
m
i
n
i
d
a
s
e
M
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
3
C
A
R
2
5
2
9
3
0
8
p
1
1

q
1
3
H
S
G
N
A
T
A
c
-
C
o
A
:
a
l
p
h
a
-
g
l
u
c
o
s
a
m
i
n
i
d
e
N
-
a
c
e
t
y
l
t
r
a
n
s
f
e
r
a
s
e
M
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
3
D
A
R
2
5
2
9
4
0
1
2
q
1
4
G
N
S
N
-
A
c
e
t
y
l
g
l
u
c
o
s
a
m
i
n
e
6
-
s
u
l
f
a
t
a
s
e
M
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
4
A
A
R
2
5
3
0
0
0
1
6
q
2
4
.
3
G
A
L
N
S
G
a
l
a
c
t
o
s
a
m
i
n
e
-
6
-
s
u
l
f
a
t
e
s
u
l
f
a
t
a
s
e
M
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
4
B
A
R
2
5
3
0
1
0
3
p
2
1
.
3
3
G
L
B
I
b
e
t
a
-
G
a
l
a
c
t
o
s
i
d
a
s
e
M
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
6
A
R
2
5
3
2
0
0
5
q
1
3
.
3
A
R
S
B
A
r
y
l
s
u
l
f
a
t
a
s
e
B
M
u
c
o
p
o
l
y
s
a
c
c
h
a
r
i
d
o
s
i
s
t
y
p
e
7
A
R
2
5
3
2
2
0
7
q
2
1
.
1
1
G
U
S
B
b
e
t
a
-
G
l
u
c
u
r
o
n
i
d
a
s
e
F
u
c
o
s
i
d
o
s
i
s
A
R
2
3
0
0
0
0
1
p
3
4
F
U
C
A
a
l
p
h
a
-
F
u
c
o
s
i
d
a
s
e
a
l
p
h
a
-
M
a
n
n
o
s
i
d
o
s
i
s
A
R
2
4
8
5
0
0
1
9
p
1
3
.
2

1
2
M
A
N
A
a
l
p
h
a
-
M
a
n
n
o
s
i
d
a
s
e
b
e
t
a
-
M
a
n
n
o
s
i
d
o
s
i
s
A
R
2
4
8
5
1
0
4
q
2
2

2
5
M
A
N
B
b
e
t
a
-
M
a
n
n
o
s
i
d
a
s
e
A
s
p
a
r
t
y
l
g
l
u
c
o
s
a
m
i
n
u
r
i
a
A
R
2
0
8
4
0
0
4
q
2
3

2
7
A
G
A
A
s
p
a
r
t
y
l
-
g
l
u
c
o
s
a
m
i
n
i
d
a
s
e
G
M
I
G
a
n
g
l
i
o
s
i
d
o
s
i
s
,
s
e
v
e
r
a
l
f
o
r
m
s
A
R
2
3
0
5
0
0
3
p
2
1

1
4
.
2
G
L
B
1
b
e
t
a
-
G
a
l
a
c
t
o
s
i
d
a
s
e
S
i
a
l
i
d
o
s
i
s
,
s
e
v
e
r
a
l
f
o
r
m
s
A
R
2
5
6
5
5
0
6
p
2
1
.
3
N
E
U
1
N
e
u
r
a
m
i
n
i
d
a
s
e
(
s
i
a
l
i
d
a
s
e
)
S
i
a
l
i
c
a
c
i
d
s
t
o
r
a
g
e
d
i
s
e
a
s
e
(
S
I
A
S
D
)
A
R
2
6
9
9
2
0
6
q
1
4

q
1
5
S
L
C
1
7
A
5
S
i
a
l
i
n
(
s
i
a
l
i
c
a
c
i
d
t
r
a
n
s
p
o
r
t
e
r
)
G
a
l
a
c
t
o
s
i
a
l
i
d
o
s
i
s
,
s
e
v
e
r
a
l
f
o
r
m
s
A
R
2
5
6
5
4
0
2
0
q
1
3
.
1
P
P
G
B
b
e
t
a
-
G
a
l
a
c
t
o
s
i
d
a
s
e
p
r
o
t
e
c
t
i
v
e
p
r
o
t
e
i
n
M
u
l
t
i
p
l
e
s
u
l
f
a
t
a
s
e
d
e

c
i
e
n
c
y
A
R
2
7
2
2
0
0
3
p
2
6
S
U
M
F
1
S
u
l
f
a
t
a
s
e
-
m
o
d
i
f
y
i
n
g
f
a
c
t
o
r
-
1
M
u
c
o
l
i
p
i
d
o
s
i
s
I
I
(
I
-
c
e
l
l
d
i
s
e
a
s
e
)
,
a
l
p
h
a
/
b
e
t
a
t
y
p
e
A
R
2
5
2
5
0
0
4
q
2
1

2
3
G
N
P
T
A
B
N
-
A
c
e
t
y
l
g
l
u
c
o
s
a
m
i
n
e
1
-
p
h
o
s
p
h
o
t
r
a
n
s
f
e
r
a
s
e
,
a
l
p
h
a
/
b
e
t
a
s
u
b
u
n
i
t
s
(
C
o
n
t
i
n
u
e
d
)
WARMAN ET AL. 957
M
u
c
o
l
i
p
i
d
o
s
i
s
I
I
I
(
P
s
e
u
d
o
-
H
u
r
l
e
r
p
o
l
y
d
y
s
t
r
o
p
h
y
)
,
a
l
p
h
a
/
b
e
t
a
t
y
p
e
A
R
2
5
2
6
0
0
4
q
2
1

2
3
G
N
P
T
A
B
N
-
A
c
e
t
y
l
g
l
u
c
o
s
a
m
i
n
e
1
-
p
h
o
s
p
h
o
t
r
a
n
s
f
e
r
a
s
e
,
a
l
p
h
a
/
b
e
t
a
s
u
b
u
n
i
t
s
M
u
c
o
l
i
p
i
d
o
s
i
s
I
I
I
(
P
s
e
u
d
o
-
H
u
r
l
e
r
p
o
l
y
d
y
s
t
r
o
p
h
y
)
,
g
a
m
m
a
t
y
p
e
A
R
2
5
2
6
0
5
4
q
2
1

2
3
G
N
P
T
G
N
-
A
c
e
t
y
l
g
l
u
c
o
s
a
m
i
n
e
1
-
p
h
o
s
p
h
o
t
r
a
n
s
f
e
r
a
s
e
,
g
a
m
m
a
s
u
b
u
n
i
t
2
8
.
O
s
t
e
o
l
y
s
i
s
g
r
o
u
p
F
a
m
i
l
i
a
l
e
x
p
a
n
s
i
l
e
o
s
t
e
o
l
y
s
i
s
A
D
1
7
4
8
1
0
1
8
q
2
2
.
1
R
A
N
K
(
T
N
F
R
S
F
1
1
A
)
I
n
c
l
u
d
e
s
e
x
p
a
n
s
i
l
e
s
k
e
l
e
t
a
l
h
y
p
e
r
p
h
o
s
p
h
a
t
a
s
i
a
(
M
I
M
6
0
2
0
8
0
)
M
a
n
d
i
b
u
l
o
a
c
r
a
l
d
y
s
p
l
a
s
i
a
t
y
p
e
A
A
D
2
4
8
3
7
0
1
q
2
1
.
2
L
M
N
A
L
a
m
i
n
A
/
C
M
a
n
d
i
b
u
l
o
a
c
r
a
l
d
y
s
p
l
a
s
i
a
t
y
p
e
B
A
R
6
0
8
6
1
2
1
p
3
4
Z
M
P
S
T
E
2
4
Z
i
n
c
m
e
t
a
l
l
o
p
r
o
t
e
i
n
a
s
e
P
r
o
g
e
r
i
a
,
H
u
t
c
h
i
n
s
o
n

G
i
l
f
o
r
d
t
y
p
e
A
D
1
7
6
6
7
0
1
q
2
1
.
2
L
M
N
A
L
a
m
i
n
A
/
C
T
o
r
g

W
i
n
c
h
e
s
t
e
r
s
y
n
d
r
o
m
e
A
R
2
5
9
6
0
0
1
6
q
1
3
M
M
P
2
M
a
t
r
i
x
m
e
t
a
l
l
o
p
r
o
t
e
i
n
a
s
e
2
I
n
c
l
u
d
e
s
N
o
d
u
l
o
s
i
s

A
r
t
h
r
o
p
a
t
h
y

O
s
t
e
o
l
y
s
i
s
s
y
n
d
r
o
m
e
(
M
I
M
6
0
5
1
5
6
)
H
a
j
d
u

C
h
e
n
e
y
s
y
n
d
r
o
m
e
A
D
1
0
2
5
0
0
M
u
l
t
i
c
e
n
t
r
i
c
c
a
r
p
a
l
-
t
a
r
s
a
l
o
s
t
e
o
l
y
s
i
s
w
i
t
h
a
n
d
w
i
t
h
o
u
t
n
e
p
h
r
o
p
a
t
h
y
A
D
1
6
6
3
0
0
L
i
p
o
m
e
m
b
r
a
n
e
o
u
s
o
s
t
e
o
d
y
s
t
r
o
p
h
y
w
i
t
h
l
e
u
k
o
e
n
c
e
p
h
a
l
o
p
a
t
h
y
(
p
r
e
s
e
n
i
l
e
d
e
m
e
n
t
i
a
w
i
t
h
b
o
n
e
c
y
s
t
s
;
N
a
s
u

H
a
k
o
l
a
)
A
R
2
2
1
7
7
0
6
p
2
1
.
2
T
R
E
M
2
T
r
i
g
g
e
r
i
n
g
r
e
c
e
p
t
o
r
e
x
p
r
e
s
s
e
d
o
n
m
y
e
l
o
i
d
c
e
l
l
s
2
L
i
p
o
m
e
m
b
r
a
n
e
o
u
s
o
s
t
e
o
d
y
s
t
r
o
p
h
y
w
i
t
h
l
e
u
k
o
e
n
c
e
p
h
a
l
o
p
a
t
h
y
(
p
r
e
s
e
n
i
l
e
d
e
m
e
n
t
i
a
w
i
t
h
b
o
n
e
c
y
s
t
s
;
N
a
s
u

H
a
k
o
l
a
)
A
R
2
2
1
7
7
0
1
9
q
1
3
.
1
T
Y
R
O
B
P
T
y
r
o
p
r
o
t
e
i
n
t
y
r
o
s
i
n
e
k
i
n
a
s
e
-
b
i
n
d
i
n
g
p
r
o
t
e
i
n
S
e
e
a
l
s
o
P
y
c
n
o
d
y
s
o
s
t
o
s
i
s
,
c
l
e
i
d
o
c
r
a
n
i
a
l
d
y
s
p
l
a
s
i
a
,
a
n
d
S
i
n
g
l
e
t
o
n

M
e
r
t
e
n
s
y
n
d
r
o
m
e
.
N
o
t
e
:
s
e
v
e
r
a
l
n
e
u
r
o
l
o
g
i
c
c
o
n
d
i
t
i
o
n
s
m
a
y
c
a
u
s
e
a
c
r
o
o
s
t
e
o
l
y
s
i
s
2
9
.
D
i
s
o
r
g
a
n
i
z
e
d
d
e
v
e
l
o
p
m
e
n
t
o
f
s
k
e
l
e
t
a
l
c
o
m
p
o
n
e
n
t
s
g
r
o
u
p
M
u
l
t
i
p
l
e
c
a
r
t
i
l
a
g
i
n
o
u
s
e
x
o
s
t
o
s
e
s
1
A
D
1
3
3
7
0
0
8
q
2
3

2
4
.
1
E
X
T
1
E
x
o
s
t
o
s
i
n
-
1
M
u
l
t
i
p
l
e
c
a
r
t
i
l
a
g
i
n
o
u
s
e
x
o
s
t
o
s
e
s
2
A
D
1
3
3
7
0
1
1
1
p
1
2

1
1
E
X
T
2
E
x
o
s
t
o
s
i
n
-
2
M
u
l
t
i
p
l
e
c
a
r
t
i
l
a
g
i
n
o
u
s
e
x
o
s
t
o
s
e
s
3
A
D
6
0
0
2
0
9
1
9
p
C
h
e
r
u
b
i
s
m
A
D
1
1
8
4
0
0
4
p
1
6
S
H
3
B
P
2
S
H
3
d
o
m
a
i
n
-
b
i
n
d
i
n
g
p
r
o
t
e
i
n
2
F
i
b
r
o
u
s
d
y
s
p
l
a
s
i
a
,
p
o
l
y
o
s
t
o
t
i
c
f
o
r
m
S
P
1
7
4
8
0
0
2
0
q
1
3
G
N
A
S
1
G
u
a
n
i
n
e
n
u
c
l
e
o
t
i
d
e
-
b
i
n
d
i
n
g
p
r
o
t
e
i
n
,
a
l
p
h
a
-
s
t
i
m
u
l
a
t
i
n
g
a
c
t
i
v
i
t
y
s
u
b
u
n
i
t
1
S
o
m
a
t
i
c
m
o
s
a
i
c
i
s
m
a
n
d
i
m
p
r
i
n
t
i
n
g
p
h
e
n
o
m
e
n
a
;
i
n
c
l
u
d
e
s
M
c
C
u
n
e

A
l
b
r
i
g
h
t
s
y
n
d
r
o
m
e
P
r
o
g
r
e
s
s
i
v
e
o
s
s
e
o
u
s
h
e
t
e
r
o
p
l
a
s
i
a
A
D
1
6
6
3
5
0
2
0
q
1
3
G
N
A
S
1
G
u
a
n
i
n
e
n
u
c
l
e
o
t
i
d
e
-
b
i
n
d
i
n
g
p
r
o
t
e
i
n
,
a
l
p
h
a
-
s
t
i
m
u
l
a
t
i
n
g
a
c
t
i
v
i
t
y
s
u
b
u
n
i
t
1
G
e
n
e
s
u
b
j
e
c
t
t
o
i
m
p
r
i
n
t
i
n
g
G
n
a
t
h
o
d
i
a
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
A
D
1
6
6
2
6
0
1
1
p
1
5
.
1

1
4
.
3
T
M
E
M
1
6
E
T
r
a
n
s
m
e
m
b
r
a
n
e
p
r
o
t
e
i
n
1
6
E
M
e
t
a
c
h
o
n
d
r
o
m
a
t
o
s
i
s
A
D
1
5
6
2
5
0
1
2
q
2
4
P
T
P
N
1
1
P
r
o
t
e
i
n
-
t
y
r
o
s
i
n
e
p
h
o
s
p
h
a
t
a
s
e
n
o
n
r
e
c
e
p
t
o
r
-
t
y
p
e
1
1
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
958 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
O
s
t
e
o
g
l
o
p
h
o
n
i
c
d
y
s
p
l
a
s
i
a
A
D
1
6
6
2
5
0
8
p
1
1
F
G
F
R
1
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
r
e
c
e
p
t
o
r
1
S
e
e
a
l
s
o
C
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
s
y
n
d
r
o
m
e
s
i
n
g
r
o
u
p
3
0
F
i
b
r
o
d
y
s
p
l
a
s
i
a
o
s
s
i

c
a
n
s
p
r
o
g
r
e
s
s
i
v
a
(
F
O
P
)
A
D
,
S
P
1
3
5
1
0
0
2
q
2
3

2
4
A
C
V
R
1
A
c
t
i
v
i
n
A
(
B
M
P
t
y
p
e
1
)
r
e
c
e
p
t
o
r
N
e
u
r
o

b
r
o
m
a
t
o
s
i
s
t
y
p
e
1
(
N
F
1
)
A
D
1
6
2
2
0
0
1
7
q
1
1
.
2
N
F
1
N
e
u
r
o

b
r
o
m
i
n
C
a
r
p
o
t
a
r
s
a
l
o
s
t
e
o
c
h
o
n
d
r
o
m
a
t
o
s
i
s
A
D
1
2
7
8
2
0
C
h
e
r
u
b
i
s
m
w
i
t
h
g
i
n
g
i
v
a
l

b
r
o
m
a
t
o
s
i
s
(
R
a
m
o
n
s
y
n
d
r
o
m
e
)
A
R
2
6
6
2
7
0
D
y
s
p
l
a
s
i
a
e
p
i
p
h
y
s
e
a
l
i
s
h
e
m
i
m
e
l
i
c
a
(
T
r
e
v
o
r
)
S
P
1
2
7
8
0
0
E
n
c
h
o
n
d
r
o
m
a
t
o
s
i
s
(
O
l
l
i
e
r
)
S
P
1
6
6
0
0
0
P
T
H
R
1
a
n
d
P
T
P
N
1
1
m
u
t
a
t
i
o
n
s
f
o
u
n
d
i
n
a
f
e
w
c
a
s
e
s
o
n
l
y
,
r
o
l
e
s
t
i
l
l
u
n
c
l
e
a
r
E
n
c
h
o
n
d
r
o
m
a
t
o
s
i
s
w
i
t
h
h
e
m
a
n
g
i
o
m
a
t
a
(
M
a
f
f
u
c
c
i
)
S
P
1
6
6
0
0
0
P
T
P
N
1
1
m
u
t
a
t
i
o
n
s
f
o
u
n
d
i
n
a
f
e
w
c
a
s
e
s
o
n
l
y
,
r
o
l
e
u
n
c
l
e
a
r
S
e
e
a
l
s
o
P
r
o
t
e
u
s
s
y
n
d
r
o
m
e
i
n
g
r
o
u
p
3
0
3
0
.
O
v
e
r
g
r
o
w
t
h
s
y
n
d
r
o
m
e
s
w
i
t
h
s
k
e
l
e
t
a
l
i
n
v
o
l
v
e
m
e
n
t
W
e
a
v
e
r
s
y
n
d
r
o
m
e
S
P
/
A
D
2
7
7
5
9
0
S
o
m
e
c
a
s
e
s
r
e
p
o
r
t
e
d
w
i
t
h
N
S
D
1
m
u
t
a
t
i
o
n
s
(
s
e
e
S
o
t
o
s
s
y
n
d
r
o
m
e
)
S
o
t
o
s
s
y
n
d
r
o
m
e
A
D
1
1
7
5
5
0
5
q
3
5
N
S
D
1
N
u
c
l
e
a
r
r
e
c
e
p
t
o
r
-
b
i
n
d
i
n
g
s
u
-
v
a
r
,
e
n
h
a
n
c
e
r
o
f
z
e
s
t
e
,
a
n
d
t
r
i
t
h
o
r
a
x
d
o
m
a
i
n
p
r
o
t
e
i
n
1
S
o
m
e
c
a
s
e
s
m
a
y
h
a
v
e
N
F
I
X
m
u
t
a
t
i
o
n
s
(
s
e
e
M
a
r
s
h
a
l
l

S
m
i
t
h
s
y
n
d
r
o
m
e
)
M
a
r
s
h
a
l
l

S
m
i
t
h
s
y
n
d
r
o
m
e
S
P
6
0
2
5
3
5
1
9
p
1
3
.
3
N
F
I
X
N
u
c
l
e
a
r
f
a
c
t
o
r
I
/
X
S
o
m
e
c
l
i
n
i
c
a
l
o
v
e
r
l
a
p
w
i
t
h
S
o
t
o
s
s
y
n
d
r
o
m
e
(
s
e
e
a
b
o
v
e
)
P
r
o
t
e
u
s
s
y
n
d
r
o
m
e
S
P
1
7
6
9
2
0
S
o
m
e
P
r
o
t
e
u
s
-
l
i
k
e
c
a
s
e
s
h
a
v
e
m
u
t
a
t
i
o
n
s
i
n
t
h
e
P
T
E
N
g
e
n
e
M
a
r
f
a
n
s
y
n
d
r
o
m
e
A
D
1
5
4
7
0
0
1
5
q
2
1
.
1
F
B
N
1
F
i
b
r
i
l
l
i
n
1
C
o
n
g
e
n
i
t
a
l
c
o
n
t
r
a
c
t
u
r
a
l
a
r
a
c
h
n
o
d
a
c
t
y
l
y
A
D
1
2
1
0
5
0
5
q
2
3
.
3
F
B
N
2
F
i
b
r
i
l
l
i
n
2
L
o
e
y
s

D
i
e
t
z
s
y
n
d
r
o
m
e
t
y
p
e
s
1
A
a
n
d
2
A
A
D
6
0
9
1
9
2
,
6
1
0
1
6
8
,
9
q
2
2
T
G
F
B
R
1
T
G
F
b
e
t
a
r
e
c
e
p
t
o
r
s
u
b
u
n
i
t
1
L
o
e
y
s

D
i
e
t
z
s
y
n
d
r
o
m
e
t
y
p
e
s
1
B
a
n
d
2
B
A
D
6
0
8
9
6
7
,
6
1
0
3
8
0
3
p
2
2
T
G
F
B
R
2
T
G
F
b
e
t
a
r
e
c
e
p
t
o
r
s
u
b
u
n
i
t
2
O
v
e
r
g
r
o
w
t
h
s
y
n
d
r
o
m
e
w
i
t
h
2
q
3
7
t
r
a
n
s
l
o
c
a
t
i
o
n
s
S
P

2
q
3
7
N
P
P
C
N
a
t
r
i
u
r
e
t
i
c
p
e
p
t
i
d
e
p
r
e
c
u
r
s
o
r
C
O
v
e
r
g
r
o
w
t
h
p
r
o
b
a
b
l
y
c
a
u
s
e
d
b
y
o
v
e
r
e
x
p
r
e
s
s
i
o
n
o
f
N
P
P
C
O
v
e
r
g
r
o
w
t
h
s
y
n
d
r
o
m
e
w
i
t
h
s
k
e
l
e
t
a
l
d
y
s
p
l
a
s
i
a
(
N
i
s
h
i
m
u
r
a

S
c
h
m
i
d
t
,
e
n
d
o
c
h
o
n
d
r
a
l
g
i
g
a
n
t
i
s
m
)
S
P
?
N
o
s
o
l
o
g
i
c
s
t
a
t
u
s
u
n
c
l
e
a
r
b
u
t
c
o
n
s
p
i
c
u
o
u
s
s
k
e
l
e
t
a
l
p
h
e
n
o
t
y
p
e
(
s
)
S
e
e
a
l
s
o
S
h
p
r
i
n
t
z
e
n

G
o
l
d
b
e
r
g
s
y
n
d
r
o
m
e
i
n
C
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
g
r
o
u
p
3
1
.
G
e
n
e
t
i
c
i
n

a
m
m
a
t
o
r
y
/
r
h
e
u
m
a
t
o
i
d
-
l
i
k
e
o
s
t
e
o
a
r
t
h
r
o
p
a
t
h
i
e
s
P
r
o
g
r
e
s
s
i
v
e
p
s
e
u
d
o
r
h
e
u
m
a
t
o
i
d
d
y
s
p
l
a
s
i
a
(
P
P
R
D
;
S
E
D
w
i
t
h
p
r
o
g
r
e
s
s
i
v
e
a
r
t
h
r
o
p
a
t
h
y
)
A
R
2
0
8
2
3
0
6
q
2
2

2
3
W
I
S
P
3
W
N
T
1
-
i
n
d
u
c
i
b
l
e
s
i
g
n
a
l
i
n
g
p
a
t
h
w
a
y
p
r
o
t
e
i
n
3
C
h
r
o
n
i
c
i
n
f
a
n
t
i
l
e
n
e
u
r
o
l
o
g
i
c
c
u
t
a
n
e
o
u
s
a
r
t
i
c
u
l
a
r
s
y
n
d
r
o
m
e
(
C
I
N
C
A
)
/
n
e
o
n
a
t
a
l
o
n
s
e
t
m
u
l
t
i
s
y
s
t
e
m
i
n

a
m
m
a
t
o
r
y
d
i
s
e
a
s
e
(
N
O
M
I
D
)
A
D
6
0
7
1
1
5
1
q
4
4
C
I
A
S
1
C
r
y
o
p
y
r
i
n
(
C
o
n
t
i
n
u
e
d
)
WARMAN ET AL. 959
S
t
e
r
i
l
e
m
u
l
t
i
f
o
c
a
l
o
s
t
e
o
m
y
e
l
i
t
i
s
,
p
e
r
i
o
s
t
i
t
i
s
,
a
n
d
p
u
s
t
u
l
o
s
i
s
(
C
I
N
C
A
/
N
O
M
I
D
-
l
i
k
e
)
A
R
1
4
7
6
7
9
2
q
1
4
.
2
I
L
1
R
N
I
n
t
e
r
l
e
u
k
i
n
1
r
e
c
e
p
t
o
r
a
n
t
a
g
o
n
i
s
t
C
h
r
o
n
i
c
r
e
c
u
r
r
e
n
t
m
u
l
t
i
f
o
c
a
l
o
s
t
e
o
m
y
e
l
i
t
i
s
w
i
t
h
c
o
n
g
e
n
i
t
a
l
d
y
s
e
r
y
t
h
r
o
p
o
i
e
t
i
c
a
n
e
m
i
a
(
C
R
M
O
w
i
t
h
C
D
A
;
M
a
j
e
e
d
s
y
n
d
r
o
m
e
)
A
R
6
0
9
6
2
8
1
8
p
1
1
.
3
L
P
I
N
2
L
i
p
i
n
2
H
y
p
e
r
o
s
t
o
s
i
s
/
h
y
p
e
r
p
h
o
s
p
h
a
t
e
m
i
a
s
y
n
d
r
o
m
e
A
R
6
1
0
2
3
3
2
q
2
4

q
3
1
G
A
L
N
T
3
U
D
P
-
N
-
a
c
e
t
y
l
-
a
l
p
h
a
-
D
-
g
a
l
a
c
t
o
s
a
m
i
n
e
:
p
o
l
y
p
e
p
t
i
d
e
N
-a
c
e
t
y
l
g
a
l
a
c
t
o
s
a
m
i
n
y
l
t
r
a
n
s
f
e
r
-
a
s
e
3
I
n
f
a
n
t
i
l
e
s
y
s
t
e
m
i
c
h
y
a
l
i
n
o
s
i
s
/
J
u
v
e
n
i
l
e
h
y
a
l
i
n
e

b
r
o
m
a
t
o
s
i
s
(
I
S
H
/
J
H
F
)
A
R
2
3
6
4
9
0
4
q
2
1
A
N
T
X
R
2
A
n
t
h
r
a
x
t
o
x
i
n
r
e
c
e
p
t
o
r
2
I
n
c
l
u
d
e
s
J
u
v
e
n
i
l
e
h
y
a
l
i
n
e

b
r
o
m
a
t
o
s
i
s
(
J
H
F
,
2
2
8
6
0
0
)
a
n
d
P
u
r
e
t
i
c
s
y
n
d
r
o
m
e
3
2
.
C
l
e
i
d
o
c
r
a
n
i
a
l
d
y
s
p
l
a
s
i
a
a
n
d
i
s
o
l
a
t
e
d
c
r
a
n
i
a
l
o
s
s
i

c
a
t
i
o
n
d
e
f
e
c
t
s
g
r
o
u
p
C
l
e
i
d
o
c
r
a
n
i
a
l
d
y
s
p
l
a
s
i
a
A
D
1
1
9
6
0
0
6
p
2
1
R
U
N
X
2
R
u
n
t
r
e
l
a
t
e
d
t
r
a
n
s
c
r
i
p
t
i
o
n
f
a
c
t
o
r
2
C
D
A
G
S
s
y
n
d
r
o
m
e
(
c
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
,
d
e
l
a
y
e
d
f
o
n
t
a
n
e
l
c
l
o
s
u
r
e
,
p
a
r
i
e
t
a
l
f
o
r
a
m
i
n
a
,
i
m
p
e
r
f
o
r
a
t
e
a
.
u
.
,
g
e
n
i
t
a
l
a
n
o
m
a
l
i
e
s
,
s
k
i
n
e
r
u
p
t
i
o
n
)
A
R
6
0
3
1
1
6
2
2
q
1
2

q
1
3
Y
u
n
i
s

V
a
r
o
n
d
y
s
p
l
a
s
i
a
A
R
2
1
6
3
4
0
P
a
r
i
e
t
a
l
f
o
r
a
m
i
n
a
(
i
s
o
l
a
t
e
d
)
A
D
1
6
8
5
0
0
1
1
q
1
1
.
2
A
L
X
4
A
r
i
s
t
a
l
e
s
s
-
l
i
k
e
4
S
e
e
a
l
s
o
F
r
o
n
t
o
n
a
s
a
l
d
y
s
p
l
a
s
i
a
t
y
p
e
1
(
g
r
o
u
p
3
4
)
P
a
r
i
e
t
a
l
f
o
r
a
m
i
n
a
(
i
s
o
l
a
t
e
d
)
A
D
1
6
8
5
0
0
5
q
3
4

3
5
M
S
X
2
M
u
s
c
l
e
s
e
g
m
e
n
t
h
o
m
e
o
b
o
x
2
S
e
e
a
l
s
o
p
y
c
n
o
d
y
s
o
s
t
o
s
i
s
,
w
r
i
n
k
l
y
s
k
i
n
s
y
n
d
r
o
m
e
,
a
n
d
s
e
v
e
r
a
l
o
t
h
e
r
s
3
3
.
C
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
s
y
n
d
r
o
m
e
s
P
f
e
i
f
f
e
r
s
y
n
d
r
o
m
e
(
F
G
F
R
1
-
r
e
l
a
t
e
d
)
A
D
1
0
1
6
0
0
8
p
1
2
F
G
F
R
1
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
r
e
c
e
p
t
o
r
1
M
o
s
t
h
a
v
e
F
G
F
R
1
P
2
5
2
R
m
u
t
a
t
i
o
n
(
p
h
e
n
o
t
y
p
e
g
e
n
e
r
a
l
l
y
m
i
l
d
e
r
t
h
a
n
F
G
F
R
2
-
r
e
l
a
t
e
d
P
f
e
i
f
f
e
r
)
P
f
e
i
f
f
e
r
s
y
n
d
r
o
m
e
(
F
G
F
R
2
-
r
e
l
a
t
e
d
)
A
D
1
0
1
6
0
0
1
0
q
2
6
.
1
2
F
G
F
R
2
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
r
e
c
e
p
t
o
r
2
I
n
c
l
u
d
e
s
J
a
c
k
s
o
n

W
e
i
s
s
s
y
n
d
r
o
m
e
(
M
I
M
1
2
3
1
5
0
)
a
n
d
A
n
t
l
e
y

B
i
x
l
e
r
v
a
r
i
a
n
t
s
c
a
u
s
e
d
b
y
F
G
F
R
2
m
u
t
a
t
i
o
n
s
(
s
e
e
b
e
l
o
w
)
A
p
e
r
t
s
y
n
d
r
o
m
e
A
D
1
0
1
2
0
0
1
0
q
2
6
.
1
2
F
G
F
R
2
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
r
e
c
e
p
t
o
r
2
C
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
w
i
t
h
c
u
t
i
s
g
y
r
a
t
a
(
B
e
a
r
e

S
t
e
v
e
n
s
o
n
)
A
D
1
2
3
7
9
0
1
0
q
2
6
.
1
2
F
G
F
R
2
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
r
e
c
e
p
t
o
r
2
C
r
o
u
z
o
n
s
y
n
d
r
o
m
e
A
D
1
2
3
5
0
0
1
0
q
2
6
.
1
2
F
G
F
R
2
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
r
e
c
e
p
t
o
r
2
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
960 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
C
r
o
u
z
o
n
-
l
i
k
e
c
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
w
i
t
h
a
c
a
n
t
h
o
s
i
s
n
i
g
r
i
c
a
n
s
(
C
r
o
u
z
o
n
o
d
e
r
m
o
s
k
e
l
e
t
a
l
s
y
n
d
r
o
m
e
)
A
D
6
1
2
2
4
7
4
p
1
6
.
3
F
G
F
R
3
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
r
e
c
e
p
t
o
r
3
D
e

n
e
d
b
y
s
p
e
c
i

c
F
G
F
R
3
A
3
9
1
E
m
u
t
a
t
i
o
n
C
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
,
M
u
e
n
k
e
t
y
p
e
A
D
6
0
2
8
4
9
4
p
1
6
.
3
F
G
F
R
3
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
r
e
c
e
p
t
o
r
3
D
e

n
e
d
b
y
s
p
e
c
i

c
F
G
F
R
3
P
2
5
0
R
m
u
t
a
t
i
o
n
A
n
t
l
e
y

B
i
x
l
e
r
s
y
n
d
r
o
m
e
A
R
2
0
1
7
5
0
7
q
1
1
.
2
3
P
O
R
C
y
t
o
c
h
r
o
m
e
P
4
5
0
o
x
i
d
o
r
e
d
u
c
t
a
s
e
S
i
m
i
l
a
r
c
a
s
e
s
w
i
t
h
F
G
F
R
2
m
u
t
a
t
i
o
n
s
c
l
a
s
s
i

e
d
a
s
P
f
e
i
f
f
e
r
s
y
n
d
r
o
m
e
(
M
I
M
2
0
7
4
1
0
)
C
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
B
o
s
t
o
n
t
y
p
e
A
D
6
0
4
7
5
7
5
q
3
5
.
2
M
S
X
2
M
S
X
2
H
e
t
e
r
o
z
y
g
o
u
s
P
1
4
8
H
m
u
t
a
t
i
o
n
i
n
a
s
i
n
g
l
e
f
a
m
i
l
y
S
a
e
t
h
r
e

C
h
o
t
z
e
n
s
y
n
d
r
o
m
e
A
D
1
0
1
4
0
0
7
p
2
1
.
1
T
W
I
S
T
1
T
W
I
S
T
S
h
p
r
i
n
t
z
e
n

G
o
l
d
b
e
r
g
s
y
n
d
r
o
m
e
A
D
1
8
2
2
1
2
S
o
m
e
c
a
s
e
s
r
e
p
o
r
t
e
d
w
i
t
h
F
B
N
1
m
u
t
a
t
i
o
n
s
B
a
l
l
e
r

G
e
r
o
l
d
s
y
n
d
r
o
m
e
A
R
2
1
8
6
0
0
8
q
2
4
.
3
R
E
C
Q
L
4
R
E
C
Q
p
r
o
t
e
i
n
-
l
i
k
e
4
R
E
C
Q
L
4
m
i
g
h
t
n
o
t
a
c
c
o
u
n
t
f
o
r
a
l
l
c
a
s
e
s
o
f
B
a
l
l
e
r

G
e
r
o
l
d
C
a
r
p
e
n
t
e
r
s
y
n
d
r
o
m
e
A
R
2
0
1
0
0
0
R
A
B
2
3
S
e
e
a
l
s
o
C
o
l
e

C
a
r
p
e
n
t
e
r
s
y
n
d
r
o
m
e
i
n
g
r
o
u
p
2
4
,
C
D
A
G
S
s
y
n
d
r
o
m
e
i
n
g
r
o
u
p
2
9
,
a
n
d
C
r
a
n
i
o
f
r
o
n
t
o
n
a
s
a
l
s
y
n
d
r
o
m
e
i
n
g
r
o
u
p
3
4
3
4
.
D
y
s
o
s
t
o
s
e
s
w
i
t
h
p
r
e
d
o
m
i
n
a
n
t
c
r
a
n
i
o
f
a
c
i
a
l
i
n
v
o
l
v
e
m
e
n
t
M
a
n
d
i
b
u
l
o
-
f
a
c
i
a
l
d
y
s
o
s
t
o
s
i
s
(
T
r
e
a
c
h
e
r
C
o
l
l
i
n
s
,
F
r
a
n
c
e
s
c
h
e
t
t
i
-
K
l
e
i
n
)
A
D
1
5
4
5
0
0
5
q
3
2
T
C
O
F
1
T
r
e
a
c
h
e
r
C
o
l
l
i
n
s
-
F
r
a
n
c
e
s
c
h
e
t
t
i
s
y
n
d
r
o
m
e
1
M
a
n
d
i
b
u
l
o
-
f
a
c
i
a
l
d
y
s
o
s
t
o
s
i
s
(
T
r
e
a
c
h
e
r
-
C
o
l
l
i
n
s
,
F
r
a
n
c
e
s
c
h
e
t
t
i
-
K
l
e
i
n
)
A
D
1
5
4
5
0
0
1
3
q
1
2
.
2
P
O
L
R
1
D
P
o
l
y
m
e
r
a
s
e
(
R
N
A
)
I
p
o
l
y
p
e
p
t
i
d
e
D
M
a
n
d
i
b
u
l
o
-
f
a
c
i
a
l
d
y
s
o
s
t
o
s
i
s
(
T
r
e
a
c
h
e
r
-
C
o
l
l
i
n
s
,
F
r
a
n
c
e
s
c
h
e
t
t
i
-
K
l
e
i
n
)
A
R
1
5
4
5
0
0
6
p
2
1
.
1
P
O
L
R
1
C
P
o
l
y
m
e
r
a
s
e
(
R
N
A
)
I
p
o
l
y
p
e
p
t
i
d
e
C
O
r
a
l
-
f
a
c
i
a
l
-
d
i
g
i
t
a
l
s
y
n
d
r
o
m
e
t
y
p
e
I
(
O
F
D
1
)
X
L
R
3
1
1
2
0
0
X
p
2
2
.
3
C
X
O
R
F
5
c
h
r
.
X
o
p
e
n
r
e
a
d
i
n
g
f
r
a
m
e
5
W
e
y
e
r
a
c
r
o
f
a
c
i
a
l
(
a
c
r
o
d
e
n
t
a
l
)
d
y
s
o
s
t
o
s
i
s
A
D
1
9
3
5
3
0
4
p
1
6
E
V
C
1
E
l
l
i
s

v
a
n
C
r
e
v
e
l
d
1
p
r
o
t
e
i
n
E
n
d
o
c
r
i
n
e
-
c
e
r
e
b
r
o
-
o
s
t
e
o
d
y
s
p
l
a
s
i
a
(
E
C
O
)
A
R
6
1
2
6
5
1
6
p
1
2
.
3
I
C
K
I
n
t
e
s
t
i
n
a
l
c
e
l
l
k
i
n
a
s
e
C
r
a
n
i
o
f
r
o
n
t
o
n
a
s
a
l
s
y
n
d
r
o
m
e
X
L
D
3
0
4
1
1
0
X
q
1
3
.
1
E
F
N
B
1
E
p
h
r
i
n
B
1
F
r
o
n
t
o
n
a
s
a
l
d
y
s
p
l
a
s
i
a
,
t
y
p
e
1
A
R
1
3
6
7
6
0
1
p
1
3
.
3
A
L
X
3
A
r
i
s
t
a
l
e
s
s
-
l
i
k
e
-
3
F
r
o
n
t
o
n
a
s
a
l
d
y
s
p
l
a
s
i
a
,
t
y
p
e
2
A
R
6
1
3
4
5
1
1
1
p
1
1
.
2
A
L
X
4
A
r
i
s
t
a
l
e
s
s
-
l
i
k
e
-
4
F
r
o
n
t
o
n
a
s
a
l
d
y
s
p
l
a
s
i
a
,
t
y
p
e
3
A
R
6
1
3
4
5
6
1
2
q
2
1
.
3
A
L
X
1
A
r
i
s
t
a
l
e
s
s
-
l
i
k
e
1
H
e
m
i
f
a
c
i
a
l
m
i
c
r
o
s
o
m
i
a
S
P
/
A
D
1
6
4
2
1
0
I
n
c
l
u
d
e
s
G
o
l
d
e
n
h
a
r
s
y
n
d
r
o
m
e
a
n
d
O
c
u
l
o
-
A
u
r
i
c
u
l
o
-
V
e
r
t
e
b
r
a
l
s
p
e
c
t
r
u
m
;
p
r
o
b
a
b
l
y
g
e
n
e
t
i
c
a
l
l
y
h
e
t
e
r
o
g
e
n
e
o
u
s
M
i
l
l
e
r
s
y
n
d
r
o
m
e
(
p
o
s
t
a
x
i
a
l
a
c
r
o
f
a
c
i
a
l
d
y
s
o
s
t
o
s
i
s
)
A
R
2
6
3
7
5
0
1
6
q
2
2
D
H
O
D
H
D
i
h
y
d
r
o
o
r
o
t
a
t
e
d
e
h
y
d
r
o
g
e
n
a
s
e
A
c
r
o
f
a
c
i
a
l
d
y
s
o
s
t
o
s
i
s
,
N
a
g
e
r
t
y
p
e
A
D
/
A
R
1
5
4
4
0
0
A
c
r
o
f
a
c
i
a
l
d
y
s
o
s
t
o
s
i
s
,
R
o
d
r
i
g
u
e
z
t
y
p
e
A
R
2
0
1
1
7
0
S
e
e
a
l
s
o
O
r
a
l
-
f
a
c
i
a
l
-
d
i
g
i
t
a
l
s
y
n
d
r
o
m
e
t
y
p
e
I
V
i
n
t
h
e
S
h
o
r
t
R
i
b
D
y
s
p
l
a
s
i
a
s
g
r
o
u
p
3
5
.
D
y
s
o
s
t
o
s
e
s
w
i
t
h
p
r
e
d
o
m
i
n
a
n
t
v
e
r
t
e
b
r
a
l
w
i
t
h
a
n
d
w
i
t
h
o
u
t
c
o
s
t
a
l
i
n
v
o
l
v
e
m
e
n
t
C
u
r
r
a
r
i
n
o
t
r
i
a
d
A
D
1
7
6
4
5
0
7
q
3
6
H
L
X
B
9
H
o
m
e
o
b
o
x
g
e
n
e
H
B
9
S
p
o
n
d
y
l
o
c
o
s
t
a
l
d
y
s
o
s
t
o
s
i
s
t
y
p
e
1
(
S
C
D
1
)
A
R
2
7
7
3
0
0
1
9
q
1
3
D
L
L
3
D
e
l
t
a
-
l
i
k
e
3
(
C
o
n
t
i
n
u
e
d
)
WARMAN ET AL. 961
S
p
o
n
d
y
l
o
c
o
s
t
a
l
d
y
s
o
s
t
o
s
i
s
t
y
p
e
2
(
S
C
D
2
)
A
R
6
0
8
6
8
1
1
5
q
2
6
M
E
S
P
2
M
e
s
o
d
e
r
m
p
o
s
t
e
r
i
o
r
(
e
x
p
r
e
s
s
e
d
i
n
)
2
S
p
o
n
d
y
l
o
c
o
s
t
a
l
d
y
s
o
s
t
o
s
i
s
t
y
p
e
3
(
S
C
D
3
)
A
R
?
6
0
9
8
1
3
7
p
2
2
L
F
N
G
L
u
n
a
t
i
c
f
r
i
n
g
e
S
p
o
n
d
y
l
o
c
o
s
t
a
l
d
y
s
o
s
t
o
s
i
s
t
y
p
e
4
(
S
C
D
4
)
A
R
1
7
p
1
3
.
1
H
E
S
7
H
a
i
r
y
-
a
n
d
-
e
n
h
a
n
c
e
r
-
o
f
-
s
p
l
i
t
-
7
S
p
o
n
d
y
l
o
t
h
o
r
a
c
i
c
d
y
s
o
s
t
o
s
i
s
A
R
1
5
q
2
6
M
E
S
P
2
M
e
s
o
d
e
r
m
p
o
s
t
e
r
i
o
r
(
e
x
p
r
e
s
s
e
d
i
n
)
2
K
l
i
p
p
e
l

F
e
i
l
a
n
o
m
a
l
y
w
i
t
h
l
a
r
y
n
g
e
a
l
m
a
l
f
o
r
m
a
t
i
o
n
A
D
1
4
8
9
0
0
8
q
2
2
.
1
G
D
F
6
G
r
o
w
t
h
a
n
d
d
i
f
f
e
r
e
n
t
i
a
t
i
o
n
f
a
c
t
o
r
6
R
o
l
e
o
f
G
D
F
6
m
u
t
a
t
i
o
n
s
i
n
d
o
m
i
n
a
n
t
s
p
o
n
d
y
l
o
t
h
o
r
a
c
i
c
d
y
s
o
s
t
o
s
i
s
u
n
c
l
e
a
r
S
p
o
n
d
y
l
o
c
o
s
t
a
l
/
t
h
o
r
a
c
i
c
d
y
s
o
s
t
o
s
i
s
,
o
t
h
e
r
f
o
r
m
s
A
D
/
A
R
S
e
e
a
l
s
o
G
D
F
6
,
a
b
o
v
e
C
e
r
e
b
r
o
-
c
o
s
t
o
-
m
a
n
d
i
b
u
l
a
r
s
y
n
d
r
o
m
e
(
r
i
b
g
a
p
s
y
n
d
r
o
m
e
)
A
D
/
A
R
1
1
7
6
5
0
C
e
r
e
b
r
o
-
c
o
s
t
o
-
m
a
n
d
i
b
u
l
a
r
-
l
i
k
e
s
y
n
d
r
o
m
e
w
i
t
h
v
e
r
t
e
b
r
a
l
d
e
f
e
c
t
s
A
R
6
1
1
2
0
9
1
7
q
2
5
C
O
G
1
C
o
m
p
o
n
e
n
t
o
f
o
l
i
g
o
m
e
r
i
c
G
o
l
g
i
c
o
m
p
l
e
x
1
A
l
s
o
c
l
a
s
s
i

e
d
a
s
C
D
G
t
y
p
e
I
I
g
D
i
a
p
h
a
n
o
s
p
o
n
d
y
l
o
d
y
s
o
s
t
o
s
i
s
A
R
6
0
8
0
2
2
7
p
1
4
B
M
P
E
R
B
o
n
e
m
o
r
p
h
o
g
e
n
e
t
i
c
p
r
o
t
e
i
n
-
b
i
n
d
i
n
g
e
n
d
o
t
h
e
l
i
a
l
c
e
l
l
p
r
e
c
u
r
s
o
r
-
d
e
r
i
v
e
d
r
e
g
u
l
a
t
o
r
P
o
s
s
i
b
l
y
o
v
e
r
l
a
p
s
w
i
t
h
i
s
c
h
i
o
s
p
i
n
a
l
d
y
s
o
s
t
o
s
i
s
S
e
e
a
l
s
o
S
p
o
n
d
y
l
o
c
a
r
p
o
t
a
r
s
a
l
d
y
s
p
l
a
s
i
a
i
n
g
r
o
u
p
7
a
n
d
s
p
o
n
d
y
l
o
-
m
e
t
a
p
h
y
s
e
a
l
-
m
e
g
a
e
p
i
p
h
y
s
e
a
l
d
y
s
p
l
a
s
i
a
i
n
g
r
o
u
p
1
3
3
6
.
P
a
t
e
l
l
a
r
d
y
s
o
s
t
o
s
e
s
I
s
c
h
i
o
p
a
t
e
l
l
a
r
d
y
s
p
l
a
s
i
a
(
s
m
a
l
l
p
a
t
e
l
l
a
s
y
n
d
r
o
m
e
)
A
D
1
4
7
8
9
1
1
7
q
2
1

q
2
2
T
B
X
4
T
-
b
o
x
g
e
n
e
4
S
m
a
l
l
p
a
t
e
l
l
a

l
i
k
e
s
y
n
d
r
o
m
e
w
i
t
h
c
l
u
b
f
o
o
t
A
D
5
q
3
1
P
I
T
X
1
P
a
i
r
e
d
-
l
i
k
e
h
o
m
e
o
d
o
m
a
i
n
t
r
a
n
s
c
r
i
p
t
i
o
n
f
a
c
t
o
r
1
(
p
i
t
u
i
t
a
r
y
h
o
m
e
o
b
o
x
1
)
I
n
c
l
u
d
e
s
i
s
o
l
a
t
e
d
d
o
m
i
n
a
n
t
f
a
m
i
l
i
a
l
c
l
u
b
f
o
o
t
N
a
i
l
-
p
a
t
e
l
l
a
s
y
n
d
r
o
m
e
A
D
1
6
1
2
0
0
9
q
3
4
.
1
L
M
X
1
B
L
I
M
h
o
m
e
o
b
o
x
t
r
a
n
s
c
r
i
p
t
i
o
n
f
a
c
t
o
r
1
G
e
n
i
t
o
p
a
t
e
l
l
a
r
s
y
n
d
r
o
m
e
A
R
?
6
0
6
1
7
0
E
a
r
-
p
a
t
e
l
l
a
-
s
h
o
r
t
s
t
a
t
u
r
e
s
y
n
d
r
o
m
e
(
M
e
i
e
r
-
G
o
r
l
i
n
)
A
R
2
2
4
6
9
0
S
e
e
a
l
s
o
M
E
D
g
r
o
u
p
f
o
r
c
o
n
d
i
t
i
o
n
s
w
i
t
h
p
a
t
e
l
l
a
r
c
h
a
n
g
e
s
a
s
w
e
l
l
a
s
i
s
c
h
i
o
-
p
u
b
i
c
-
p
a
t
e
l
l
a
r
d
y
s
p
l
a
s
i
a
a
s
m
i
l
d
e
x
p
r
e
s
s
i
o
n
o
f
c
a
m
p
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
3
7
.
B
r
a
c
h
y
d
a
c
t
y
l
i
e
s
(
w
i
t
h
o
r
w
i
t
h
o
u
t
e
x
t
r
a
s
k
e
l
e
t
a
l
m
a
n
i
f
e
s
t
a
t
i
o
n
s
)
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
A
1
A
D
1
1
2
5
0
0
2
q
3
5

3
6
I
H
H
I
n
d
i
a
n
H
e
d
g
e
h
o
g
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
A
1
A
D
5
p
3
1
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
A
2
A
D
1
1
2
6
0
0
4
q
2
3
B
M
P
R
1
B
B
o
n
e
m
o
r
p
h
o
g
e
n
e
t
i
c
p
r
o
t
e
i
n
r
e
c
e
p
t
o
r
,
1
B
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
A
2
A
D
1
1
2
6
0
0
B
M
P
2
B
o
n
e
m
o
r
p
h
o
g
e
n
e
t
i
c
p
r
o
t
e
i
n
t
y
p
e
2
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
A
2
A
D
1
1
2
6
0
0
2
0
q
1
1
.
2
G
D
F
5
G
r
o
w
t
h
a
n
d
d
i
f
f
e
r
e
n
t
i
a
t
i
o
n
f
a
c
t
o
r
5
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
A
3
A
D
1
1
2
7
0
0
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
962 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
B
A
D
1
1
3
0
0
0
9
q
2
2
R
O
R
2
R
e
c
e
p
t
o
r
t
y
r
o
s
i
n
e
k
i
n
a
s
e
-
l
i
k
e
o
r
p
h
a
n
r
e
c
e
p
t
o
r
2
S
e
e
a
l
s
o
R
o
b
i
n
o
w
s
y
n
d
r
o
m
e
/
C
O
V
E
S
D
E
M
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
B
2
A
D
6
1
1
3
7
7
1
7
q
N
O
G
N
o
g
g
i
n
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
C
A
D
,
A
R
1
1
3
1
0
0
2
0
q
1
1
.
2
G
D
F
5
G
r
o
w
t
h
a
n
d
d
i
f
f
e
r
e
n
t
i
a
t
i
o
n
f
a
c
t
o
r
5
S
e
e
a
l
s
o
A
S
P
E
D
(
g
r
o
u
p
1
4
)
a
n
d
o
t
h
e
r
G
D
F
5
d
i
s
o
r
d
e
r
s
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
D
A
D
1
1
3
2
0
0
2
q
3
1
H
O
X
D
1
3
H
o
m
e
o
b
o
x
D
1
3
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
E
A
D
1
1
3
3
0
0
1
2
p
1
1
.
2
2
P
T
H
L
H
P
a
r
a
t
h
y
r
o
i
d
h
o
r
m
o
n
e
-
l
i
k
e
h
o
r
m
o
n
e
(
p
a
r
a
t
h
y
r
o
i
d
h
o
r
m
o
n
e
r
e
l
a
t
e
d
p
e
p
t
i
d
e
,
P
T
H
R
P
)
B
r
a
c
h
y
d
a
c
t
y
l
y
t
y
p
e
E
A
D
1
1
3
3
0
0
2
q
3
1
H
O
X
D
1
3
H
o
m
e
o
b
o
x
D
1
3
B
r
a
c
h
y
d
a
c
t
y
l
y

m
e
n
t
a
l
r
e
t
a
r
d
a
t
i
o
n
s
y
n
d
r
o
m
e
A
D
6
0
0
4
3
0
2
q
3
7
.
3
H
D
A
C
4
H
i
s
t
o
n
e
d
e
a
c
e
t
y
l
a
s
e
4
S
o
m
e
p
a
t
i
e
n
t
s
h
a
v
e
m
i
c
r
o
d
e
l
e
t
i
o
n
s
i
n
v
o
l
v
i
n
g
c
o
n
t
i
g
u
o
u
s
g
e
n
e
s
(
c
h
r
.
2
q
3
7
d
e
l
e
t
i
o
n
s
y
n
d
r
o
m
e
)
H
y
p
e
r
p
h
o
s
p
h
a
t
a
s
i
a
w
i
t
h
m
e
n
t
a
l
r
e
t
a
r
d
a
t
i
o
n
,
b
r
a
c
h
y
t
e
l
e
p
h
a
l
a
n
g
y
,
a
n
d
d
i
s
t
i
n
c
t
f
a
c
e
A
R
1
p
3
6
.
1
1
P
I
G
V
P
h
o
s
p
h
a
t
i
d
y
l
i
n
o
s
i
t
o
l
-
g
l
y
c
a
n
b
i
o
s
y
n
t
h
e
s
i
s
c
l
a
s
s
V
p
r
o
t
e
i
n
(
G
P
I
m
a
n
n
o
s
y
l
t
r
a
n
s
f
e
r
a
s
e
2
)
B
r
a
c
h
y
d
a
c
t
y
l
y
-
h
y
p
e
r
t
e
n
s
i
o
n
s
y
n
d
r
o
m
e
(
B
i
l
g
i
n
t
u
r
i
a
n
)
A
D
1
1
2
4
1
0
1
2
p
1
2
.
2

1
1
.
2
P
o
s
s
i
b
l
y
P
T
H
L
H
B
r
a
c
h
y
d
a
c
t
y
l
y
w
i
t
h
a
n
o
n
y
c
h
i
a
(
C
o
o
k
s
s
y
n
d
r
o
m
e
)
A
D
1
0
6
9
9
5
1
7
q
2
4
.
3
S
O
X
9
R
e
g
u
l
a
t
o
r
y
m
u
t
a
t
i
o
n
s
M
i
c
r
o
c
e
p
h
a
l
y
-
o
c
u
l
o
-
d
i
g
i
t
o
-
e
s
o
p
h
a
g
e
a
l
-
d
u
o
d
e
n
a
l
s
y
n
d
r
o
m
e
(
F
e
i
n
g
o
l
d
s
y
n
d
r
o
m
e
)
A
D
1
6
4
2
8
0
2
p
2
4
.
1
M
Y
C
N
n
M
Y
C
o
n
c
o
g
e
n
e
H
a
n
d
-
f
o
o
t
-
g
e
n
i
t
a
l
s
y
n
d
r
o
m
e
A
D
1
4
0
0
0
0
7
p
1
4
.
2
H
O
X
A
1
3
H
o
m
e
o
b
o
x
A
1
3
B
r
a
c
h
y
d
a
c
t
y
l
y
w
i
t
h
e
l
b
o
w
d
y
s
p
l
a
s
i
a
(
L
i
e
b
e
n
b
e
r
g
s
y
n
d
r
o
m
e
)
A
D
1
8
6
5
5
0
K
e
u
t
e
l
s
y
n
d
r
o
m
e
A
R
2
4
5
1
5
0
1
2
p
1
3
.
1

1
2
.
3
M
G
P
M
a
t
r
i
x
G
l
a
p
r
o
t
e
i
n
A
l
b
r
i
g
h
t
h
e
r
e
d
i
t
a
r
y
o
s
t
e
o
d
y
s
t
r
o
p
h
y
(
A
H
O
)
A
D
1
0
3
5
8
0
2
0
q
1
3
G
N
A
S
1
G
u
a
n
i
n
e
n
u
c
l
e
o
t
i
d
e
b
i
n
d
i
n
g
p
r
o
t
e
i
n
o
f
a
d
e
n
y
l
a
t
e
c
y
c
l
a
s
e

s
u
b
u
n
i
t
S
e
e
a
l
s
o
p
o
l
y
o
s
t
o
t
i
c

b
r
o
u
s
d
y
s
p
l
a
s
i
a
a
n
d
p
r
o
g
r
e
s
s
i
v
e
o
s
s
e
o
u
s
h
e
t
e
r
o
p
l
a
s
i
a
,
g
r
o
u
p
2
8
R
u
b
i
n
s
t
e
i
n

T
a
y
b
i
s
y
n
d
r
o
m
e
A
D
1
8
0
8
4
9
1
6
p
1
3
.
3
C
R
E
B
B
P
C
R
E
B
-
b
i
n
d
i
n
g
p
r
o
t
e
i
n
R
u
b
i
n
s
t
e
i
n

T
a
y
b
i
s
y
n
d
r
o
m
e
A
D
1
8
0
8
4
9
2
2
q
1
3
E
P
3
0
0
E
1
A
-
b
i
n
d
i
n
g
p
r
o
t
e
i
n
,
3
0
0
-
k
D
a
C
a
t
e
l

M
a
n
z
k
e
s
y
n
d
r
o
m
e
X
L
R
?
3
0
2
3
8
0
B
r
a
c
h
y
d
a
c
t
y
l
y
,
T
e
m
t
a
m
y
t
y
p
e
A
R
6
0
5
2
8
2
C
h
r
i
s
t
i
a
n
t
y
p
e
b
r
a
c
h
y
d
a
c
t
y
l
y
A
D
1
1
2
4
5
0
C
o
f

S
i
r
i
s
s
y
n
d
r
o
m
e
A
R
1
3
5
9
0
0
M
o
n
o
n
e
n
t
y
p
e
b
r
a
c
h
y
d
a
c
t
y
l
y
X
L
D
?
3
0
1
9
4
0
P
o
l
a
n
d
a
n
o
m
a
l
y
S
P
1
7
3
8
0
0
S
e
e
a
l
s
o
g
r
o
u
p
2
0
f
o
r
o
t
h
e
r
c
o
n
d
i
t
i
o
n
s
w
i
t
h
b
r
a
c
h
y
d
a
c
t
y
l
y
a
s
w
e
l
l
a
s
b
r
a
c
h
y
t
e
l
e
p
h
a
l
a
n
g
i
c
C
D
P
3
8
.
L
i
m
b
h
y
p
o
p
l
a
s
i
a

r
e
d
u
c
t
i
o
n
d
e
f
e
c
t
s
g
r
o
u
p
U
l
n
a
r
-
m
a
m
m
a
r
y
s
y
n
d
r
o
m
e
A
D
1
8
1
4
5
0
T
B
X
3
T
-
b
o
x
g
e
n
e
3
d
e
L
a
n
g
e
s
y
n
d
r
o
m
e
A
D
1
2
2
4
7
0
5
p
1
3
.
1
N
I
P
B
L
N
i
p
p
e
d
-
B
-
l
i
k
e
F
a
n
c
o
n
i
a
n
e
m
i
a
(
s
e
e
n
o
t
e
b
e
l
o
w
)
A
R
2
2
7
6
5
0
S
e
v
e
r
a
l
S
e
v
e
r
a
l
S
e
v
e
r
a
l
c
o
m
p
l
e
m
e
n
t
a
t
i
o
n
g
r
o
u
p
s
a
n
d
g
e
n
e
s
(
C
o
n
t
i
n
u
e
d
)
WARMAN ET AL. 963
T
h
r
o
m
b
o
c
y
t
o
p
e
n
i
a
-
a
b
s
e
n
t
r
a
d
i
u
s
(
T
A
R
)
A
R
?
/
A
D
?
2
7
4
0
0
0
1
q
2
1
.
1
S
e
v
e
r
a
l
M
i
c
r
o
d
e
l
e
t
i
o
n
o
n
1
q
2
1
.
1
T
h
r
o
m
b
o
c
y
t
h
e
m
i
a
w
i
t
h
d
i
s
t
a
l
l
i
m
b
d
e
f
e
c
t
s
A
D
3
q
2
7
T
H
P
O
T
h
r
o
m
b
o
p
o
i
e
t
i
n
D
i
s
t
a
l
l
i
m
b
d
e
f
e
c
t
s
p
o
s
t
u
l
a
t
e
d
a
s
c
o
n
s
e
q
u
e
n
c
e
o
f
v
a
s
c
u
l
a
r
o
c
c
l
u
s
i
o
n
s
H
o
l
t

O
r
a
m
s
y
n
d
r
o
m
e
A
D
1
4
2
9
0
0
1
2
q
2
4
.
1
T
B
X
5
T
-
b
o
x
g
e
n
e
5
O
k
i
h
i
r
o
s
y
n
d
r
o
m
e
(
D
u
a
n
e

r
a
d
i
a
l
r
a
y
a
n
o
m
a
l
y
)
A
D
6
0
7
3
2
3
2
0
q
1
3
S
A
L
L
4
S
A
L
-
l
i
k
e
4
C
o
u
s
i
n
s
y
n
d
r
o
m
e
A
R
2
6
0
6
6
0
1
p
1
3
T
B
X
1
5
T
-
b
o
x
g
e
n
e
1
5
R
o
b
e
r
t
s
s
y
n
d
r
o
m
e
A
R
2
6
8
3
0
0
8
p
2
1
.
1
E
S
C
O
2
H
o
m
o
l
o
g
o
f
e
s
t
a
b
l
i
s
h
m
e
n
t
o
f
c
o
h
e
s
i
o
n

2
S
p
l
i
t
-
h
a
n
d
-
f
o
o
t
m
a
l
f
o
r
m
a
t
i
o
n
w
i
t
h
l
o
n
g
b
o
n
e
d
e

c
i
e
n
c
y
(
S
H
F
L
D
1
)
A
D
1
1
9
1
0
0
1
q
4
2
.
2

q
4
3
S
p
l
i
t
-
h
a
n
d
-
f
o
o
t
m
a
l
f
o
r
m
a
t
i
o
n
w
i
t
h
l
o
n
g
b
o
n
e
d
e

c
i
e
n
c
y
(
S
H
F
L
D
2
)
A
D
6
1
0
6
8
5
6
q
1
4
.
1
S
p
l
i
t
-
h
a
n
d
-
f
o
o
t
m
a
l
f
o
r
m
a
t
i
o
n
w
i
t
h
l
o
n
g
b
o
n
e
d
e

c
i
e
n
c
y
(
S
H
F
L
D
3
)
A
D
6
1
2
5
7
6
1
7
p
1
3
.
1
T
i
b
i
a
l
h
e
m
i
m
e
l
i
a
A
R
2
7
5
2
2
0
T
i
b
i
a
l
h
e
m
i
m
e
l
i
a
-
p
o
l
y
s
y
n
d
a
c
t
y
l
y
-
t
r
i
p
h
a
l
a
n
g
e
a
l
t
h
u
m
b
A
D
1
8
8
7
7
0
A
c
h
e
i
r
o
p
o
d
i
a
A
R
2
0
0
5
0
0
7
q
3
6
L
M
B
R
1
P
u
t
a
t
i
v
e
r
e
c
e
p
t
o
r
p
r
o
t
e
i
n
P
a
r
t
i
a
l
L
M
B
R
1
d
e
l
e
t
i
o
n
a
f
f
e
c
t
i
n
g
e
x
p
r
e
s
s
i
o
n
o
f
S
o
n
i
c
H
e
d
g
e
h
o
g
(
S
H
H
)
g
e
n
e
T
e
t
r
a
-
a
m
e
l
i
a
X
L
3
0
1
0
9
0
T
e
t
r
a
-
a
m
e
l
i
a
A
R
2
7
3
3
9
5
1
7
q
2
1
W
N
T
3
W
i
n
g
l
e
s
s
-
t
y
p
e
M
M
T
V
i
n
t
e
g
r
a
t
i
o
n
s
i
t
e
f
a
m
i
l
y
,
m
e
m
b
e
r
3
A
n
k
y
l
o
b
l
e
p
h
a
r
o
n
-
e
c
t
o
d
e
r
m
a
l
d
y
s
p
l
a
s
i
a
-
c
l
e
f
t
l
i
p
/
p
a
l
a
t
e
(
A
E
C
)
A
D
1
0
6
2
6
0
3
q
2
7
P
6
3
(
T
P
6
3
)
T
u
m
o
r
p
r
o
t
e
i
n
p
6
3
E
c
t
r
o
d
a
c
t
y
l
y
-
e
c
t
o
d
e
r
m
a
l
d
y
s
p
l
a
s
i
a
c
l
e
f
t
-
p
a
l
a
t
e
s
y
n
d
r
o
m
e
T
y
p
e
3
(
E
E
C
3
)
A
D
6
0
4
2
9
2
3
q
2
7
P
6
3
(
T
P
6
3
)
T
u
m
o
r
p
r
o
t
e
i
n
p
6
3
E
c
t
r
o
d
a
c
t
y
l
y
-
e
c
t
o
d
e
r
m
a
l
d
y
s
p
l
a
s
i
a
c
l
e
f
t
-
p
a
l
a
t
e
s
y
n
d
r
o
m
e
t
y
p
e
1
(
E
E
C
1
)
A
D
1
2
9
9
0
0
7
q
1
1
.
2

1
2
.
3
E
c
t
r
o
d
a
c
t
y
l
y
-
e
c
t
o
d
e
r
m
a
l
d
y
s
p
l
a
s
i
a
-
m
a
c
u
l
a
r
d
y
s
t
r
o
p
h
y
s
y
n
d
r
o
m
e
(
E
E
M
)
A
R
2
2
5
2
8
0
1
6
q
2
2
C
D
H
3
C
a
d
h
e
r
i
n
3
L
i
m
b
-
m
a
m
m
a
r
y
s
y
n
d
r
o
m
e
(
i
n
c
l
u
d
i
n
g
A
D
U
L
T
s
y
n
d
r
o
m
e
)
A
D
6
0
3
2
7
3
3
q
2
7
P
6
3
(
T
P
6
3
)
T
u
m
o
r
p
r
o
t
e
i
n
p
6
3
S
p
l
i
t
h
a
n
d
-
f
o
o
t
m
a
l
f
o
r
m
a
t
i
o
n
,
i
s
o
l
a
t
e
d
f
o
r
m
,
t
y
p
e
4
(
S
H
F
M
4
)
A
D
6
0
5
2
8
9
3
q
2
7
P
6
3
(
T
P
6
3
)
T
u
m
o
r
p
r
o
t
e
i
n
p
6
3
S
p
l
i
t
h
a
n
d
-
f
o
o
t
m
a
l
f
o
r
m
a
t
i
o
n
,
i
s
o
l
a
t
e
d
f
o
r
m
,
t
y
p
e
1
(
S
H
F
M
1
)
A
D
1
8
3
6
0
0
7
q
2
1
.
3

2
2
.
1
S
p
l
i
t
h
a
n
d
-
f
o
o
t
M
a
l
f
o
r
m
a
t
i
o
n
,
i
s
o
l
a
t
e
d
f
o
r
m
,
t
y
p
e
2
(
S
H
F
M
2
)
X
L
3
1
3
3
5
0
X
q
2
6
S
p
l
i
t
h
a
n
d
-
f
o
o
t
m
a
l
f
o
r
m
a
t
i
o
n
,
i
s
o
l
a
t
e
d
f
o
r
m
,
t
y
p
e
3
(
S
H
F
M
3
)
A
D
6
0
0
0
9
5
1
0
q
2
4
F
B
X
W
4
D
a
c
t
y
l
i
n
S
p
l
i
t
h
a
n
d
-
f
o
o
t
m
a
l
f
o
r
m
a
t
i
o
n
,
i
s
o
l
a
t
e
d
f
o
r
m
,
t
y
p
e
5
(
S
H
F
M
5
)
A
D
6
0
6
7
0
8
2
q
3
1
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
964 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
A
l
-
A
w
a
d
i
R
a
a
s

R
o
t
h
s
c
h
i
l
d
l
i
m
b
-
p
e
l
v
i
s
h
y
p
o
p
l
a
s
i
a

a
p
l
a
s
i
a
A
R
2
7
6
8
2
0
3
p
2
5
W
N
T
7
A
W
i
n
g
l
e
s
s
-
t
y
p
e
M
M
T
V
i
n
t
e
g
r
a
t
i
o
n
s
i
t
e
f
a
m
i
l
y
,
m
e
m
b
e
r
7
A
F
u
h
r
m
a
n
n
s
y
n
d
r
o
m
e
A
R
2
2
8
9
3
0
3
p
2
5
W
N
T
7
A
W
i
n
g
l
e
s
s
-
t
y
p
e
M
M
T
V
i
n
t
e
g
r
a
t
i
o
n
s
i
t
e
f
a
m
i
l
y
,
m
e
m
b
e
r
7
A
R
A
P
A
D
I
L
I
N
O
s
y
n
d
r
o
m
e
A
R
2
6
6
2
8
0
8
q
2
4
.
3
R
E
C
Q
L
4
R
E
C
Q
p
r
o
t
e
i
n
-
l
i
k
e
4
A
d
a
m
s

O
l
i
v
e
r
s
y
n
d
r
o
m
e
A
D
/
A
R
1
0
0
3
0
0
F
e
m
o
r
a
l
h
y
p
o
p
l
a
s
i
a
-
u
n
u
s
u
a
l
f
a
c
e
s
y
n
d
r
o
m
e
(
F
H
U
F
S
)
S
P
/
A
D
?
1
3
4
7
8
0
S
o
m
e
p
h
e
n
o
t
y
p
i
c
o
v
e
r
l
a
p
w
i
t
h
F
F
U
s
y
n
d
r
o
m
e
(
b
e
l
o
w
)
F
e
m
u
r
-

b
u
l
a
-
u
l
n
a
s
y
n
d
r
o
m
e
(
F
F
U
)
S
P
?
2
2
8
2
0
0
H
a
n
h
a
r
t
s
y
n
d
r
o
m
e
(
h
y
p
o
g
l
o
s
s
i
a

h
y
p
o
d
a
c
t
y
l
i
a
)
A
D
1
0
3
3
0
0
S
c
a
p
u
l
o
-
i
l
i
a
c
d
y
s
p
l
a
s
i
a
(
K
o
s
e
n
o
w
)
A
D
1
6
9
5
5
0
N
o
t
e
:
t
h
e
p
a
r
t
i
c
u
l
a
r
l
y
c
o
m
p
l
e
x
g
e
n
e
t
i
c
b
a
s
i
s
o
f
F
a
n
c
o
n
i
a
n
e
m
i
a
a
n
d
i
t
s
c
o
m
p
l
e
m
e
n
t
a
t
i
o
n
g
r
o
u
p
s
a
r
e
a
c
k
n
o
w
l
e
d
g
e
d
b
u
t
n
o
t
f
u
r
t
h
e
r
l
i
s
t
e
d
i
n
t
h
i
s
N
o
s
o
l
o
g
y
.
T
h
e
R
e
a
d
e
r
i
s
r
e
f
e
r
r
e
d
t
o
M
I
M
o
r
t
o
s
p
e
c
i
a
l
i
z
e
d
r
e
v
i
e
w
s
.
S
e
e
a
l
s
o
C
H
I
L
D
i
n
g
r
o
u
p
2
0
a
n
d
t
h
e
m
e
s
o
m
e
l
i
c
a
n
d
a
c
r
o
m
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
s
3
9
.
P
o
l
y
d
a
c
t
y
l
y

S
y
n
d
a
c
t
y
l
y

T
r
i
p
h
a
l
a
n
g
i
s
m
g
r
o
u
p
P
r
e
a
x
i
a
l
p
o
l
y
d
a
c
t
y
l
y
t
y
p
e
1
(
P
P
D
1
)
A
D
1
7
4
4
0
0
7
q
3
6
S
H
H
S
o
n
i
c
H
e
d
g
e
h
o
g
R
e
g
u
l
a
t
o
r
y
m
u
t
a
t
i
o
n
P
r
e
a
x
i
a
l
p
o
l
y
d
a
c
t
y
l
y
t
y
p
e
1
(
P
P
D
1
)
A
D
1
7
4
4
0
0
S
o
m
e
i
n
s
t
a
n
c
e
s
n
o
t
l
i
n
k
e
d
t
o
S
H
H
P
r
e
a
x
i
a
l
p
o
l
y
d
a
c
t
y
l
y
t
y
p
e
2
(
P
P
D
2
)
/
t
r
i
p
h
a
l
a
n
g
e
a
l
t
h
u
m
b
(
T
P
T
)
A
D
1
7
4
5
0
0
7
q
3
6
S
H
H
S
o
n
i
c
H
e
d
g
e
h
o
g
R
e
g
u
l
a
t
o
r
y
m
u
t
a
t
i
o
n
P
r
e
a
x
i
a
l
p
o
l
y
d
a
c
t
y
l
y
t
y
p
e
3
(
P
P
D
3
)
A
D
1
7
4
6
0
0
P
r
e
a
x
i
a
l
p
o
l
y
d
a
c
t
y
l
y
t
y
p
e
4
(
P
P
D
4
)
A
D
1
7
4
7
0
0
7
p
1
3
G
L
I
3
G
l
i
-
K
r
u
p
p
e
l
f
a
m
i
l
y
m
e
m
b
e
r
3
G
r
e
i
g
c
e
p
h
a
l
o
p
o
l
y
s
y
n
d
a
c
t
y
l
y
s
y
n
d
r
o
m
e
A
D
1
7
5
7
0
0
7
p
1
3
G
L
I
3
G
l
i
-
K
r
u
p
p
e
l
f
a
m
i
l
y
m
e
m
b
e
r
3
P
a
l
l
i
s
t
e
r

H
a
l
l
s
y
n
d
r
o
m
e
A
D
1
4
6
5
1
0
7
p
1
3
G
L
I
3
G
l
i
-
K
r
u
p
p
e
l
f
a
m
i
l
y
m
e
m
b
e
r
3
S
y
n
p
o
l
y
d
a
c
t
y
l
y
(
c
o
m
p
l
e
x
,

b
u
l
i
n
1

a
s
s
o
c
i
a
t
e
d
)
A
D
6
0
8
1
8
0
2
2
q
1
3
.
3
F
B
L
N
1
F
i
b
u
l
i
n
1
S
y
n
p
o
l
y
d
a
c
t
y
l
y
A
D
1
8
6
0
0
0
2
q
3
1
H
O
X
D
1
3
H
o
m
e
o
b
o
x
D
1
3
T
o
w
n
e
s

B
r
o
c
k
s
s
y
n
d
r
o
m
e
(
R
e
n
a
l
-
E
a
r
-
A
n
a
l
-
R
a
d
i
a
l
s
y
n
d
r
o
m
e
)
A
D
1
0
7
4
8
0
1
6
q
1
2
.
1
S
A
L
L
1
S
A
L
-
l
i
k
e
1
L
a
c
r
i
m
o
-
a
u
r
i
c
u
l
o
-
d
e
n
t
o
-
d
i
g
i
t
a
l
s
y
n
d
r
o
m
e
(
L
A
D
D
)
A
D
1
4
9
7
3
0
1
0
q
2
6
.
1
2
F
G
F
R
2
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
r
e
c
e
p
t
o
r
2
L
a
c
r
i
m
o
-
a
u
r
i
c
u
l
o
-
d
e
n
t
o
-
d
i
g
i
t
a
l
s
y
n
d
r
o
m
e
(
L
A
D
D
)
A
D
1
4
9
7
3
0
4
p
1
6
.
3
F
G
F
R
3
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
r
e
c
e
p
t
o
r
3
L
a
c
r
i
m
o
-
a
u
r
i
c
u
l
o
-
d
e
n
t
o
-
d
i
g
i
t
a
l
s
y
n
d
r
o
m
e
(
L
A
D
D
)
A
D
1
4
9
7
3
0
5
p
1
3

p
1
2
F
G
F
1
0
F
i
b
r
o
b
l
a
s
t
g
r
o
w
t
h
f
a
c
t
o
r
1
0
A
c
r
o
c
a
l
l
o
s
a
l
s
y
n
d
r
o
m
e
A
R
2
0
0
9
9
0
7
p
1
3
A
c
r
o
-
p
e
c
t
o
r
a
l
s
y
n
d
r
o
m
e
A
D
6
0
5
9
6
7
7
q
3
6
A
c
r
o
-
p
e
c
t
o
r
o
-
v
e
r
t
e
b
r
a
l
d
y
s
p
l
a
s
i
a
(
F
-
s
y
n
d
r
o
m
e
)
A
D
1
0
2
5
1
0
2
q
3
6
M
i
r
r
o
r
-
i
m
a
g
e
p
o
l
y
d
a
c
t
y
l
y
o
f
h
a
n
d
s
a
n
d
f
e
e
t
(
L
a
u
r
i
n

S
a
n
d
r
o
w
s
y
n
d
r
o
m
e
)
A
D
1
3
5
7
5
0
7
q
3
6
S
H
H
S
o
n
i
c
H
e
d
g
e
h
o
g
M
i
r
r
o
r
-
i
m
a
g
e
p
o
l
y
d
a
c
t
y
l
y
o
f
h
a
n
d
s
a
n
d
f
e
e
t
(
L
a
u
r
i
n

S
a
n
d
r
o
w
s
y
n
d
r
o
m
e
)
U
n
l
i
n
k
e
d
t
o
S
H
H
C
e
n
a
n
i

L
e
n
z
s
y
n
d
a
c
t
y
l
y
A
R
2
1
2
7
8
0
1
1
p
1
1
.
2
L
R
P
4
L
o
w
d
e
n
s
i
t
y
l
i
p
o
p
r
o
t
e
i
n
r
e
c
e
p
t
o
r
-
r
e
l
a
t
e
d
p
r
o
t
e
i
n
4
(
C
o
n
t
i
n
u
e
d
)
WARMAN ET AL. 965
C
e
n
a
n
i

L
e
n
z
l
i
k
e
s
y
n
d
a
c
t
y
l
y
S
P
(
A
D
?
)
1
5
q
1
3

q
1
4
G
R
E
M
1
,
F
M
N
1
G
r
e
m
l
i
n
1
,
F
o
r
m
i
n
1
M
o
n
o
a
l
l
e
l
i
c
d
u
p
l
i
c
a
t
i
o
n
o
f
b
o
t
h
l
o
c
i
(
o
b
s
e
r
v
e
d
i
n
o
n
e
c
a
s
e
o
n
l
y
s
o
f
a
r
)
O
l
i
g
o
s
y
n
d
a
c
t
y
l
y
,
r
a
d
i
o
-
u
l
n
a
r
s
y
n
o
s
t
o
s
i
s
,
h
e
a
r
i
n
g
l
o
s
s
,
a
n
d
r
e
n
a
l
d
e
f
e
c
t
s
s
y
n
d
r
o
m
e
S
P
(
A
R
?
)
1
5
q
1
3

q
1
4
F
M
N
1
F
o
r
m
i
n
1
D
e
l
e
t
i
o
n
S
y
n
d
a
c
t
y
l
y
,
M
a
l
i
k

P
e
r
c
i
n
t
y
p
e
A
D
6
0
9
4
3
2
1
7
p
1
3
.
3
S
T
A
R
s
y
n
d
r
o
m
e
(
s
y
n
d
a
c
t
y
l
y
o
f
t
o
e
s
,
t
e
l
e
c
a
n
t
h
u
s
,
a
n
o
-
,
a
n
d
r
e
n
a
l
m
a
l
f
o
r
m
a
t
i
o
n
s
)
X
L
3
0
0
7
0
7
X
q
2
8
F
A
M
5
8
A
S
y
n
d
a
c
t
y
l
y
t
y
p
e
1
(
I
I
I

I
V
)
A
D
1
8
5
9
0
0
2
q
3
4

3
6
S
y
n
d
a
c
t
y
l
y
t
y
p
e
3
(
I
V

V
)
A
D
1
8
5
9
0
0
6
q
2
1

2
3
G
J
A
1
S
y
n
d
a
c
t
y
l
y
t
y
p
e
4
(
I

V
)
H
a
a
s
t
y
p
e
A
D
1
8
6
2
0
0
7
q
3
6
S
H
H
S
o
n
i
c
H
e
d
g
e
h
o
g
S
y
n
d
a
c
t
y
l
y
t
y
p
e
5
(
s
y
n
d
a
c
t
y
l
y
w
i
t
h
m
e
t
a
c
a
r
p
a
l
a
n
d
m
e
t
a
t
a
r
s
a
l
f
u
s
i
o
n
)
A
D
1
8
6
3
0
0
2
q
3
1
H
O
X
D
1
3
S
y
n
d
a
c
t
y
l
y
w
i
t
h
c
r
a
n
i
o
s
y
n
o
s
t
o
s
i
s
(
P
h
i
l
a
d
e
l
p
h
i
a
t
y
p
e
)
A
D
6
0
1
2
2
2
2
q
3
5

3
6
.
3
S
y
n
d
a
c
t
y
l
y
w
i
t
h
m
i
c
r
o
c
e
p
h
a
l
y
a
n
d
m
e
n
t
a
l
r
e
t
a
r
d
a
t
i
o
n
(
F
i
l
i
p
p
i
s
y
n
d
r
o
m
e
)
A
R
2
7
2
4
4
0
M
e
c
k
e
l
s
y
n
d
r
o
m
e
t
y
p
e
1
A
R
2
4
9
0
0
0
1
7
q
2
3
M
K
S
1
M
e
c
k
e
l
s
y
n
d
r
o
m
e
t
y
p
e
2
A
R
6
0
3
1
9
4
1
1
q
M
e
c
k
e
l
s
y
n
d
r
o
m
e
t
y
p
e
3
A
R
6
0
7
3
6
1
8
q
2
1
T
M
E
M
6
7
M
e
c
k
e
l
s
y
n
d
r
o
m
e
t
y
p
e
4
A
R
6
1
1
1
3
4
1
2
q
C
E
P
2
9
0
M
e
c
k
e
l
s
y
n
d
r
o
m
e
t
y
p
e
5
A
R
6
1
1
5
6
1
1
6
q
1
2
.
1
R
P
G
R
I
P
1
L
M
e
c
k
e
l
s
y
n
d
r
o
m
e
t
y
p
e
6
A
R
6
1
2
2
8
4
4
p
1
5
C
C
2
D
2
A
N
o
t
e
:
t
h
e
S
m
i
t
h

L
e
m
l
i

O
p
i
t
z
s
y
n
d
r
o
m
e
c
a
n
p
r
e
s
e
n
t
w
i
t
h
p
o
l
y
d
a
c
t
y
l
y
a
n
d
/
o
r
s
y
n
d
a
c
t
y
l
y
.
S
e
e
a
l
s
o
t
h
e
S
R
P
S
g
r
o
u
p
4
0
.
D
e
f
e
c
t
s
i
n
j
o
i
n
t
f
o
r
m
a
t
i
o
n
a
n
d
s
y
n
o
s
t
o
s
e
s
M
u
l
t
i
p
l
e
s
y
n
o
s
t
o
s
e
s
s
y
n
d
r
o
m
e
t
y
p
e
1
A
D
1
8
6
5
0
0
1
7
q
2
2
N
O
G
N
o
g
g
i
n
M
u
l
t
i
p
l
e
s
y
n
o
s
t
o
s
e
s
s
y
n
d
r
o
m
e
t
y
p
e
2
A
D
1
8
6
5
0
0
2
0
q
1
1
.
2
G
D
F
5
G
r
o
w
t
h
a
n
d
d
i
f
f
e
r
e
n
t
i
a
t
i
o
n
f
a
c
t
o
r
5
M
u
l
t
i
p
l
e
s
y
n
o
s
t
o
s
e
s
s
y
n
d
r
o
m
e
t
y
p
e
3
A
D
6
1
2
9
6
1
1
3
q
1
1

q
1
2
F
G
F
9
P
r
o
x
i
m
a
l
s
y
m
p
h
a
l
a
n
g
i
s
m
t
y
p
e
1
A
D
1
8
5
8
0
0
1
7
q
2
2
N
O
G
N
o
g
g
i
n
P
r
o
x
i
m
a
l
s
y
m
p
h
a
l
a
n
g
i
s
m
t
y
p
e
2
A
D
1
8
5
8
0
0
2
0
q
1
1
.
2
G
D
F
5
G
r
o
w
t
h
a
n
d
d
i
f
f
e
r
e
n
t
i
a
t
i
o
n
f
a
c
t
o
r
5
R
a
d
i
o
-
u
l
n
a
r
s
y
n
o
s
t
o
s
i
s
w
i
t
h
a
m
e
g
a
k
a
r
y
o
c
y
t
i
c
t
h
r
o
m
b
o
c
y
t
o
p
e
n
i
a
A
D
6
0
5
4
3
2
7
p
1
5

1
4
.
2
H
O
X
A
1
1
H
o
m
e
o
b
o
x
A
1
1
S
e
e
a
l
s
o
S
p
o
n
d
y
l
o
-
C
a
r
p
a
l
-
T
a
r
s
a
l
d
y
s
p
l
a
s
i
a
;
m
e
s
o
m
e
l
i
c
d
y
s
p
l
a
s
i
a
w
i
t
h
a
c
r
a
l
s
y
n
o
s
t
o
s
e
s
;
a
n
d
o
t
h
e
r
s
T
A
B
L
E
I
(
C
o
n
t
i
n
u
e
d
)
G
r
o
u
p
/
n
a
m
e
o
f
d
i
s
o
r
d
e
r
I
n
h
e
r
i
t
a
n
c
e
M
I
M
N
o
.
L
o
c
u
s
G
e
n
e
P
r
o
t
e
i
n
N
o
t
e
s
966 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
eachgene separately, advocatedby some scholars, is more confusing
than helpful in clinical practice.
Group 26 has seen the identication of several novel molecular
mechanisms leading to hypophosphatemic rickets.
In Group 29 (Disorganized Development of Skeletal Com-
ponents), neurobromatosis 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 signicant skeletal
involvement) and Group 31 (Genetic inammatory/rheumatoid-
like osteoarthropathies) have been newly added. Group 30 com-
prises disorders that present as overgrowth syndromes and have a
signicant skeletal component that is part of the diagnostic criteria
for a specic 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. Group31 includes disorders withfeatures of
inammation 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 identication of the genetic basis of such disorders in recent
years, allowing for a more precise delineation of the phenotypes.
Finally, groups 3240 are dedicated to the dysostoses and
follow again anatomical criteria (cranium, face, axial skeleton,
extremities) with additional criteria reecting 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 identied 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 rst versions of the Nomenclature. At that
time, withlittle biochemical or molecular informationavailable, the
grouping of disorders reectedthe belief that disorders with similar
phenotypic features (e.g., dysostosis multiplex) might be caused by
disturbances inrelatedmetabolic pathways or gene networks (inthe
case of dysostosis multiplex, lysosomal degradation). This notion
has been conrmed by the identication 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 DTDSTfamily. 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 ndings, for example, in the mesomelic dysplasias or in
chondrodysplasia punctata. Some groups are still dened 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 t equally well in another group.
Which Classication Criteria to Use?
Criticismtothe previous versions of the Nosology has focusedonits
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 classied on phenotypic similarities
rst, and as their molecular bases become understood they may be
reclassied based on the gene or pathway that is abnormal. The rst
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 classications 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 classications 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 Dysostoses
Dysostoses are disorders affecting individual bones or group of
bones. In contrast to the dysplasias, that arise frequently from
defects in structural proteins, metabolic processes or in growth
plate regulation, the dysostoses often arise from embryonic mor-
phogenic defects and are thus more closely related to multiple
malformation syndromes. Since the rst inclusion of dysostoses in
the 2001 revision, the number of dysostoses included in the
Nosology has grown signicantly. The present revision includes an
even larger number of dysostoses reecting 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 Franckter Haar syndrome can be
cited as examples. The MIMcatalogue 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 Nosology
Because 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 ling 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, MIMis in general
more appositional, while the Nosology tries to do some
housekeeping of entities by regrouping them and by eliminating
those that have been incorporated into others. Efforts to made to
harmonize the MIM and the Nosology are underway.
Outlook
The increasing availability of massive parallel sequencing and other
new sequencing technologies will likely result in a rapid identica-
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 denition 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 givendisorder. As anexpert-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 Faculte de Biologie et Medicine
of the Lausanne University.
REFERENCES
1970. International nomenclature of constitutional diseases of bones. Ann
Radiol (Paris) 13:455464.
1971a. A nomenclature for constitutional (intrinsic) diseases of bones.
J Pediatr 78:177179.
1971b. International nomenclature of constitutional bone diseases. Con-
stitutional bone diseases without known pathogenesis. Arch Fr Pediatr
28:553557.
1971c. Nomenclature for constitutional (intrinsic) diseases of bones.
Pediatrics 47:431434.
1971d. Nomenclature for the constitutional (intrinsic) diseases of bone.
Radiology 99:699702.
1978. International nomenclature of constitutional diseases of bone.
RevisionMay, 1977. J Pediatr 93:614616.
1979. International nomenclature of constitutional diseases of bone:
RevisionMay 1977. Am J Med Genet 3:2126.
1983. International nomenclature of constitutional diseases of bone.
Revision, May, 1983. Ann Radiol (Paris) 26:457462.
1998. International nomenclature and classication of the osteochondro-
dysplasias (1997). International working group on constitutional dis-
eases of bone. Am J Med Genet 79:376382.
Hall CM. 2002. International nosology and classication of constitutional
disorders of bone (2001). Am J Med Genet 113:6577.
Lachman RS. 1998. International nomenclature and classication of the
osteochondrodysplasias (1997). Pediatr Radiol 28:737744.
McKusick VA, Scott CI. 1971. Anomenclature for constitutional disorders
of bone. J Bone Joint Surg Am 53:978986.
Nishimura G, Hasegawa T, Kinoshita E, Tanaka Y, Kurosawa K, Yoshimoto
M. 2004. Newly recognized syndrome of metaphyseal undermodeling,
spondylar dysplasia, and overgrowth: Report of two adolescents and a
child. Am J Med Genet Part A 128A:204208.
Rimoin DL. 1979. International nomenclature of constitutional diseases of
bone with bibliography. Birth Defects Orig Artic Ser 15:30.
Schmidt H, Kammer B, Grasser M, Enders A, Rost I, Kiess W. 2007.
Endochondral gigantism: Anewly recognized skeletal dysplasia with pre-
andpostnatal overgrowth and endocrine abnormalities. AmJ Med Genet
Part A 143A:18681875.
Sillence DO, Rimoin DL. 1978. Classication of osteogenesis imperfect.
Lancet 1:10411042.
Sillence DO, Rimoin DL, Danks DM. 1979a. Clinical variability in osteo-
genesis imperfecta-variable expressivity or genetic heterogeneity. Birth
Defects Orig Artic Ser 15:113129.
Sillence DO, Senn A, Danks DM. 1979b. Genetic heterogeneity in osteo-
genesis imperfecta. J Med Genet 16:101116.
Spranger J. 1992. International classication of osteochondrodysplasias.
The international working grouponconstitutional diseases of bone. Eur J
Pediatr 151:407415.
StevensonDA, Viskochil DH, Carey JC. 2007. Neurobromatosis type 1 is a
genetic skeletal disorder. AmJ MedGenet Part A143A:20822083;author
reply 2084.
Superti-Furga A, Unger S. 2007. Nosology and classication of genetic
skeletal disorders: 2006 revision. Am J Med Genet Part A 143A:118.
968 AMERICAN JOURNAL OF MEDICAL GENETICS PART A