Home >Documents >Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf ·...

Nosology and classification of genetic skeletal disorders ...BIB_31F9B1D3B25E.P001/REF.pdf ·...

Date post:22-Mar-2020
Category:
View:8 times
Download:0 times
Share this document with a friend
Transcript:
  • RESEARCH ARTICLE

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

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

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

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

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

    Received 16 December 2010; Accepted 30 December 2010

    Genetic disorders involving the skeletal system arise through

    disturbances in the complex processes of skeletal development,

    growth and homeostasis and remain a diagnostic challenge

    because of their variety. The Nosology and Classification of

    Genetic Skeletal Disorders provides an overview of recognized

    diagnostic entities and groups them by clinical and radiographic

    features and molecular pathogenesis. The aim is to provide the

    Genetics, Pediatrics and Radiology community with a list of

    recognized genetic skeletal disorders that can be of help in the

    diagnosis of individual cases, in the delineation of novel disor-

    ders, and in building bridges between clinicians and scientists

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

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

    lar, biochemical, and/or radiographic criteria. Of these

    conditions, 316 were associated with mutations in one or more

    of 226 different genes, ranging from common, recurrent muta-

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

    the Nosology is a hybrid between a list of clinically defined

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

    July 2009 and supported by The Manton Center for Orphan Disease

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

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

    Osteogenesis Imperfecta Foundation, Gaithersburg, Maryland;

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

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

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

    *Correspondence to:

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

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

    Published online 15 March 2011 in Wiley Online Library

    (wileyonlinelibrary.com).

    DOI 10.1002/ajmg.a.33909

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

    Krakow D, Lachman R, LeMerrer M, Mortier

    G, Mundlos S, Nishimura G, Rimoin DL,

    Robertson S, Savarirayan R, Sillence D,

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

    2011. Nosology and classification of genetic

    skeletal disorders: 2010 revision.

    Am J Med Genet Part A 155:943–968.

    � 2011 Wiley-Liss, Inc. 943

  • disorders, waiting for molecular clarification, and an annotated

    database documenting the phenotypic spectrum produced by

    mutations in a given gene. The Nosology should be useful for the

    diagnosis of patients with genetic skeletal diseases, particularly

    in view of the information flood expected with the novel se-

    quencing technologies; in the delineation of clinical entities and

    novel disorders, by providing an overview of established noso-

    logic entities; and for scientists looking for the clinical correlates

    of genes, proteins and pathways involved in skeletal biology.

    � 2011 Wiley-Liss, Inc.

    Key words: skeletal genetics; osteochondrodysplasias; nosology;dysostoses; molecular basis of disease

    INTRODUCTION

    In the 1960s, accumulating evidence that genetic skeletal disorders

    were clinically and genetically heterogeneous prompted a group of

    international experts to prepare a document to reach an agreement

    on the nomenclature of what was then called ‘‘constitutional (or

    intrinsic) disorders of bone’’ [1970, 1971a,b,c,d; McKusick and

    Scott, 1971]. The ‘‘Nomenclature’’ was meant to bring together

    experts in radiology, clinical genetics, and pediatrics to agree on the

    denomination and classification of skeletal disorders, syndromes

    and metabolic diseases that were being newly described. Revisions

    have been prepared in 1977, 1983, 1992, and 1997 [1978, 1979, 1983,

    1998, Rimoin, 1979; Spranger, 1992; Lachman, 1998]. Following

    the establishment of the International Skeletal Dysplasia Society

    (ISDS) in 1999, and to cope with the increasing complexity of

    information, revisions of the Nosology have been delegated to an

    expert group nominated ad hoc within the ISDS to ensure an

    adequate representation of clinical, radiological and molecular

    expertise (2001 and 2006 revisions) [Hall, 2002; Superti-Furga and

    Unger, 2007].

    METHODS

    The Nosology Group of the International Skeletal Dysplasia Society

    met in August 2009. A consensus was reached for changes to be

    made to the grouping of disorders and about the inclusion of

    individual disorders. The drafts were circulated after the meeting

    and an effort was made to monitor recent publications up to

    November 2010. The criteria used for inclusion of individual

    disorders were unchanged from the previous revision. They were:

    (1) Significant skeletal involvement, corresponding to the defini-

    tion of skeletal dysplasias, metabolic bone disorders, dysos-

    toses, and skeletal malformation and/or reduction syndromes.

    (2) Publication and/or listing in MIM (meaning that observations

    should not find their way into the Nosology before they achieve

    peer-reviewed publication status).

    (3) Genetic basis proven by pedigree or very likely based on

    homogeneity of phenotype in unrelated families.

    (4) Nosologic autonomy confirmed by molecular or linkage anal-

    ysis and/or by the presence of distinctive diagnostic features

    and of observation in multiple individuals or families.

    RESULTS

    Four hundred fifty-six different conditions were included and

    placed in 40 groups defined by molecular, biochemical and/or

    radiographic criteria. Of these conditions, 316 (2006 revision: 215)

    were associated with one or more of 226 (2006 revision: 140)

    different genes. The results are presented in Table I. Within a

    group, disorders with known molecular basis have been listed

    preceding those with lesser degree of evidence; however, variants

    of the same disorder have been kept together.

    The organization of groups has been further changed in com-

    parison to the 2006 version. Two new groups based on a common

    affected molecule or biochemical pathway have been created

    (TRPV4 group and Aggrecan group). The TRPV4 group includes

    disorders that are relatively common and that constitute a new

    prototypic spectrum ranging from mild to lethal. Aggrecan is one of

    the important structural molecules in cartilage and it would not be

    surprising if more disorders would find their way into this group in

    the future. Thus, groups 1–8 are based on a common underlyinggene or pathway.

    Groups 9–17 are based on the localization of radiographicchanges to specific bone structures (vertebrae, epiphyses, meta-

    physes, diaphysis, or combination thereof) or of the involved

    segment (rhizo, meso, or acro). Groups 18–20 are defined bymacroscopic criteria in combination with clinical features (bent

    bones, slender bones, presence of multiple dislocations). Groups

    21–25 and 28 take into account features of mineralization(increased or reduced bone density, impaired mineralization,

    stippling, osteolysis). Group 27 encompasses the large group of

    lysosomal disorders with skeletal involvement. Group 29 comprises

    disorders with so-called abnormal (previously ‘‘anarchic’’) devel-

    opment of skeletal components such as exostoses, ecnhondromas,

    and ectopic calcification. It is particularly heterogeneous and may

    need to be revised in the future with the help of newer molecular

    data.

    Group 23, comprising the osteopetrosis (OP) variants and

    related disorders, has been expanded following the identification

    of distinct genetic defects in various variants of osteopetrosis. The

    diversity of molecular mechanisms involved and the presence of

    clinical, biochemical and/or histologic features that distinguish

    between the various OP forms justify the subdivision of the ‘‘OP

    phenotype’’ in the many subtypes.

    Group 25 (Osteogenesis Imperfecta and decreased bone density

    group) has had special attention. The Sillence classification, pub-

    lished 30 years ago, provided a first systematic clinical classification

    and made correlations to the inheritance pattern of individual

    clinical types [Sillence and Rimoin, 1978; Sillence et al., 1979a,b].

    Today, a surprising genetic complexity of the molecular bases of OI

    has been revealed, and at the same time the extensive phenotypic

    variation arising from single loci has been documented clearly. It

    seemed therefore untenable to try and maintain tight correlations

    between ‘‘Sillence types’’ and their molecular basis. It was agreed

    upon to retain the Sillence classification as the prototypic and

    universally accepted way to classify the degree of severity in OI; and

    to free the Sillence classification from any direct molecular refer-

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

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

    944 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

  • TAB

    LEI.

    Gro

    up/n

    ame

    ofdi

    sord

    erIn

    heri

    tan

    ceM

    IMN

    o.Lo

    cus

    Gen

    ePr

    otei

    nN

    otes

    1.

    FGFR

    3ch

    ondr

    odys

    plas

    iagr

    oup

    Than

    atop

    hori

    cdy

    spla

    sia

    type

    1(T

    D1

    )AD

    18

    76

    00

    4p1

    6.3

    FGFR

    3FG

    FR3

    Incl

    ud

    esp

    revi

    ous

    San

    Die

    goty

    pe

    Than

    atop

    hori

    cdy

    spla

    sia

    type

    2(T

    D2

    )AD

    18

    76

    01

    4p1

    6.3

    FGFR

    3FG

    FR3

    Seve

    reac

    hon

    drop

    lasi

    aw

    ith

    deve

    lopm

    enta

    lde

    lay

    and

    acan

    thos

    isn

    igri

    can

    s(S

    ADD

    AN)

    ADSe

    e1

    87

    60

    04

    p16

    .3FG

    FR3

    FGFR

    3

    Acho

    ndr

    opla

    sia

    AD1

    00

    80

    04

    p16

    .3FG

    FR3

    FGFR

    3H

    ypoc

    hon

    drop

    lasi

    aAD

    14

    60

    00

    4p1

    6.3

    FGFR

    3FG

    FR3

    Cam

    ptod

    acty

    ly,

    tall

    stat

    ure,

    and

    hear

    ing

    loss

    syn

    drom

    e(C

    ATSH

    L)AD

    18

    76

    00

    4p1

    6.3

    FGFR

    3FG

    FR3

    Inac

    tiva

    tin

    gm

    uta

    tion

    Hyp

    ocho

    ndr

    opla

    sia-

    like

    dysp

    lasi

    a(s)

    AD,

    SPSi

    mila

    rto

    hy

    poc

    hon

    dro

    pla

    sia

    bu

    tu

    nlin

    ked

    toFG

    FR3

    ,p

    rob

    ably

    het

    erog

    eneo

    us;

    un

    cert

    ain

    dia

    gnos

    tic

    crit

    eria

    See

    also

    grou

    p3

    3fo

    rcr

    anio

    syno

    stos

    essy

    ndro

    mes

    linke

    dto

    FGFR

    3m

    utat

    ions

    ,as

    wel

    las

    LAD

    Dsy

    ndro

    me

    ingr

    oup

    39

    for

    anot

    her

    FGFR

    3-r

    elat

    edph

    enot

    ype

    2.

    Type

    2co

    llage

    ngr

    oup

    and

    sim

    ilar

    diso

    rder

    sAc

    hon

    drog

    enes

    isty

    pe2

    (ACG

    2;

    Lan

    ger–

    Sald

    ino)

    AD2

    00

    61

    01

    2q1

    3.1

    COL2

    A1Ty

    pe2

    colla

    gen

    Plat

    yspo

    ndy

    licdy

    spla

    sia,

    Torr

    ance

    type

    AD1

    51

    21

    01

    2q1

    3.1

    COL2

    A1Ty

    pe2

    colla

    gen

    See

    also

    seve

    resp

    ond

    ylo

    dy

    spla

    stic

    dy

    spla

    sias

    (gro

    up

    13

    )H

    ypoc

    hon

    drog

    enes

    isAD

    20

    06

    10

    12

    q13

    .1CO

    L2A1

    Type

    2co

    llage

    nSp

    ondy

    loep

    iphy

    seal

    dysp

    lasi

    aco

    nge

    nit

    a(S

    EDC)

    AD1

    83

    90

    01

    2q1

    3.1

    COL2

    A1Ty

    pe2

    colla

    gen

    Spon

    dylo

    epim

    etap

    hyse

    aldy

    spla

    sia

    (SEM

    D)

    Stru

    dwic

    kty

    peAD

    18

    42

    50

    12

    q13

    .1CO

    L2A1

    Type

    2co

    llage

    n

    Kn

    iest

    dysp

    lasi

    aAD

    15

    65

    50

    12

    q13

    .1CO

    L2A1

    Type

    2co

    llage

    nSp

    ondy

    lope

    riph

    eral

    dysp

    lasi

    aAD

    27

    17

    00

    12

    q13

    .1CO

    L2A1

    Type

    2co

    llage

    nM

    ildSE

    Dw

    ith

    prem

    atur

    eon

    set

    arth

    rosi

    sAD

    12

    q13

    .1CO

    L2A1

    Type

    2co

    llage

    nO

    ften

    asso

    ciat

    edw

    ith

    p.R

    71

    9C

    and

    p.G

    47

    4S

    mu

    tati

    ons

    SED

    wit

    hm

    etat

    arsa

    lsh

    orte

    nin

    g(f

    orm

    erly

    Czec

    hdy

    spla

    sia)

    AD6

    09

    16

    21

    2q1

    3.1

    COL2

    A1Ty

    pe2

    colla

    gen

    Oft

    enas

    soci

    ated

    wit

    hth

    ep

    .R2

    75

    Cm

    uta

    tion

    Stic

    kler

    syn

    drom

    ety

    pe1

    AD1

    08

    30

    01

    2q1

    3.1

    COL2

    A1Ty

    pe2

    colla

    gen

    Stic

    kler

    -like

    syn

    drom

    e(s)

    Un

    linke

    dto

    eith

    erCO

    L2A1

    ,CO

    L11

    A1,

    orCO

    L11

    A2.

    See

    also

    COL9

    A1fo

    rre

    cess

    ive

    form

    3.

    Type

    11

    colla

    gen

    grou

    pSt

    ickl

    ersy

    ndr

    ome

    type

    2AD

    60

    48

    41

    1p2

    1CO

    L11

    A1Ty

    pe1

    1co

    llage

    nal

    ph

    a-1

    chai

    nM

    arsh

    all

    syn

    drom

    eAD

    15

    47

    80

    1p2

    1CO

    L11

    A1Ty

    pe1

    1co

    llage

    nal

    ph

    a-1

    chai

    nFi

    broc

    hon

    drog

    enes

    isAR

    22

    85

    20

    1p2

    1CO

    L11

    A1Ty

    pe1

    1co

    llage

    nal

    ph

    a-1

    chai

    nO

    tosp

    ondy

    lom

    egae

    piph

    ysea

    ldy

    spla

    sia

    (OSM

    ED),

    rece

    ssiv

    ety

    peAR

    21

    51

    50

    6p2

    1.3

    COL1

    1A2

    Type

    11

    colla

    gen

    alp

    ha-

    2ch

    ain

    WARMAN ET AL. 945

  • Oto

    spon

    dylo

    meg

    aepi

    phys

    eal

    dysp

    lasi

    a(O

    SMED

    ),do

    min

    ant

    type

    (Wei

    ssen

    bach

    er–

    Zwey

    m€ ul

    ler

    syn

    drom

    e,St

    ickl

    ersy

    ndr

    ome

    type

    3)

    AD2

    15

    15

    06

    p21

    .3CO

    L11

    A2Ty

    pe1

    1co

    llage

    nal

    ph

    a-2

    chai

    n

    See

    also

    Stic

    kler

    synd

    rom

    ety

    pe1

    ingr

    oup

    24

    .Su

    lfat

    ion

    diso

    rder

    sgr

    oup

    Acho

    ndr

    ogen

    esis

    type

    1B

    (ACG

    1B

    )AR

    60

    09

    72

    5q3

    2–

    33

    DTD

    STSL

    C26

    A2su

    lfate

    tran

    spor

    ter

    Form

    erly

    know

    nas

    Frac

    caro

    typ

    eac

    hon

    dro

    gen

    esis

    Atel

    oste

    ogen

    esis

    type

    2(A

    O2

    )AR

    25

    60

    50

    5q3

    2–

    33

    DTD

    STSL

    C26

    A2su

    lfate

    tran

    spor

    ter

    Incl

    ud

    esd

    ela

    Chap

    elle

    dy

    spla

    sia,

    McA

    liste

    rd

    ysp

    lasi

    a,an

    d‘‘n

    eon

    atal

    osse

    ous

    dy

    spla

    sia’

    ’D

    iast

    roph

    icdy

    spla

    sia

    (DTD

    )AR

    22

    26

    00

    5q3

    2–

    33

    DTD

    STSL

    C26

    A2su

    lfate

    tran

    spor

    ter

    MED

    ,au

    toso

    mal

    rece

    ssiv

    ety

    pe(r

    MED

    ;ED

    M4

    )AR

    22

    69

    00

    5q3

    2–

    33

    DTD

    STSL

    C26

    A2su

    lfate

    tran

    spor

    ter

    See

    also

    mu

    ltip

    leep

    iph

    yse

    ald

    ysp

    lasi

    asan

    dp

    seu

    doa

    chon

    dro

    pla

    sia

    grou

    p(g

    rou

    p9

    )SE

    MD

    ,PA

    PSS2

    type

    AR6

    03

    00

    51

    0q2

    3–

    q24

    PAPS

    S2PA

    PS-S

    ynth

    etas

    e2

    Form

    erly

    ‘‘Pak

    ista

    ni

    typ

    e.’’

    See

    also

    SEM

    Dgr

    oup

    (gro

    up

    11

    )Ch

    ondr

    odys

    plas

    iaw

    ith

    con

    gen

    ital

    join

    tdi

    sloc

    atio

    ns,

    CHST

    3ty

    pe(r

    eces

    sive

    Lars

    ensy

    ndr

    ome)

    AR6

    08

    63

    71

    0q2

    2.1

    CHST

    3Ca

    rboh

    ydra

    tesu

    lfotr

    ansf

    eras

    e3

    ;ch

    ondr

    oiti

    n6

    -su

    lfotr

    ansf

    eras

    e

    Incl

    ud

    esre

    cess

    ive

    Lars

    ensy

    nd

    rom

    e,h

    um

    ero-

    spin

    ald

    yso

    stos

    is,

    and

    SED

    Om

    ani

    typ

    eEh

    lers

    –D

    anlo

    ssy

    ndr

    ome,

    CHST

    14

    type

    (‘‘m

    uscu

    lo-s

    kele

    tal

    vari

    ant’’

    )AR

    60

    17

    76

    15

    q14

    CHST

    14

    Carb

    ohyd

    rate

    sulfo

    tran

    sfer

    ase

    14

    ;de

    rmat

    an4

    -su

    lfotr

    ansf

    eras

    e

    Incl

    ud

    esAd

    du

    cted

    Thu

    mb–

    Clu

    bfo

    otsy

    nd

    rom

    e

    See

    also

    grou

    p7

    and

    grou

    p2

    6fo

    rot

    her

    cond

    itio

    nsw

    ith

    mul

    tipl

    edi

    sloc

    atio

    ns5

    .Pe

    rlec

    angr

    oup

    Dys

    segm

    enta

    ldy

    spla

    sia,

    Silv

    erm

    an-H

    andm

    aker

    type

    AR2

    24

    41

    01

    q36–

    34

    PLC (H

    SPG

    2)

    Perl

    ecan

    Dys

    segm

    enta

    ldy

    spla

    sia,

    Rol

    lan

    d-D

    esbu

    quoi

    sty

    peAR

    22

    44

    00

    1q3

    6–

    34

    PLC (H

    SPG

    2)

    Perl

    ecan

    Schw

    artz

    –Ja

    mpe

    lsy

    ndr

    ome

    (myo

    ton

    icch

    ondr

    odys

    trop

    hy)

    AR2

    55

    80

    01

    q36–

    34

    PLC (H

    SPG

    2)

    Perl

    ecan

    Mild

    and

    seve

    refo

    rms;

    incl

    ud

    esp

    revi

    ous

    Bu

    rton

    dy

    spla

    sia

    6.

    Aggr

    ecan

    grou

    pSE

    D,

    Kim

    berl

    eyty

    peAD

    60

    83

    61

    15

    q26

    AGC1

    Aggr

    ecan

    SEM

    D,

    Aggr

    ecan

    type

    AR6

    12

    81

    31

    5q2

    6AG

    C1Ag

    grec

    anFa

    mili

    alos

    teoc

    hon

    drit

    isdi

    ssec

    ans

    AD1

    65

    80

    01

    5q2

    6AG

    C1Ag

    grec

    an7

    .Fi

    lam

    ingr

    oup

    and

    rela

    ted

    diso

    rder

    sFr

    onto

    met

    aphy

    seal

    dysp

    lasi

    aXL

    D3

    05

    62

    0Xq

    28

    FLN

    AFi

    lam

    inA

    Som

    eca

    ses

    app

    aren

    tly

    lack

    FLN

    Am

    uta

    tion

    sO

    steo

    dysp

    last

    yM

    eln

    ick–

    Nee

    dles

    XLD

    30

    93

    50

    Xq2

    8FL

    NA

    Fila

    min

    A

    TAB

    LEI(

    Con

    tin

    ued)

    Gro

    up/n

    ame

    ofdi

    sord

    erIn

    heri

    tan

    ceM

    IMN

    o.Lo

    cus

    Gen

    ePr

    otei

    nN

    otes

    946 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

  • Oto

    pala

    todi

    gita

    lsy

    ndr

    ome

    type

    1(O

    PD1

    )XL

    D3

    11

    30

    0Xq

    28

    FLN

    AFi

    lam

    inA

    Oto

    pala

    todi

    gita

    lsy

    ndr

    ome

    type

    2(O

    PD2

    )XL

    D3

    04

    12

    0Xq

    28

    FLN

    AFi

    lam

    inA

    Term

    inal

    osse

    ous

    dysp

    lasi

    aw

    ith

    pigm

    enta

    ryde

    fect

    s(T

    OD

    PD)

    XLD

    30

    02

    44

    Xq2

    8FL

    NA

    Fila

    min

    A

    Atel

    oste

    ogen

    esis

    type

    1(A

    O1

    )AD

    10

    87

    20

    3p1

    4.3

    FLN

    BFi

    lam

    inB

    Incl

    ud

    esB

    oom

    eran

    gd

    ysp

    lasi

    a,P

    iep

    korn

    dy

    spla

    sia,

    and

    spon

    dy

    loh

    um

    erof

    emor

    al(g

    ian

    tce

    ll)d

    ysp

    lasi

    aAt

    elos

    teog

    enes

    isty

    pe3

    (AO

    3)

    AD1

    08

    72

    13

    p14

    .3FL

    NB

    Fila

    min

    BLa

    rsen

    syn

    drom

    e(d

    omin

    ant)

    AD1

    50

    25

    03

    p14

    .3FL

    NB

    Fila

    min

    BSp

    ondy

    lo-c

    arp

    al-t

    arsa

    ldy

    spla

    sia

    AR2

    72

    46

    03

    p14

    .3FL

    NB

    Fila

    min

    BSp

    ondy

    lo-c

    arp

    al-t

    arsa

    ldy

    spla

    sia

    AR2

    72

    46

    0U

    nlin

    ked

    toFL

    NB

    Fran

    ck–

    ter

    Haa

    rsy

    ndr

    ome

    AR2

    49

    42

    05

    q35

    .1SH

    3PX

    D2

    BTK

    S4Se

    rpen

    tin

    efi

    bula

    —po

    lycy

    stic

    kidn

    eysy

    ndr

    ome

    AD?

    60

    03

    30

    See

    also

    grou

    p4

    for

    rece

    ssiv

    eLa

    rsen

    synd

    rom

    ean

    dgr

    oup

    26

    for

    cond

    itio

    nsw

    ith

    mul

    tipl

    edi

    sloc

    atio

    ns8

    .TR

    PV4

    grou

    pM

    etat

    ropi

    cdy

    spla

    sia

    AD1

    56

    53

    01

    2q2

    4.1

    TRPV

    4Tr

    ansi

    ent

    rece

    pto

    rpo

    ten

    tial

    cati

    onch

    ann

    el,

    subf

    amily

    V,m

    emb

    er4

    Incl

    ud

    esle

    thal

    and

    non

    -leth

    alfo

    rms

    Spon

    dylo

    epim

    etap

    hyse

    aldy

    spla

    sia,

    Mar

    otea

    uxty

    pe(P

    seud

    o–M

    orqu

    iosy

    ndr

    ome

    type

    2)

    AD1

    84

    09

    51

    2q2

    4.1

    TRPV

    4Tr

    ansi

    ent

    rece

    pto

    rpo

    ten

    tial

    cati

    onch

    ann

    el,

    subf

    amily

    V,m

    emb

    er4

    Spon

    dylo

    met

    aphy

    seal

    dysp

    lasi

    a,K

    ozlo

    wsk

    ity

    peAD

    18

    42

    52

    12

    q24

    .1TR

    PV4

    Tran

    sien

    tre

    cep

    tor

    pote

    nti

    alca

    tion

    chan

    nel

    ,su

    bfam

    ilyV,

    mem

    ber

    4B

    rach

    yolm

    ia,

    auto

    som

    aldo

    min

    ant

    type

    AD1

    13

    50

    01

    2q2

    4.1

    TRPV

    4Tr

    ansi

    ent

    rece

    pto

    rpo

    ten

    tial

    cati

    onch

    ann

    el,

    subf

    amily

    V,m

    emb

    er4

    Fam

    ilial

    digi

    tal

    arth

    ropa

    thy

    wit

    hbr

    achy

    dact

    yly

    AD6

    06

    83

    51

    2q2

    4.1

    TRPV

    4Tr

    ansi

    ent

    rece

    pto

    rpo

    ten

    tial

    cati

    onch

    ann

    el,

    subf

    amily

    V,m

    emb

    er4

    9.

    Shor

    t-ri

    bsdy

    spla

    sias

    (wit

    hor

    wit

    hout

    poly

    dact

    yly)

    grou

    pCh

    ondr

    oect

    oder

    mal

    dysp

    lasi

    a(E

    llis–

    van

    Crev

    eld)

    AR2

    25

    50

    04

    p16

    EVC1

    EvC

    gen

    e1

    4p1

    6EV

    C2Ev

    Cge

    ne

    2Sh

    ort

    rib—

    poly

    dact

    yly

    syn

    drom

    e(S

    RPS

    )ty

    pe1

    /3(S

    aldi

    no-

    Noo

    nan

    /Ve

    rma-

    Nau

    mof

    f)

    AR2

    63

    51

    01

    1q2

    2.3

    DYN

    C2H

    1D

    ynei

    n,

    cyto

    pla

    smic

    2,

    heav

    ych

    ain

    1

    SRPS

    type

    1/3

    (Sal

    din

    o-N

    oon

    an/

    Verm

    a-N

    aum

    off)

    AR2

    63

    51

    03

    q25

    .33

    IFT8

    0In

    trafl

    agel

    lar

    tran

    spor

    t8

    0(h

    omol

    ogof

    )SR

    PSty

    pe1

    /3(S

    aldi

    no-

    Noo

    nan

    /Ve

    rma-

    Nau

    mof

    f)AR

    26

    35

    10

    Un

    linke

    dto

    eith

    erD

    YNC2

    H1

    orIF

    T80

    SRPS

    type

    2(M

    ajew

    ski)

    AR2

    63

    52

    0N

    EK1

    Nim

    are

    late

    dki

    nas

    e1

    (Contin

    ued)

    WARMAN ET AL. 947

  • SRPS

    type

    4(B

    eem

    er)

    AR2

    69

    86

    0O

    ral-f

    acia

    l-dig

    ital

    syn

    drom

    ety

    pe4

    (Moh

    r–M

    ajew

    ski)

    AR2

    58

    86

    0

    Asph

    yxia

    tin

    gth

    orac

    icdy

    spla

    sia

    (ATD

    ;Je

    une)

    AR2

    08

    50

    03

    q25

    .33

    IFT8

    0In

    trafl

    agel

    lar

    tran

    spor

    t8

    0(h

    omol

    ogof

    )As

    phyx

    iati

    ng

    thor

    acic

    dysp

    lasi

    a(A

    TD;

    Jeun

    e)AR

    20

    85

    00

    11

    q22

    .3D

    YNC2

    H1

    Dyn

    ein

    ,cy

    top

    lasm

    ic2

    ,he

    avy

    chai

    n1

    Asph

    yxia

    tin

    gth

    orac

    icdy

    spla

    sia

    (ATD

    ;Je

    une)

    AR2

    08

    50

    0U

    nlin

    ked

    toei

    ther

    DYN

    C2H

    1or

    IFT8

    0Th

    orac

    olar

    yngo

    pelv

    icdy

    spla

    sia

    (Bar

    nes

    )AD

    18

    77

    60

    See

    also

    pate

    rnal

    UPD

    14

    and

    cere

    bro-

    cost

    o-m

    andi

    bula

    rsy

    ndro

    me

    10

    .M

    ulti

    ple

    epip

    hyse

    aldy

    spla

    sia

    and

    pseu

    doac

    hon

    drop

    lasi

    agr

    oup

    Pseu

    doac

    hon

    drop

    lasi

    a(P

    SACH

    )AD

    17

    71

    70

    19

    p12–

    13

    .1CO

    MP

    COM

    PM

    ulti

    ple

    epip

    hyse

    aldy

    spla

    sia

    (MED

    )ty

    pe1

    (ED

    M1

    )AD

    13

    24

    00

    19

    p13

    .1CO

    MP

    COM

    P

    Mul

    tipl

    eep

    iphy

    seal

    dysp

    lasi

    a(M

    ED)

    type

    2(E

    DM

    2)

    AD6

    00

    20

    41

    p32

    .2–

    33

    COL9

    A2Co

    llage

    n9

    alp

    ha-

    2ch

    ain

    Mul

    tipl

    eep

    iphy

    seal

    dysp

    lasi

    a(M

    ED)

    type

    3(E

    DM

    3)

    AD6

    00

    96

    92

    0q1

    3.3

    COL9

    A3Co

    llage

    n9

    alp

    ha-

    3ch

    ain

    Mul

    tipl

    eep

    iphy

    seal

    dysp

    lasi

    a(M

    ED)

    type

    5(E

    DM

    5)

    AD6

    07

    07

    82

    p23–

    24

    MAT

    N3

    Mat

    rilin

    3

    Mul

    tipl

    eep

    iphy

    seal

    dysp

    lasi

    a(M

    ED)

    type

    6(E

    DM

    6)

    AD1

    20

    21

    06

    q13

    COL9

    A1Co

    llage

    n9

    alp

    ha-

    1ch

    ain

    Mul

    tipl

    eep

    iphy

    seal

    dysp

    lasi

    a(M

    ED),

    othe

    rty

    pes

    Som

    eM

    ED

    -like

    case

    su

    nlin

    ked

    tokn

    own

    gen

    esSt

    ickl

    ersy

    ndr

    ome,

    rece

    ssiv

    ety

    peAR

    12

    02

    10

    6q1

    3CO

    L9A1

    Colla

    gen

    9al

    ph

    a-1

    chai

    nFa

    mili

    alhi

    pdy

    spla

    sia

    (Beu

    kes)

    AD1

    42

    66

    94

    q35

    Mul

    tipl

    eep

    iphy

    seal

    dysp

    lasi

    aw

    ith

    mic

    roce

    phal

    yan

    dn

    ysta

    gmus

    (Low

    ry-W

    ood)

    AR2

    26

    96

    0

    See

    also

    mul

    tipl

    eep

    iphy

    seal

    dysp

    lasi

    a,re

    cess

    ive

    type

    (rM

    ED;E

    DM

    4)

    insu

    lfati

    ondi

    sord

    ers

    (gro

    up4

    ),fa

    mili

    alos

    teoc

    hond

    riti

    sdi

    ssec

    ans

    inth

    eag

    grec

    angr

    oup,

    asw

    ella

    sAS

    PED

    inth

    eAc

    rom

    elic

    grou

    p1

    1.

    Met

    aphy

    seal

    dysp

    lasi

    asM

    etap

    hyse

    aldy

    spla

    sia,

    Schm

    idty

    pe(M

    CS)

    AD1

    56

    50

    06

    q21–

    22

    .3CO

    L10

    A1Co

    llage

    n1

    0al

    ph

    a-1

    chai

    n

    Cart

    ilage

    -hai

    rhy

    popl

    asia

    (CH

    H;

    met

    aphy

    seal

    dysp

    lasi

    a,M

    cKus

    ick

    type

    )

    AR2

    50

    25

    09

    p13

    RM

    RP

    RN

    Aco

    mpo

    nen

    tof

    RN

    Ase

    HIn

    clu

    des

    anau

    xeti

    cd

    ysp

    lasi

    a

    Met

    aphy

    seal

    dysp

    lasi

    a,Ja

    nse

    nty

    peAD

    15

    64

    00

    3p2

    2–

    21

    .1PT

    HR

    1PT

    H/P

    THrP

    rece

    pto

    r1

    Acti

    vati

    ng

    mu

    tati

    ons—

    see

    also

    Blo

    mst

    ran

    dd

    ysp

    lasi

    a(g

    rou

    p2

    2,

    23

    )Ei

    ken

    dysp

    lasi

    aAR

    60

    00

    02

    3p2

    2–

    21

    .1PT

    HR

    1PT

    H/P

    THrP

    rece

    pto

    r1

    Acti

    vati

    ng

    mu

    tati

    ons—

    see

    also

    Blo

    mst

    ran

    dd

    ysp

    lasi

    a(g

    rou

    p2

    2,

    23

    )

    TAB

    LEI(

    Con

    tin

    ued)

    Gro

    up/n

    ame

    ofdi

    sord

    erIn

    heri

    tan

    ceM

    IMN

    o.Lo

    cus

    Gen

    ePr

    otei

    nN

    otes

    948 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

  • Met

    aphy

    seal

    dysp

    lasi

    aw

    ith

    pan

    crea

    tic

    insu

    ffici

    ency

    and

    cycl

    icn

    eutr

    open

    ia(S

    hwac

    hman

    –B

    odia

    n–

    Dia

    mon

    dsy

    ndr

    ome,

    SBD

    S)

    AR2

    60

    40

    07

    q11

    SBD

    SSB

    DS

    prot

    ein

    Met

    aphy

    seal

    anad

    yspl

    asia

    type

    1AD

    ,AR

    30

    96

    45

    11

    q22

    .2M

    MP1

    3M

    atri

    xm

    etal

    lopr

    otei

    nas

    e1

    3In

    clu

    des

    SEM

    DM

    isso

    uri

    typ

    e.B

    oth

    dom

    inan

    tan

    dre

    cess

    ive

    mu

    tati

    ons

    des

    crib

    edM

    etap

    hyse

    alan

    adys

    plas

    iaty

    pe2

    AR2

    0q1

    3.1

    2M

    MP9

    Mat

    rix

    met

    allo

    prot

    ein

    ase

    9M

    etap

    hyse

    aldy

    spla

    sia,

    Spah

    rty

    peAR

    25

    04

    00

    Met

    aphy

    seal

    acro

    scyp

    hody

    spla

    sia

    (var

    ious

    type

    s)AR

    25

    02

    15

    Gen

    ocho

    ndr

    omat

    osis

    (typ

    e1

    /typ

    e2

    )AD

    /SP

    13

    73

    60

    Met

    aphy

    seal

    chon

    drom

    atos

    isw

    ith

    D-2

    -hyd

    roxy

    glut

    aric

    acid

    uria

    AR/S

    PSe

    e2

    71

    55

    01

    2.

    Spon

    dylo

    met

    aph

    ysea

    ldy

    spla

    sias

    (SM

    D)

    Spon

    dylo

    ench

    ond

    rody

    spla

    sia

    (SPE

    NCD

    )AR

    27

    15

    50

    19

    p13

    .2AC

    P5Ta

    rtra

    te-r

    esis

    tan

    tac

    idph

    osp

    hat

    ase

    (TR

    AP)

    Incl

    ud

    esco

    mb

    ined

    imm

    un

    odefi

    cien

    cyw

    ith

    auto

    imm

    un

    ity

    and

    spon

    dy

    lom

    etap

    hy

    seal

    dy

    spla

    sia

    (MIM

    60

    79

    44

    )O

    don

    toch

    ondr

    odys

    plas

    ia(O

    DCD

    )AR

    18

    42

    60

    Spon

    dylo

    met

    aphy

    seal

    dysp

    lasi

    a,Su

    tclif

    fety

    peor

    corn

    erfr

    actu

    res

    type

    AD1

    84

    25

    5

    SMD

    wit

    hse

    vere

    gen

    uva

    lgum

    AD1

    84

    25

    3In

    clu

    des

    SMD

    Sch

    mid

    tty

    pe

    and

    SMD

    Alge

    rian

    typ

    eSM

    Dw

    ith

    con

    e-ro

    ddy

    stro

    phy

    AR6

    08

    94

    0SM

    Dw

    ith

    reti

    nal

    dege

    ner

    atio

    n,

    axia

    lty

    peAR

    60

    22

    71

    Dys

    spon

    dylo

    ench

    ondr

    omat

    osis

    SPCh

    eiro

    -spo

    ndy

    loen

    chon

    drom

    atos

    isSP

    See

    also

    grou

    p2

    9Se

    eal

    soSM

    DK

    ozlo

    wsk

    i(gr

    oup

    TRPV

    4)

    diso

    rder

    sin

    grou

    p1

    1as

    wel

    las

    SMD

    Seda

    ghat

    ian

    type

    ingr

    oup

    12

    ;the

    rear

    em

    any

    indi

    vidu

    alre

    port

    sof

    SMD

    vari

    ants

    13

    .Sp

    ondy

    lo-e

    pi-(

    met

    a)-p

    hyse

    aldy

    spla

    sias

    (SE(

    M)D

    )D

    yggv

    e–M

    elch

    ior–

    Clau

    sen

    dysp

    lasi

    a(D

    MC)

    AR2

    23

    80

    01

    8q1

    2–

    21

    .1D

    YMD

    ymec

    linIn

    clu

    des

    Smit

    h–

    McC

    ort

    dy

    spla

    sia

    Imm

    uno-

    osse

    ous

    dysp

    lasi

    a(S

    chim

    ke)

    AR2

    42

    90

    02

    q34–

    36

    SMAR

    CAL1

    SWI/

    SNF-

    rela

    ted

    regu

    lato

    rof

    chro

    mat

    insu

    bfa

    mily

    A-lik

    epr

    otei

    n1

    SED

    ,W

    olco

    tt–

    Ral

    lison

    type

    AR2

    26

    98

    02

    p12

    EIF2

    AK3

    Tran

    slat

    ion

    init

    iati

    onfa

    ctor

    2-a

    lpha

    kin

    ase-

    3SE

    MD

    ,M

    atri

    linty

    peAR

    60

    87

    28

    2p2

    3–

    p24

    MAT

    N3

    Mat

    rilin

    3Se

    eal

    som

    atri

    lin-r

    elat

    edM

    ED

    ingr

    oup

    8SE

    MD

    ,sh

    ort

    limb—

    abn

    orm

    alca

    lcifi

    cati

    onty

    peAR

    27

    16

    65

    1q2

    3D

    DR

    2D

    isco

    idin

    dom

    ain

    rece

    pto

    rfa

    mily

    ,m

    emb

    er2

    See

    also

    oth

    erd

    ysp

    lasi

    asw

    ith

    stip

    plin

    gin

    grou

    p2

    0SE

    Dta

    rda,

    X-lin

    ked

    (SED

    -XL)

    XLR

    31

    34

    00

    Xp2

    2SE

    DL

    Sedl

    inSp

    ondy

    lo-m

    egae

    piph

    ysea

    l-m

    etap

    hyse

    aldy

    spla

    sia

    (SM

    MD

    )AR

    61

    33

    30

    4p1

    6.1

    NK

    X3-2

    NK

    3H

    omeo

    box

    2

    (Contin

    ued)

    WARMAN ET AL. 949

  • Spon

    dylo

    dysp

    last

    icEh

    lers

    –D

    anlo

    ssy

    ndr

    ome

    AR6

    12

    35

    01

    1p1

    1.2

    SLC3

    9A1

    3Zi

    nc

    tran

    spor

    ter

    ZIP

    13

    SPO

    NAS

    TRIM

    Edy

    spla

    sia

    AR2

    71

    51

    0SE

    MD

    wit

    hjo

    int

    laxi

    ty(S

    EMD

    -JL)

    lept

    odac

    tylic

    orH

    all

    type

    AD6

    03

    54

    6

    SEM

    Dw

    ith

    join

    tla

    xity

    (SEM

    D-J

    L)B

    eigh

    ton

    type

    AR2

    71

    64

    0

    Plat

    yspo

    ndy

    ly(b

    rach

    yolm

    ia)

    wit

    ham

    elog

    enes

    isim

    perf

    ecta

    AR6

    01

    21

    6

    Late

    onse

    tSE

    D,

    auto

    som

    alre

    cess

    ive

    type

    AR6

    09

    22

    3

    Bra

    chyo

    lmia

    ,H

    obae

    k,an

    dTo

    ledo

    type

    sAR

    27

    15

    30

    ,2

    71

    63

    0N

    osol

    ogic

    rela

    tion

    ship

    bet

    wee

    nth

    eTo

    lead

    oan

    dH

    obae

    kty

    pes

    ofb

    rach

    yol

    mia

    and

    rece

    ssiv

    ela

    te-o

    nse

    tSE

    Dar

    eu

    ncl

    ear,

    dis

    tin

    ctiv

    ecr

    iter

    iala

    ckin

    gso

    far

    See

    also

    Bra

    chyo

    lmia

    (gro

    up8

    ),O

    psis

    mod

    yspl

    asia

    (gro

    up1

    4),

    SEM

    Ds

    (gro

    up1

    1),

    muc

    opol

    ysac

    char

    idos

    isty

    pe4

    (Mor

    quio

    synd

    rom

    e)an

    dot

    her

    cond

    itio

    nsin

    grou

    p2

    6,

    asw

    ell

    asPP

    RD

    (SED

    wit

    hpr

    ogre

    ssiv

    ear

    thro

    path

    y)in

    grou

    p3

    11

    4.

    Seve

    resp

    ondy

    lody

    spla

    stic

    dysp

    lasi

    asAc

    hon

    drog

    enes

    isty

    pe1

    A(A

    CG1

    A)AR

    20

    06

    00

    14

    q32

    .12

    TRIP

    11

    Gol

    gi-m

    icro

    tub

    ule

    -ass

    ocia

    ted

    prot

    ein

    ,2

    10

    -kD

    a;G

    MAP

    21

    0Sc

    hnec

    ken

    beck

    endy

    spla

    sia

    AR2

    69

    25

    01

    p31

    .3SL

    C35

    D1

    Solu

    teca

    rrie

    rfa

    mily

    35

    mem

    ber

    D1

    ;U

    DP-

    glu

    curo

    nic

    acid

    /U

    DP-

    N-a

    cety

    lgal

    acto

    sam

    ine

    dual

    tran

    spor

    ter

    Spon

    dylo

    met

    aphy

    seal

    dysp

    lasi

    a,Se

    dagh

    atia

    nty

    peAR

    25

    02

    20

    Seve

    resp

    ondy

    lom

    etap

    hyse

    aldy

    spla

    sia

    (SM

    DSe

    dagh

    atia

    n-l

    ike)

    AR7

    q11

    SBD

    SSB

    DS

    gen

    e,fu

    nct

    ion

    still

    uncl

    ear

    Ops

    ism

    odys

    plas

    iaAR

    25

    84

    80

    See

    also

    Than

    atop

    hori

    cdy

    spla

    sia,

    type

    s1

    and

    2(g

    roup

    1);

    ACG

    2an

    dTo

    rran

    cedy

    spla

    sia

    (gro

    up2

    );Fi

    broc

    hond

    roge

    nesi

    s(g

    roup

    3);

    Acho

    ndro

    gene

    sis

    type

    1B

    (ACG

    1B

    ,gro

    up4

    );an

    dM

    etat

    ropi

    cdy

    spla

    sia

    (TR

    PV4

    grou

    p)1

    5.

    Acro

    mel

    icdy

    spla

    sias

    Tric

    horh

    inop

    hala

    nge

    aldy

    spla

    sia

    type

    s1

    /3AD

    19

    03

    50

    8q2

    4TR

    PS1

    Zin

    cfi

    nge

    rtr

    ansc

    ript

    ion

    fact

    orTr

    icho

    rhin

    opha

    lan

    geal

    dysp

    lasi

    aty

    pe2

    (Lan

    ger–

    Gie

    dion

    )AD

    15

    02

    30

    8q2

    4TR

    PS1

    and

    EXT1

    Zin

    cfi

    nge

    rtr

    ansc

    rip

    tion

    fact

    oran

    dE

    xost

    osin

    1M

    icro

    del

    etio

    nsy

    nd

    rom

    e;se

    eal

    soM

    ult

    iple

    Cart

    ilagi

    neo

    us

    Exo

    stos

    esin

    grou

    p2

    8Ac

    roca

    pito

    fem

    oral

    dysp

    lasi

    aAR

    60

    77

    78

    2q3

    3–

    q35

    IHH

    Indi

    anhe

    dgeh

    ogCr

    anio

    ecto

    derm

    aldy

    spla

    sia

    (Lev

    in–

    Sen

    sen

    bren

    ner

    )ty

    pe1

    AR2

    18

    33

    03

    q21

    IFT1

    22

    Intr

    aflag

    ella

    rtr

    ansp

    ort

    12

    2(C

    hlam

    yd

    omon

    as,

    hom

    olog

    of)

    Cran

    ioec

    tode

    rmal

    dysp

    lasi

    a(L

    evin

    –Se

    nse

    nbr

    enn

    er)

    type

    2AR

    61

    36

    10

    2p2

    4.1

    WD

    R3

    5W

    Dre

    peat

    -con

    tain

    ing

    prot

    ein

    35

    TAB

    LEI(

    Con

    tin

    ued)

    Gro

    up/n

    ame

    ofdi

    sord

    erIn

    heri

    tan

    ceM

    IMN

    o.Lo

    cus

    Gen

    ePr

    otei

    nN

    otes

    950 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

  • Gel

    eoph

    ysic

    dysp

    lasi

    aAR

    23

    10

    50

    9q3

    4.2

    ADAM

    TSL2

    ADAM

    TS-li

    kep

    rote

    in2

    Gel

    eoph

    ysic

    dysp

    lasi

    a,ot

    her

    type

    sAR

    Un

    linke

    dto

    ADAM

    TSL2

    Acro

    mic

    ric

    dysp

    lasi

    aAD

    10

    23

    70

    Incl

    ud

    esac

    rola

    ryn

    geal

    dy

    spla

    sia,

    pre

    viou

    sly

    know

    nas

    Fan

    tasy

    Isla

    nd

    dy

    spla

    sia

    orTa

    ttoo

    dy

    spla

    sia

    Acro

    dyso

    stos

    isAD

    10

    18

    00

    Ange

    l-sha

    ped

    phal

    ango

    -epi

    phys

    eal

    dysp

    lasi

    a(A

    SPED

    )AD

    10

    58

    35

    Pos

    sib

    lyre

    late

    dor

    alle

    licto

    Bra

    chy

    dac

    tyly

    typ

    eC

    Sald

    ino–

    Mai

    nze

    rdy

    spla

    sia

    AR2

    66

    92

    0Se

    eal

    sosh

    ort

    rib

    dysp

    lasi

    asgr

    oup

    16

    .Ac

    rom

    esom

    elic

    dysp

    lasi

    asAc

    rom

    esom

    elic

    dysp

    lasi

    aty

    peM

    arot

    eaux

    (AM

    DM

    )AR

    60

    28

    75

    9p1

    3–

    12

    NPR

    2N

    atri

    uret

    icp

    epti

    de

    rece

    ptor

    2G

    rebe

    dysp

    lasi

    aAR

    20

    07

    00

    20

    q11

    .2G

    DF5

    Gro

    wth

    and

    diff

    eren

    tiat

    ion

    fact

    or5

    Incl

    ud

    esac

    rom

    esom

    elic

    dy

    spla

    sia

    Hu

    nte

    r-Th

    omp

    son

    typ

    e;se

    eal

    soB

    rach

    yd

    acty

    lies

    (gro

    up

    34

    )Fi

    bula

    rhy

    popl

    asia

    and

    com

    plex

    brac

    hyda

    ctyl

    y(D

    uPa

    n)

    AR2

    28

    90

    02

    0q1

    1.2

    GD

    F5G

    row

    than

    dd

    iffer

    enti

    atio

    nfa

    ctor

    5Se

    eal

    soB

    rach

    yd

    acty

    lies

    (gro

    up

    34

    )Ac

    rom

    esom

    elic

    dysp

    lasi

    aw

    ith

    gen

    ital

    anom

    alie

    sAR

    60

    94

    41

    4q2

    3–

    24

    BM

    PR1

    BB

    one

    mor

    phog

    enet

    icpr

    otei

    nre

    cep

    tor

    1B

    Acro

    mes

    omel

    icdy

    spla

    sia,

    Ose

    bold

    -Rem

    ondi

    ni

    type

    AD1

    12

    91

    0

    17

    .M

    esom

    elic

    and

    rhiz

    o-m

    esom

    elic

    dysp

    lasi

    asD

    ysch

    ondr

    oste

    osis

    (Ler

    i–W

    eill)

    Pseu

    do-A

    D1

    27

    30

    0Xp

    ter-

    p22

    .32

    SHO

    XSh

    ort

    stat

    ure—

    hom

    eob

    oxge

    ne

    Incl

    ud

    esR

    ein

    har

    dt–

    Pfe

    iffer

    dy

    spla

    sia,

    MIM

    19

    14

    00

    Lan

    ger

    type

    (hom

    ozyg

    ous

    dysc

    hon

    dros

    teos

    is)

    Pseu

    do-A

    R2

    49

    70

    0Xp

    ter-

    p22

    .32

    SHO

    XSh

    ort

    stat

    ure—

    hom

    eob

    oxge

    ne

    Om

    odys

    plas

    iaAR

    25

    83

    15

    13

    q31–

    q32

    GPC

    6G

    lypi

    can

    6E

    xist

    ence

    of‘‘d

    omin

    ant

    omod

    ysp

    lasi

    a’’(

    MIM

    16

    47

    45

    )re

    mai

    ns

    tob

    eco

    nfi

    rmed

    Rob

    inow

    syn

    drom

    e,re

    cess

    ive

    type

    AR2

    68

    31

    09

    q22

    RO

    R2

    Rec

    epto

    rty

    rosi

    ne

    kin

    ase-

    like

    orph

    anre

    cep

    tor

    2In

    clu

    des

    pre

    viou

    sco

    sto-

    vert

    ebra

    lseg

    men

    tati

    ond

    efec

    tw

    ith

    mes

    omel

    ia(C

    OVE

    SDE

    M);

    see

    also

    bra

    chy

    dac

    tyly

    typ

    eB

    Rob

    inow

    syn

    drom

    e,do

    min

    ant

    type

    AD1

    80

    70

    0M

    esom

    elic

    dysp

    lasi

    a,K

    orea

    nty

    peAD

    2q2

    4–

    32

    Dup

    licat

    ion

    inH

    OXD

    gen

    ecl

    ust

    erM

    esom

    elic

    dysp

    lasi

    a,K

    anta

    putr

    aty

    peAD

    15

    62

    32

    2q2

    4–

    32

    Dup

    licat

    ion

    sin

    HO

    XDge

    ne

    clu

    ster

    Mes

    omel

    icdy

    spla

    sia,

    Nie

    verg

    elt

    type

    AD1

    63

    40

    0M

    esom

    elic

    dysp

    lasi

    a,K

    ozlo

    wsk

    i-Rea

    rdon

    type

    AR2

    49

    71

    0

    Mes

    omel

    icdy

    spla

    sia

    wit

    hac

    ral

    syn

    osto

    ses

    (Ver

    loes

    –D

    avid

    –Pf

    eiff

    erty

    pe)

    AD6

    00

    38

    38

    q13

    SULF

    1an

    dSL

    CO5

    A1H

    epar

    ansu

    lfate

    6-O

    -en

    dosu

    lfata

    se1

    and

    solu

    teca

    rrie

    ror

    gan

    ican

    ion

    tran

    s-po

    rter

    fam

    ilym

    emb

    er5

    A1

    Mic

    rod

    elet

    ion

    syn

    dro

    me

    invo

    lvin

    gtw

    oad

    jace

    nt

    gen

    es

    (Contin

    ued)

    WARMAN ET AL. 951

  • Mes

    omel

    icdy

    spla

    sia,

    Sava

    rira

    yan

    type

    (Tri

    angu

    lar

    Tibi

    a–Fi

    bula

    rAp

    lasi

    a)SP

    60

    52

    74

    Pos

    sib

    lyre

    late

    dto

    Nie

    verg

    elt

    dy

    spla

    sia.

    On

    eca

    sere

    por

    ted

    wit

    h2

    q1

    1.2

    mic

    rod

    elet

    ion

    ofu

    ncl

    ear

    sign

    ifica

    nce

    18

    .B

    ent

    bon

    esdy

    spla

    sias

    Cam

    pom

    elic

    dysp

    lasi

    a(C

    D)

    AD1

    14

    29

    01

    7q2

    4.3

    –2

    5.1

    SOX9

    SRY-

    box

    9In

    clu

    des

    acam

    pom

    elic

    cam

    pom

    elic

    dy

    spla

    sia

    (ACD

    )as

    wel

    las

    mild

    cam

    pom

    elic

    dy

    spla

    sia

    (MIM

    60

    21

    96

    )St€ uv

    e–W

    iede

    man

    ndy

    spla

    sia

    AR6

    01

    55

    95

    p13

    .1LI

    FRLe

    ukem

    iain

    hib

    itor

    yfa

    ctor

    rece

    pto

    rIn

    clu

    des

    form

    erly

    neo

    nat

    alSc

    hw

    artz

    –Ja

    mp

    elsy

    nd

    rom

    eor

    SJS

    typ

    e2

    Kyp

    hom

    elic

    dysp

    lasi

    a,se

    vera

    lfo

    rms

    21

    13

    50

    Pro

    bab

    lyh

    eter

    ogen

    eou

    sB

    ent

    bone

    sat

    birt

    hca

    nbe

    seen

    ina

    vari

    ety

    ofco

    ndit

    ions

    ,in

    clud

    ing

    oste

    ogen

    esis

    impe

    rfec

    ta,

    Antl

    ey–

    Bix

    ler

    synd

    rom

    e,ca

    rtila

    ge-h

    air

    hypo

    plas

    ia,

    Cum

    min

    gssy

    ndro

    me,

    hypo

    phos

    phat

    asia

    ,dy

    sseg

    men

    tal

    dysp

    lasi

    a,TD

    ,ATD

    ,and

    othe

    rs1

    9.

    Slen

    der

    bon

    edy

    spla

    sia

    grou

    p3

    -Msy

    ndr

    ome

    (3M

    1)

    AR2

    73

    75

    06

    p21

    .1CU

    L7Cu

    llin

    7In

    clu

    des

    dol

    ich

    osp

    ond

    ylic

    dy

    spla

    sia

    and

    Yaku

    tsh

    ort

    stat

    ure

    syn

    dro

    me

    3-M

    syn

    drom

    e(3

    M2

    )AR

    61

    29

    21

    2q3

    5O

    BSL

    1O

    bscu

    rin

    -like

    1K

    enn

    y–

    Caff

    eydy

    spla

    sia

    type

    1AR

    24

    44

    60

    1q4

    2–

    q43

    TBCE

    Tubu

    lin-s

    peci

    fic

    chap

    eron

    eE

    Ken

    ny–

    Caff

    eydy

    spla

    sia

    type

    2AD

    12

    70

    00

    Mic

    roce

    phal

    icos

    teod

    yspl

    asti

    cpr

    imor

    dial

    dwar

    fism

    type

    1/3

    (MO

    PD1

    )AR

    21

    07

    10

    2q

    Incl

    ud

    esTa

    yb

    i–Li

    nd

    erce

    ph

    alos

    kele

    tal

    dy

    spla

    sia

    Mic

    roce

    phal

    icos

    teod

    yspl

    asti

    cpr

    imor

    dial

    dwar

    fism

    type

    2(M

    OPD

    2;

    Maj

    ewsk

    ity

    pe)

    AR2

    10

    72

    02

    1q

    PCN

    T2Pe

    rice

    ntr

    in2

    IMAG

    Esy

    ndr

    ome

    (in

    trau

    teri

    ne

    grow

    thre

    tard

    atio

    n,

    met

    aphy

    seal

    dysp

    lasi

    a,ad

    ren

    alhy

    popl

    asia

    ,an

    dge

    nit

    alan

    omal

    ies)

    XL/A

    D3

    00

    29

    0P

    ossi

    bly

    het

    erog

    eneo

    us

    Ost

    eocr

    anio

    sten

    osis

    SP6

    02

    36

    1O

    ccu

    rren

    cein

    sib

    sre

    por

    ted

    ,in

    her

    itan

    ceu

    ncl

    ear

    Hal

    lerm

    ann–

    Stre

    iffsy

    ndr

    ome

    AR2

    34

    10

    0M

    uta

    tion

    sin

    GJA

    1re

    por

    ted

    inon

    eca

    seon

    lySe

    eal

    soCe

    rebr

    o-ar

    thro

    -dig

    ital

    dysp

    lasi

    a2

    0.

    Dys

    plas

    ias

    wit

    hm

    ulti

    ple

    join

    tdi

    sloc

    atio

    ns

    Des

    buqu

    ois

    dysp

    lasi

    a(w

    ith

    acce

    ssor

    yos

    sifi

    cati

    once

    nte

    rin

    digi

    t2

    )AR

    25

    14

    50

    17

    q25

    .3CA

    NT1

    Des

    buqu

    ois

    dysp

    lasi

    aw

    ith

    shor

    tm

    etac

    arpa

    lsan

    del

    onga

    ted

    phal

    ange

    s(K

    imty

    pe)

    AR2

    51

    45

    01

    7q2

    5.3

    CAN

    T1

    TAB

    LEI(

    Con

    tin

    ued)

    Gro

    up/n

    ame

    ofdi

    sord

    erIn

    heri

    tan

    ceM

    IMN

    o.Lo

    cus

    Gen

    ePr

    otei

    nN

    otes

    952 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

  • Des

    buqu

    ois

    dysp

    lasi

    a(o

    ther

    vari

    ants

    wit

    hor

    wit

    hout

    acce

    ssor

    yos

    sifi

    cati

    once

    nte

    r)

    ARP

    rob

    ably

    gen

    etic

    ally

    het

    erog

    eneo

    us

    Pseu

    dodi

    astr

    oph

    icdy

    spla

    sia

    AR2

    64

    18

    0Se

    eal

    soSE

    Dw

    ith

    cong

    enit

    aldi

    sloc

    atio

    ns,

    CHST

    3ty

    pe(g

    roup

    4);

    Atel

    oste

    ogen

    esis

    type

    3an

    dLa

    rsen

    synd

    rom

    e(g

    roup

    6);

    SEM

    Ds

    wit

    hjo

    int

    laxi

    ty(g

    roup

    11

    )2

    1.

    Chon

    drod

    yspl

    asia

    pun

    ctat

    a(C

    DP)

    grou

    pCD

    P,X-

    linke

    ddo

    min

    ant,

    Con

    radi

    –H€ un

    erm

    ann

    type

    (CD

    PX2

    )XL

    D3

    02

    96

    0Xp

    11

    EBP

    Emop

    amil-

    bin

    din

    gp

    rote

    in

    CDP,

    X-lin

    ked

    rece

    ssiv

    e,br

    achy

    tele

    phal

    angi

    cty

    pe(C

    DPX

    1)

    XLR

    30

    29

    50

    Xp2

    2.3

    ARSE

    Aryl

    sulfa

    tase

    E

    Con

    gen

    ital

    hem

    idys

    plas

    ia,

    icht

    hyos

    is,

    limb

    defe

    cts

    (CH

    ILD

    )XL

    D3

    08

    05

    0Xp

    11

    NSD

    HL

    NAD

    (P)H

    ster

    oid

    dehy

    drog

    enas

    e-lik

    ep

    rote

    inCo

    nge

    nit

    alhe

    mid

    yspl

    asia

    ,ic

    hthy

    osis

    ,lim

    bde

    fect

    s(C

    HIL

    D)

    XLD

    30

    80

    50

    Xq2

    8EB

    PEm

    opam

    il-bi

    nd

    ing

    pro

    tein

    Gre

    enbe

    rgdy

    spla

    sia

    AR2

    15

    14

    01

    q42

    .1LB

    RLa

    min

    Bre

    cep

    tor,

    3-b

    eta-

    hyd

    roxy

    ster

    old

    elta

    (14

    )-re

    duct

    ase

    Incl

    ud

    esh

    yd

    rop

    s-ec

    top

    icca

    lcifi

    cati

    on-m

    oth

    -eat

    enap

    pea

    ran

    ced

    ysp

    lasi

    a(H

    EM

    )an

    dd

    app

    led

    dia

    ph

    yse

    ald

    ysp

    lasi

    aR

    hizo

    mel

    icCD

    Pty

    pe1

    AR2

    15

    10

    06

    q22–

    24

    PEX7

    Pero

    xiso

    mal

    PTS

    2re

    cep

    tor

    Rhi

    zom

    elic

    CDP

    type

    2AR

    22

    27

    65

    1q4

    2D

    HPA

    TD

    ihyd

    roxy

    acet

    onep

    hos

    ph

    ate

    acyl

    tran

    sfer

    ase

    (DH

    APAT

    )R

    hizo

    mel

    icCD

    Pty

    pe3

    AR6

    00

    12

    12

    q31

    AGPS

    Alky

    lgly

    cero

    ne-

    ph

    osp

    hat

    esy

    nth

    ase

    (AG

    PS)

    CDP

    tibi

    al-m

    etac

    arpa

    lty

    peAD

    /AR

    11

    86

    51

    Nos

    olog

    icst

    atu

    su

    nce

    rtai

    nAs

    tley

    -Ken

    dall

    dysp

    lasi

    aAR

    ?R

    elat

    ion

    ship

    toO

    Ian

    dto

    Gre

    enb

    erg

    dy

    spla

    sia

    un

    clea

    rN

    ote

    that

    stip

    plin

    gca

    noc

    curi

    nse

    vera

    lsyn

    drom

    essu

    chas

    Zellw

    eger

    ,Sm

    ith–

    Lem

    li–O

    pitz

    and

    othe

    rs.S

    eeal

    sode

    smos

    tero

    losi

    sas

    wel

    las

    SEM

    Dsh

    ortl

    imb—

    abno

    rmal

    calc

    ifica

    tion

    type

    ingr

    oup

    11

    22

    .N

    eon

    atal

    oste

    oscl

    erot

    icdy

    spla

    sias

    Blo

    mst

    ran

    ddy

    spla

    sia

    AR2

    15

    04

    53

    p22–

    21

    .1PT

    HR

    1PT

    H/P

    THrP

    rece

    pto

    r1

    Cau

    sed

    by

    rece

    ssiv

    ein

    acti

    vati

    ng

    mu

    tati

    ons;

    see

    also

    Eik

    end

    ysp

    lasi

    aan

    dJa

    nse

    nd

    ysp

    lasi

    aD

    esm

    oste

    rolo

    sis

    AR6

    02

    39

    81

    p33–

    31

    .1D

    HCR

    24

    3-b

    eta-

    hydr

    oxy

    ster

    olde

    lta-

    24

    -red

    uct

    ase

    See

    also

    oth

    erst

    erol

    -m

    etab

    olis

    mre

    late

    dco

    nd

    itio

    ns

    Caff

    eydi

    seas

    e(i

    ncl

    udin

    gin

    fan

    tile

    and

    atte

    nua

    ted

    form

    s)AD

    11

    40

    00

    17

    q21–

    22

    COL1

    A1Co

    llage

    n1

    ,al

    ph

    a-1

    chai

    nSe

    eal

    soos

    teog

    enes

    isim

    per

    fect

    are

    late

    dto

    colla

    gen

    1ge

    nes

    (gro

    up

    24

    )Ca

    ffey

    dise

    ase

    (sev

    ere

    vari

    ants

    wit

    hpr

    enat

    alon

    set)

    AR1

    14

    00

    0

    Rai

    ne

    dysp

    lasi

    a(l

    etha

    lan

    dn

    on-le

    thal

    form

    s)AR

    25

    97

    75

    7p2

    2FA

    M2

    0C

    Incl

    ud

    esle

    thal

    and

    non

    -leth

    alca

    ses

    See

    also

    Astl

    ey-K

    end

    alld

    yspl

    asia

    and

    CDPs

    ingr

    oup

    21

    23

    .In

    crea

    sed

    bon

    ede

    nsi

    tygr

    oup

    (wit

    hout

    mod

    ifica

    tion

    ofbo

    ne

    shap

    e)O

    steo

    petr

    osis

    ,se

    vere

    neo

    nat

    alor

    infa

    nti

    lefo

    rms

    (OPT

    B1

    )AR

    25

    97

    00

    11

    q13

    TCIR

    G1

    Subu

    nit

    ofAT

    Pas

    ep

    roto

    npu

    mp

    Ost

    eope

    tros

    is,

    seve

    ren

    eon

    atal

    orin

    fan

    tile

    form

    s(O

    PTB

    4)

    AR6

    11

    49

    01

    6p1

    3CL

    CN7

    Chlo

    ride

    chan

    nel

    7

    ( Contin

    ued)

    WARMAN ET AL. 953

  • Ost

    eope

    tros

    is,

    infa

    nti

    lefo

    rm,

    wit

    hn

    ervo

    ussy

    stem

    invo

    lvem

    ent

    (OPT

    B5

    )AR

    25

    97

    20

    6q2

    1O

    STM

    1G

    ray

    leth

    al/o

    steo

    pet

    rosi

    sas

    soci

    ated

    tran

    smem

    bra

    ne

    prot

    ein

    Ost

    eope

    tros

    is,

    inte

    rmed

    iate

    form

    ,os

    teoc

    last

    -poo

    r(O

    PTB

    2)

    AR2

    59

    71

    01

    3q1

    4.1

    1R

    ANK

    L(T

    NFS

    F11

    )R

    ecep

    tor

    acti

    vato

    rof

    NF-

    kap

    pa-

    Blig

    and

    (tum

    orn

    ecro

    sis

    fact

    orli

    gan

    dsu

    perf

    amily

    ,mem

    ber

    11

    )O

    steo

    petr

    osis

    ,in

    fan

    tile

    form

    ,os

    teoc

    last

    -poo

    rw

    ith

    imm

    unog

    lobu

    linde

    fici

    ency

    (OPT

    B7

    )

    AR6

    12

    30

    21

    8q2

    1.3

    3R

    ANK

    (TN

    FRSF

    11

    A)R

    ecep

    tor

    acti

    vato

    rof

    NF-

    kapp

    a-B

    See

    also

    fam

    ilial

    exp

    ansi

    leos

    teol

    ysi

    sin

    Ost

    eoly

    sis

    grou

    p(g

    rou

    p2

    8)

    Ost

    eope

    tros

    is,

    inte

    rmed

    iate

    form

    (OPT

    B6

    )AR

    61

    14

    97

    17

    q21

    .3PL

    EKH

    M1

    Plec

    kstr

    inho

    mol

    ogy

    dom

    ain

    -con

    tain

    ing

    pro

    tein

    ,fa

    mily

    M,

    mem

    ber

    1O

    steo

    petr

    osis

    ,in

    term

    edia

    tefo

    rm(O

    PTA2

    )AR

    25

    97

    10

    16

    p13

    CLCN

    7Ch

    lori

    dech

    ann

    elp

    um

    p

    Ost

    eope

    tros

    isw

    ith

    ren

    altu

    bula

    rac

    idos

    is(O

    PTB

    3)

    AR2

    59

    73

    08

    q22

    CA2

    Carb

    onic

    anh

    yd

    rase

    2

    Ost

    eope

    tros

    is,

    late

    -on

    set

    form

    type

    1(O

    PTA1

    )AD

    60

    76

    34

    11

    q13

    .4LR

    P5Lo

    wde

    nsi

    tylip

    opro

    tein

    rece

    ptor

    -rel

    ated

    pro

    tein

    5In

    clu

    des

    Wor

    thty

    pe

    oste

    oscl

    eros

    is(M

    IM1

    44

    75

    0)

    Ost

    eope

    tros

    is,

    late

    -on

    set

    form

    type

    2(O

    PTA2

    )AD

    16

    66

    00

    16

    p13

    CLCN

    7Ch

    lori

    dech

    ann

    el7

    Ost

    eope

    tros

    isw

    ith

    ecto

    derm

    aldy

    spla

    sia

    and

    imm

    une

    defe

    ct(O

    LED

    AID

    )XL

    30

    03

    01

    Xq2

    8IK

    BK

    G(N

    EMO

    )In

    hibi

    tor

    ofka

    pp

    alig

    ht

    poly

    pept

    ide

    gen

    een

    han

    cer,

    kin

    ase

    ofO

    steo

    petr

    osis

    ,m

    oder

    ate

    form

    wit

    hde

    fect

    ive

    leuc

    ocyt

    ead

    hesi

    on(L

    AD3

    )AR

    61

    28

    40

    11

    q12

    FER

    MT3

    (KIN

    D3

    )Fe

    rmit

    in3

    (Kin

    dlin

    3)

    Ost

    eope

    tros

    is,

    mod

    erat

    efo

    rmw

    ith

    defe

    ctiv

    ele

    ucoc

    yte

    adhe

    sion

    AR6

    12

    84

    01

    1q1

    3R

    ASG

    RP2

    (Cal

    DAG

    -GEF

    1)

    Ras

    guan

    yln

    ucl

    eoti

    de-

    rele

    asin

    gp

    rote

    in2

    Pykn

    odys

    osto

    sis

    AR2

    65

    80

    01

    q21

    CTSK

    Cath

    epsi

    nK

    Ost

    eopo

    ikilo

    sis

    AD1

    55

    95

    01

    2q1

    4LE

    MD

    3LE

    Mdo

    mai

    n-c

    onta

    inin

    g3

    Incl

    ud

    esB

    usc

    hke

    –O

    llen

    dor

    ffsy

    nd

    rom

    e(M

    IM1

    66

    70

    0)

    Mel

    orhe

    osto

    sis

    wit

    hos

    teop

    oiki

    losi

    sAD

    15

    59

    50

    12

    q14

    LEM

    D3

    LEM

    dom

    ain

    -con

    tain

    ing

    3In

    clu

    des

    mix

    edsc

    lero

    sin

    gb

    one

    dy

    spla

    sia

    Ost

    eopa

    thia

    stri

    ata

    wit

    hcr

    ania

    lsc

    lero

    sis

    (OSC

    S)XL

    D3

    00

    37

    3Xq

    11

    .1W

    TXFA

    M1

    23

    B

    Mel

    orhe

    osto

    sis

    SPN

    oge

    rmlin

    eLE

    MD

    3m

    uta

    tion

    sid

    enti

    fied

    sofa

    rD

    ysos

    teos

    cler

    osis

    AR2

    24

    30

    0P

    ossi

    bly

    rela

    ted

    to‘‘o

    steo

    scle

    roti

    cm

    etap

    hy

    seal

    dy

    spla

    sia’

    ’O

    steo

    mes

    opyk

    nos

    isAD

    16

    64

    50

    Ost

    eope

    tros

    isw

    ith

    infa

    nti

    len

    euro

    axon

    aldy

    spla

    sia

    AR?

    60

    03

    29

    Sam

    eas

    oste

    opet

    rosi

    sw

    ith

    ner

    vou

    ssy

    stem

    invo

    lvem

    ent

    (see

    abov

    e)?

    TAB

    LEI(

    Con

    tin

    ued

    )

    Gro

    up/n

    ame

    ofdi

    sord

    erIn

    heri

    tan

    ceM

    IMN

    o.Lo

    cus

    Gen

    ePr

    otei

    nN

    otes

    954 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

  • 24

    .In

    crea

    sed

    bon

    ede

    nsi

    tygr

    oup

    wit

    hm

    etap

    hyse

    al

    and/

    ordi

    aphy

    seal

    invo

    lvem

    ent

    Cran

    iom

    etap

    hyse

    aldy

    spla

    sia,

    auto

    som

    aldo

    min

    ant

    type

    AD1

    23

    00

    05

    p15

    .2–

    14

    .2AN

    KH

    Hom

    olog

    ofm

    ouse

    ANK

    (an

    kylo

    sis)

    gen

    eG

    ain

    offu

    nct

    ion

    mu

    tati

    ons

    Dia

    phys

    eal

    dysp

    lasi

    aCa

    mur

    ati-E

    nge

    lman

    nAD

    13

    13

    00

    19

    q13

    TGFb

    eta1

    Tran

    sfor

    min

    ggr

    owth

    fact

    orbe

    ta1

    Hem

    atod

    iaph

    ysea

    ldy

    spla

    sia

    Gho

    sal

    AR2

    31

    09

    57

    q34

    TBXA

    S1Th

    rom

    boxa

    ne

    Asy

    nth

    ase

    1H

    yper

    trop

    hic

    oste

    oart

    hrop

    athy

    AR2

    59

    10

    04

    q34–

    35

    HPG

    D1

    5-a

    lpha

    -hy

    drox

    ypro

    stag

    lan

    din

    dehy

    drog

    enas

    e

    Incl

    udes

    cran

    io-o

    steo

    arth

    ropa

    thy

    and

    case

    sof

    rece

    ssiv

    ep

    ach

    yd

    erm

    oper

    iost

    osis

    Pach

    yder

    mop

    erio

    stos

    is(h

    yper

    trop

    hic

    oste

    oart

    hrop

    ath

    y,pr

    imar

    y,au

    toso

    mal

    dom

    inan

    t)

    AD1

    67

    10

    0R

    elat

    ion

    ship

    tore

    cess

    ive

    form

    (MIM

    25

    91

    00

    ,H

    PG

    Dd

    efici

    ency

    )u

    ncl

    ear

    Ocu

    lode

    nto

    osse

    ous

    dysp

    lasi

    a(O

    DO

    D)

    mild

    type

    AD1

    64

    20

    06

    q22–

    23

    GJA

    1G

    apju

    nct

    ion

    pro

    tein

    alph

    a-1

    Ocu

    lode

    nto

    osse

    ous

    dysp

    lasi

    a(O

    DO

    D)

    seve

    rety

    peAR

    25

    78

    50

    Pos

    sib

    lyh

    omoz

    ygo

    us

    form

    ofm

    ildO

    DO

    DO

    steo

    ecta

    sia

    wit

    hhy

    perp

    hosp

    hata

    sia

    (juv

    enile

    Page

    tdi

    seas

    e)AR

    23

    90

    00

    8q2

    4O

    PGO

    steo

    prot

    eger

    in

    Scle

    rost

    eosi

    sAR

    26

    95

    00

    17

    q12–

    21

    SOST

    Scle

    rost

    inEn

    dost

    eal

    hype

    rost

    osis

    ,va

    nB

    uche

    mty

    peAR

    23

    91

    00

    17

    q12–

    21

    SOST

    Scle

    rost

    inSp

    ecifi

    c5

    2kb

    del

    etio

    nd

    own

    stre

    amof

    SOST

    Tric

    hode

    nto

    osse

    ous

    dysp

    lasi

    aAD

    19

    03

    20

    17

    q21

    DLX

    3D

    ista

    l-les

    sh

    omeo

    box

    3Cr

    anio

    met

    aphy

    seal

    dysp

    lasi

    a,au

    toso

    mal

    rece

    ssiv

    ety

    peAR

    21

    84

    00

    6q2

    1–

    22

    Dia

    phys

    eal

    med

    ulla

    ryst

    enos

    isw

    ith

    bon

    em

    alig

    nan

    cyAD

    11

    22

    50

    9p2

    1–

    p22

    Cran

    iodi

    aphy

    seal

    dysp

    lasi

    aAD

    12

    28

    60

    Cran

    iom

    etad

    iap

    hyse

    aldy

    spla

    sia,

    Wor

    mia

    nbo

    ne

    type

    AR—

    Endo

    stea

    lsc

    lero

    sis

    wit

    hce

    rebe

    llar

    hypo

    plas

    iaAR

    21

    30

    02

    Len

    z–M

    ajew

    ski

    hype

    rost

    otic

    dysp

    lasi

    aSP

    15

    10

    50

    Met

    aphy

    seal

    dysp

    lasi

    a,B

    raun

    –Ti

    nsc

    hert

    type

    XL6

    05

    94

    6

    Pyle

    dise

    ase

    AR2

    65

    90

    02

    5.

    Ost

    eoge

    nes

    isim

    perf

    ecta

    and

    decr

    ease

    dbo

    ne

    den

    sity

    grou

    pFo

    rco

    mm

    ents

    the

    clas

    sific

    atio

    nof

    oste

    ogen

    esis

    impe

    rfec

    ta,

    plea

    sere

    fer

    toth

    ete

    xtO

    steo

    gen

    esis

    impe

    rfec

    ta,

    non

    -def

    orm

    ing

    form

    (OI

    type

    1)

    ADCO

    L1A1

    ,CO

    L1A2

    COL1

    A1:

    colla

    gen

    1al

    pha-

    1ch

    ain

    ,CO

    L1A2

    :co

    llage

    n1

    alp

    ha-

    2ch

    ain

    ,CR

    TAP:

    cart

    ilage

    -ass

    ocia

    ted

    prot

    ein

    ,LE

    PR

    E1

    :le

    uci

    ne

    prol

    ine-

    enri

    ched

    pro

    teog

    lyca

    n(l

    epre

    can

    )1

    ,PP

    IB:p

    epti

    dy

    lpro

    lyl

    isom

    eras

    eB

    (cy

    clop

    hili

    nB

    ),FK

    BP1

    0:

    FK5

    06

    bin

    din

    gp

    rote

    in1

    0,

    SER

    PIN

    H:

    serp

    inp

    epti

    das

    ein

    hibi

    tor

    clad

    eH

    1,

    SP7

    :SP

    7tr

    ansc

    ript

    ion

    fact

    or(O

    ster

    ix)

    Ost

    eoge

    nes

    isim

    perf

    ecta

    ,pe

    rin

    atal

    leth

    alfo

    rm(O

    Ity

    pe2

    )AD

    ,AR

    COL1

    A1,

    COL1

    A2,

    CRTA

    P,LE

    PRE1

    ,PPI

    BO

    steo

    gen

    esis

    impe

    rfec

    ta,

    prog

    ress

    ivel

    yde

    form

    ing

    type

    (OI

    type

    3)

    AD,

    ARCO

    L1A1

    ,CO

    L1A2

    ,CR

    TAP,

    LEPR

    E1,

    PPIB

    ,FK

    BP1

    0,

    SER

    PIN

    H1

    See

    also

    Bru

    cksy

    nd

    rom

    ety

    pe

    1(b

    elow

    )

    Ost

    eoge

    nes

    isim

    perf

    ecta

    ,m

    oder

    ate

    form

    (OI

    type

    4)

    AD,

    ARCO

    L1A1

    ,CO

    L1A2

    ,CR

    TAP,

    FKB

    P10

    ,SP

    7

    (Contin

    ued)

    WARMAN ET AL. 955

  • Ost

    eoge

    nes

    isim

    perf

    ecta

    wit

    hca

    lcifi

    cati

    onof

    the

    inte

    ross

    eou

    sm

    embr

    anes

    and/

    orhy

    pert

    roph

    icca

    llus

    (OI

    type

    5)

    AD6

    10

    96

    7

    Ost

    eoge

    nes

    isim

    perf

    ecta

    ,ot

    her

    type

    sB

    ruck

    syn

    drom

    ety

    pe1

    (BS1

    )AR

    25

    94

    50

    17

    q21

    FKB

    P10

    FK5

    06

    bin

    din

    gp

    rote

    in1

    0Se

    eau

    toso

    mal

    rece

    ssiv

    eO

    I,ab

    ove;

    intr

    afam

    ilial

    vari

    abili

    tyb

    etw

    een

    OI3

    and

    BS1

    doc

    um

    ente

    dB

    ruck

    syn

    drom

    ety

    pe2

    (BS2

    )AR

    60

    92

    20

    3q2

    3–

    24

    PLO

    D2

    Proc

    olla

    gen

    lysy

    lhy

    drox

    ylas

    e2

    Ost

    eopo

    rosi

    s-ps

    eudo

    glio

    ma

    syn

    drom

    eAR

    25

    97

    70

    11

    q12–

    13

    LRP5

    LDL-

    rece

    ptor

    rela

    ted

    prot

    ein

    5Ca

    lvar

    ial

    doug

    hnut

    lesi

    ons

    wit

    hbo

    ne

    frag

    ility

    AD1

    26

    55

    0

    Idio

    path

    icju

    ven

    ileos

    teop

    oros

    isSP

    25

    97

    50

    Som

    ep

    atie

    nts

    rep

    orte

    dw

    ith

    het

    eroz

    ygo

    us

    mu

    tati

    ons

    inth

    eLR

    P5ge

    ne

    Cole

    -Car

    pen

    ter

    dysp

    lasi

    a(b

    one

    frag

    ility

    wit

    hcr

    anio

    syn

    osto

    sis)

    SP1

    12

    24

    0Se

    eal

    socr

    anio

    syn

    osto

    sis

    syn

    dro

    mes

    ingr

    oup

    30

    Spon

    dylo

    -ocu

    lar

    dysp

    lasi

    aAR

    60

    58

    22

    Un

    linke

    dto

    colla

    gen

    1an

    dco

    llage

    n2

    gen

    esor

    LRP5

    Ost

    eope

    nia

    wit

    hra

    diol

    ucen

    tle

    sion

    sof

    the

    man

    dibl

    eAD

    16

    62

    60

    Ehle

    rs–

    Dan

    los

    syn

    drom

    e,pr

    oger

    oid

    form

    AR1

    30

    07

    05

    q35

    B4

    GAL

    T7Xy

    losy

    lpro

    tein

    4-b

    eta-

    gala

    ctos

    yltr

    ansf

    eras

    ede

    fici

    ency

    Ger

    oder

    ma

    oste

    odys

    plas

    ticu

    mAR

    23

    10

    70

    1q2

    4.2

    GO

    RAB

    SCYL

    1-b

    ind

    ing

    pro

    tein

    1Cu

    tis

    laxa

    ,au

    toso

    mal

    rece

    ssiv

    efo

    rm,

    type

    2B

    (AR

    CL2

    B)

    AR6

    12

    94

    01

    7q2

    5.3

    PYCR

    1Py

    rrol

    ine-

    5-c

    arb

    oxy

    late

    redu

    ctas

    e1

    Skel

    etal

    feat

    ure

    sov

    erla

    pp

    ing

    wit

    hp

    roge

    roid

    ED

    San

    dge

    rod

    erm

    aos

    teod

    ysp

    last

    icu

    mCu

    tis

    laxa

    ,au

    toso

    mal

    rece

    ssiv

    efo

    rm,

    type

    2A

    (AR

    CL2

    A)(W

    rin

    kly

    skin

    syn

    drom

    e)

    AR2

    78

    25

    0,

    21

    92

    00

    12

    q24

    .3AT

    P6VO

    A2AT

    Pase

    ,Hþ

    tran

    spor

    tin

    g,ly

    soso

    mal

    ,V0

    sub

    un

    itA2

    Skel

    etal

    feat

    ure

    sov

    erla

    pp

    ing

    wit

    hp

    roge

    roid

    ED

    San

    dge

    rod

    erm

    aos

    teod

    ysp

    last

    icu

    mSi

    ngl

    eton

    –M

    erte

    ndy

    spla

    sia

    AD1

    82

    25

    02

    6.

    Abn

    orm

    alm

    iner

    aliz

    atio

    ngr

    oup

    Hyp

    opho

    spha

    tasi

    a,pe

    rin

    atal

    leth

    alan

    din

    fan

    tile

    form

    sAR

    24

    15

    00

    1p3

    6.1

    –p3

    4AL

    PLAl

    kalin

    eph

    osp

    hat

    ase,

    tiss

    uen

    on-s

    pec

    ific

    (TN

    SALP

    )

    Intr

    afam

    ilial

    vari

    abili

    ty

    Hyp

    opho

    spha

    tasi

    a,ad

    ult

    form

    AD1

    46

    30

    01

    p36

    .1–

    p34

    ALPL

    Alka

    line

    phos

    ph

    atas

    e,ti

    ssue

    non

    -sp

    ecifi

    c(T

    NSA

    LP)

    Incl

    ud

    esod

    onto

    hy

    pop

    hos

    ph

    atas

    ia

    TAB

    LEI(

    Con

    tin

    ued

    )

    Gro

    up/n

    ame

    ofdi

    sord

    erIn

    heri

    tan

    ceM

    IMN

    o.Lo

    cus

    Gen

    ePr

    otei

    nN

    otes

    956 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

  • Hyp

    opho

    spha

    tem

    icri

    cket

    s,X-

    linke

    ddo

    min

    ant

    XLD

    30

    78

    00

    Xp2

    2PH

    EXX-

    linke

    dhy

    pop

    hos

    ph

    atem

    iam

    embr

    ane

    pro

    teas

    eH

    ypop

    hosp

    hate

    mic

    rick

    ets,

    auto

    som

    aldo

    min

    ant

    AD1

    93

    10

    01

    2p1

    3.3

    FGF2

    3Fi

    brob

    last

    grow

    thfa

    ctor

    23

    Hyp

    opho

    spha

    tem

    icri

    cket

    s,au

    toso

    mal

    rece

    ssiv

    e,ty

    pe1

    (AR

    HR

    1)

    AR2

    41

    52

    04

    q21

    DM

    P1D

    enti

    nm

    atri

    xac

    idic

    phos

    phop

    rote

    in1

    Hyp

    opho

    spha

    tem

    icri

    cket

    s,au

    toso

    mal

    rece

    ssiv

    e,ty

    pe2

    (AR

    HR

    2)

    AR6

    13

    31

    26

    q23

    ENPP

    1Ec

    ton

    ucle

    otid

    epy

    roph

    osp

    hat

    ase/

    phos

    phod

    iest

    eras

    e1

    Hyp

    opho

    spha

    tem

    icri

    cket

    sw

    ith

    hype

    rcal

    ciur

    ia,

    X-lin

    ked

    rece

    ssiv

    eXL

    R3

    00

    55

    4Xp

    11

    .22

    ClCN

    5Ch

    lori

    dech

    ann

    el5

    Par

    tof

    Den

    t’sd

    isea

    seco

    mp

    lex

    Hyp

    opho

    spha

    tem

    icri

    cket

    sw

    ith

    hype

    rcal

    ciur

    ia,

    auto

    som

    alre

    cess

    ive

    (HH

    RH

    )

    AR2

    41

    53

    99

    q34

    SLC3

    4A3

    Sodi

    um-p

    hosp

    hat

    eco

    tran

    spor

    ter

    Neo

    nat

    alhy

    perp

    arat

    hyro

    idis

    m,

    seve

    refo

    rmAR

    23

    92

    00

    3q1

    3

of 26/26
RESEARCH ARTICLE Nosology and Classification 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, Children’s 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 Children’s Medical Center, Fuchu, Tokyo, Japan 9 Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand 10 Murdoch Children’s Research Institute, Royal Children’s Hospital, Department of Paediatrics, University of Melbourne, Victoria, Australia 11 Discipline of Genetic Medicine, The Children’s 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 Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disor- ders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 condi- tions were included and placed in 40 groups defined by molecu- lar, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent muta- tions to ‘‘private’’ found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined The 9th ISDS meeting and the Nosology workshop were held in Boston in July 2009 and supported by The Manton Center for Orphan Disease Research, Children’s Hospital, Boston, Massachusetts; Children’s Orthopaedic Surgery Foundation, Inc., Boston, Massachusetts; The Osteogenesis Imperfecta Foundation, Gaithersburg, Maryland; Biomarin, Novato, California; and Enobia Pharma, Montreal, Quebec, Canada. The 2010 Nosology tables are available online at the International Skeletal Dysplasia Society web site (www.isds.ch). *Correspondence to: Andrea Superti-Furga, Centre Hospitalier Universitaire Vaudois (CHUV), Av. Decker, 2, 1011 Lausanne, Switzerland. E-mail: [email protected] Published online 15 March 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ajmg.a.33909 How to Cite this Article: Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabel B, Superti-Furga A. 2011. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet Part A 155:943968. Ó 2011 Wiley-Liss, Inc. 943
Embed Size (px)
Recommended