Revised: 13 January 2023
Accepted: 17 January 2023
DOI: 10.1002/ajmg.a.63132
ORIGINAL ARTICLE
Nosology of genetic skeletal disorders: 2023 revision
Sheila Unger 1 | Carlos R. Ferreira 2 | Geert R. Mortier 3 | Houda Ali 4
| Alistair Calder 7 | Daniel H. Cohn 8,9
|
Débora R. Bertola 5,6
Valerie Cormier-Daire 10 | Katta M. Girisha 11
| Outi Makitie 14,15
|
Deborah Krakow 13
|
| Christine Hall 12 |
Stefan Mundlos 16 |
| Ravi Savarirayan 19 |
Gen Nishimura 17 | Stephen P. Robertson 18
David Sillence 20 | Marleen Simon 21 | V. Reid Sutton 22 |
Matthew L. Warman 23,24 |
Andrea Superti-Furga 1
1
Division of Genetic Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
2
Skeletal Genomics Unit, Metabolic Medicine Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
3
Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium
4
INSERM, US14-Orphanet, Paris, France
5
Unidade de Genética, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
6
Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
7
Radiology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
8
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA
9
Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, California, USA
10
Paris Cité University, Reference Center for Skeletal Dysplasia, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital (AP-HP), Paris, France
11
Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
12
Emerita Consultant Paediatric Radiologist at Great Ormond Street Childrens' Hospital, London, UK
13
Departments of Obstetrics and Gynecology, Orthopaedic Surgery and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los
Angeles, California, USA
14
Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
15
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
16
Institut für medizinische Genetik und Humangenetik, Charité - Universitätsmedizin Berlin, Berlin, Germany
17
Department of Radiology, Musashino-Yowakai Hospital, Tokyo, Japan
18
Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
19
Murdoch Children's Research Institute and University of Melbourne, Parkville, Victoria, Australia
20
Specialities of Genomic Medicine and Paediatrics and Adolescent Health, Sydney University Clinical School, Children's Hospital, Westmead, NSW, Australia
21
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
22
Department of Molecular & Human Genetics, Baylor College of Medicine & Texas Children's Hospital, Houston, Texas, USA
23
Department of Orthopedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
24
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
Equal contributions from Sheila Unger and Carlos R. Ferreira.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
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© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government
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Am J Med Genet. 2023;1–46.
wileyonlinelibrary.com/journal/ajmga
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Received: 22 December 2022
UNGER ET AL.
Correspondence
Andrea Superti-Furga, Division of Genetic
Medicine, Lausanne University Hospital,
Lausanne, Switzerland.
Email: asuperti@unil.ch
Abstract
The “Nosology of genetic skeletal disorders” has undergone its 11th revision and
now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology.
Funding information
The International Skeletal Dysplasia Society;
University of Lausanne; DBT/Wellcome Trust;
India Alliance; Sigrid Jusélius Foundation;
CureKids New ZEaland; National Health and
Medical Research Council of Australia,
Grant/Award Number: #GNT2018081
The most significant change as compared to previous versions is the adoption of
the dyadic naming system, systematically associating a phenotypic entity with the
gene it arises from. We consider this a significant step forward as dyadic naming is
more informative and less prone to errors than the traditional use of list numberings
and eponyms. Despite the adoption of dyadic naming, efforts have been made to
maintain strong ties to the MIM catalog and its historical data. As with the previous
versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of nextgeneration sequencing results, and providing a basis for novel advances in biology
and medicine.
When the first “Nosology” was compiled and published in 1970, few
[International nomenclature of constitutional bone diseases. Constitu-
would have predicted that it would gain such an important role in
tional bone diseases without known pathogenesis], 1971; [Interna-
genetics clinics and research to motivate an 11th revision 52 years
tional nomenclature of constitutional diseases of bone], 1970;
later (Table 1). Yet, the reasons that stimulated the first Nosology are
McKusick & Scott, 1971). At that time, however, the work was called
the same that uphold the present new revision: coping with the
a “Nomenclature” rather than a Nosology; the goal was to bring all
wealth of novel information on the growing number and variety of
scholars to use the same name for the same condition.
skeletal phenotypes with a genetic basis and trying to assure a common naming system to facilitate diagnosis and communication.
Molecular criteria began to inform the Nosology in the 1980s,
first with osteogenesis imperfecta and the discovery of genetic vari-
The recognition of chromosomal aneuploidies at the transition
ants in collagen 1. The concept of “bone dysplasia families” originating
between the 50s and the 60s provided a biological foundation to
from different pathogenic variants in a single gene was proposed in
genetics and ushered in a first golden era of clinical genetics. The
the 1980s (Spranger, 1985) and confirmed in the 1990s, with the
Birth Defects Conferences between 1969 and 1971 signaled the
COL2A1 and FGFR3 disorders being prominent examples. Ever since,
awareness and importance of clinical genetics throughout the sixties
the Nosology has straddled the fence between defining disorders
and initiated a prolific period in disease identification, delineation,
based either on their clinical and radiographic features or on the
and description. In this context, it became apparent that “chondro-
responsible genes (Beighton et al., 1992; Bonafe et al., 2015;
dysplasia” was not a single diagnosis, but that many distinct, true-
Hall, 2002; International nomenclature and classification of the osteo-
breeding forms existed; for example, diastrophic dysplasia, spondylo-
chondrodysplasias (1997). International working group on constitu-
epiphyseal dysplasia congenita, and the so-called “pseudo-Morquio”
tional diseases of bone, 1998; International nomenclature of
disorders were distinguished and clinically described. In addition,
constitutional diseases of bone, 1979; International nomenclature of
biochemistry allowed subtypes of clinically similar disorders to be
constitutional diseases of bone. Revision, May 1983, 1983;
distinguished, the most notable example at the time being the muco-
Lachman, 1998; Mortier et al., 2019; Superti-Furga & Unger, 2007;
polysaccharidoses. The contribution of radiologic features and radi-
Warman et al., 2011).
ologists to the delineation of skeletal dysplasias deserves explicit
Traditionally, the Nosology has been organized into groups of
recognition. In many instances, it was the radiographic features and
disorders—initially based on radiographic criteria, then by biochemical
their time dependent evolution (the “fourth dimension” emphasized
criteria (metabolic pathways) and subsequently, more and more, by
by the late Andres Giedion) that permitted not only to discriminate
functional and molecular criteria. The organization into groups has
between disorders that had outward similarities but also to recog-
been maintained in the current revision as it helps in finding the disor-
nize a gene's radiographic signature in phenotypically distinct disor-
ders relevant for a particular patient of finding. On the other hand,
ders (e.g., Achondrogenesis type 2 and Spondyloepiphyseal dysplasia
Nature has more complexity than can be captured in the Nosology,
congenita) and thus create the first gene families (Spranger, 1985)
and our attempt at classification is necessarily both arbitrary and a
(and see below).
simplification, as many disorders might warrant classification in more
In 1970, the first prototype of the “Nosology” was drafted
(A nomenclature for constitutional (intrinsic) diseases of bone, 1971;
than one group. Thus, we have elected to drop the term “classification” from the title; this is just a “Nosology”.
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2
Thanatophoric dysplasia (type 1), FGFR3‐related
Thanatophoric dysplasia (type 2), FGFR3‐related
Severe achondroplasia with developmental delay and
acanthosis nigricans (SADDAN), FGFR3‐related
Achondroplasia, FGFR3‐related
Hypochondroplasia, FGFR3‐related
NOS 01‐0010
NOS 01‐0020
NOS 01‐0030
NOS 01‐0040
NOS 01‐0050
AD
AD
AD
AD
AD
Inheritance
FGFR3
FGFR3
FGFR3
FGFR3
FGFR3
Gene or locus
146000
100800
616482
187601
187600
MIM No.
Radiographic differences between types 1 and 2 are
correlated to specific FGFR3 variants
Includes previous “platyspondylyic dysplasia type San
Diego”
Notes
Achondrogenesis, COL2A1‐related (formerly type 2, type
Langer‐Saldino)
Hypochondrogenesis, COL2A1‐related
Platyspondylic dysplasia, type Torrance, COL2A1‐related
Spondyloepiphyseal dysplasia congenita (SEDC), COL2A1‐
related
Spondyloepimetaphyseal dysplasia, COL2A1‐related
Kniest dysplasia, COL2A1‐related
Spondyloperipheral dysplasia, COL2A1‐related
SED with metatarsal shortening, COL2A1‐related
Stickler syndrome, COL2A1‐related
Dysplasia of the proximal femoral epiphyses, COL2A1‐
related
NOS 02‐0010
NOS 02‐0020
NOS 02‐0030
NOS 02‐0040
NOS 02‐0050
NOS 02‐0060
NOS 02‐0070
NOS 02‐0080
NOS 02‐0090
NOS 02‐0100
AD
AD
AD
AD
AD
AD
AD, AR*
AD
AD
AD
COL2A1
COL2A1
COL2A1
COL2A1
COL2A1
COL2A1
COL2A1
COL2A1
COL2A1
COL2A1
150600, 608805
108300
609162
271700
156550
184250, 184253, 184255,
616583
183900, 604864
151210
200610
200610
Heterogeneous condition, not all cases are due to
COL2A1 variants (usually p.G393S; p.G717S; p.
G1170S). The condition called “Meyer dysplasia of the
hip” is not associated with COL2A1 variants
Monoallelic loss‐of‐function variants; see also COL11A1,
COL11A2, COL9A1, COL9A2, COL9A3
Often associated with the p.R275C variant; formerly
“Czech dysplasia”
Like Torrance dysplasia, often variants in the C‐propeptide
of collagen 2
Also known as “SED with marked metaphyseal changes”.
Includes SEMD type Strudwick, SMD type Algerian,
SED type Stanescu, dysspondyloenchondromatosis, and
some cases of SMD “corner fracture” type
Includes mild SED with premature onset arthrosis, also
known as osteoarthrosis with mild chondrodysplasia;
includes Namaqualand type hip dysplasia. Mild SED
cases may resemble MED (see note). AR*: very rare SED
cases with biallelic COL2A1 variants have been reported
Often variants in the C‐propeptide of collagen 2
Achondrogenesis type 2 and hypochondrogenesis form
one phenotypic continuum
Achondrogenesis type 2 and hypochondrogenesis form
one phenotypic continuum
3
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(Continues)
See also the pseudoachondroplasia‐multiple epiphyseal dysplasia group for recessively inherited variants of Stickler syndrome as well as for overlapping phenotypes with normal stature
and premature onset arthrosis; as well as spondylometaphyseal dysplasia Sutcliffe (or “corner fractures” type), FN1‐related
Type 2 collagen disorders
Group 2
See also group 33 for craniosynostosis syndromes linked to FGFR3 variants, as well as CATSHL in group 30 and LADD syndrome in group 40 for other FGFR3‐related phenotypes; rare
FGFR3 missense variants have been reported in idiopathic short stature but a causal link is not yet established and their significance remains unclear
Name of group/name of disorder
FGFR3 chondrodysplasias
Group 1
The nosology of genetic skeletal disorders: 2023 revision.
Group number/number of
disorder
TABLE 1
UNGER ET AL.
Stickler syndrome, COL11A1‐related
Marshall syndrome, COL11A1‐related
Stickler syndrome, COL11A2‐related (non‐ocular type)
Fibrochondrogenesis, COL11A1‐related
Fibrochondrogenesis, COL11A2‐related
Otospondylomegaepiphyseal dysplasia (OSMED),
recessive type, COL11A2‐related
Otospondylomegaepiphyseal dysplasia (OSMED),
dominant type, COL11A2‐related
NOS 03‐0010
NOS 03‐0020
NOS 03‐0030
NOS 03‐0040
NOS 03‐0050
NOS 03‐0060
NOS 03‐0070
AD
AR
AR, AD
AR, AD
AD
AD
AD, MOS
Inheritance
COL11A2
COL11A2
COL11A2
COL11A1
COL11A2
COL11A1
COL11A1
Gene or locus
184840
215150
614524
228520
184840
154780
604841
MIM No.
Formerly Weissenbacher‐Zweymüller syndrome and
Stickler syndrome type 3
One report with homozygous p.G901E variant in two
affected sibs (PMID 22499343)
Can also result from somatic mosaicism for a COL11A1
variant
Notes
Sulfation disorders
Achondrogenesis, SLC26A2‐related (formerly
achondrogenesis type 1B, or type Fraccaro)
Atelosteogenesis, SLC26A2‐related (formerly
atelosteogenesis type 2)
Diastrophic dysplasia, SLC26A2‐related
Multiple epiphyseal dysplasia, SLC26A2‐related
(autosomal recessive type, rMED)
Spondylo‐epi‐metaphyseal dysplasia, PAPSS2‐related
Chondrodysplasia with congenital joint dislocations,
IMPAD1‐related
Chondrodysplasia with congenital joint dislocations,
CHST3‐related
Chondrodysplasia with hypomyelinating leucodystrophy,
SLC35B2‐related
Ehlers‐Danlos syndrome, musculocontractural type,
CHST14‐related
Ehlers‐Danlos syndrome, musculocontractural type, DSE‐
related
Osteochondrodysplasia, brachydactyly, and overlapping
malformed digits (OCBMD), CHST11‐related
NOS 04‐0010
NOS 04‐0020
NOS 04‐0030
NOS 04‐0040
NOS 04‐0050
NOS 04‐0060
NOS 04‐0070
NOS 04‐0080
NOS 04‐0090
NOS 04‐0100
NOS 04‐0110
AR
AR
AR
AR
AR
AR
AR
CHST11
DSE
CHST14
SLC35B2
CHST3
IMPAD1
PAPSS2
SLC26A2
SLC26A2
AR
SLC26A2
SLC26A2
AR
AR
AR
618167
615539
601776
See 610788
143095
614078
612847
226900
222600
256050
600972
Includes adducted thumb‐clubfoot syndrome
Includes recessive Larsen syndrome, humero‐spinal
dysostosis, and SED type Omani
Some features similar to Catel‐Manzke syndrome, TGDS‐
related, as well as to Desbuquois syndrome, CANT1‐
related
Formerly “SEMD Pakistani type”; includes the former
“recessive brachyolmia, recessive type” as well as the
older entities “Toledo brachyolmia” and “Hobaek
brachyolmia”
See also multiple epiphyseal dysplasias and
pseudoachondroplasia group (group 9)
Includes former entities de la Chapelle dysplasia, McAlister
dysplasia, and neonatal osseous dysplasia
Formerly known as achondrogenesis, type Fraccaro
UNGER ET AL.
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Group 4
See also Stickler syndrome type 1 in collagen 2 group (Group 2) as well as recessive forms of Stickler syndrome in the pseudoachondroplasia‐multiple epiphyseal dysplasia group (Group 9)
Name of group/name of disorder
Type 11 collagen disorders
Group 3
(Continued)
Group number/number of
disorder
TABLE 1
4
(Continued)
Inheritance
AR
Gene or locus
HS2ST1
MIM No.
619194
Notes
Baratela‐Scott syndrome, XYLT1‐related
Desbuquois dysplasia (with accessory ossification center
in digit 2), CANT1‐related
Desbuquois dysplasia (with short metacarpals and
elongated phalanges, Kim type), CANT1‐related
SEMD with joint laxity (Hall type or leptodactylic type),
KIF22‐related
SEMD with joint laxity, EXOC6B‐related
SEMD with joint laxity (Beighton type), B3GALT6‐related
(Ehlers‐Danlos syndrome, spondylodysplastic type 2,
EDSSPD2)
Ehlers‐Danlos syndrome, spondylodysplastic type 1
(EDSSPD1), B4GALT7‐related
Multiple joint dislocations, short stature, craniofacial
dysmorphisms, and skeletal dysplasia, with or without
heart defects, B3GAT3‐related
Skeletal dysplasia with joint laxity and advanced bone age
(SDJLABA), CSGALNACT1‐related
Skeletal dysplasia with joint dislocations and amelogenesis
imperfecta, SLC10A7‐related
NOS 05‐0020
NOS 05‐0030
NOS 05‐0040
NOS 05‐0050
NOS 05‐0060
NOS 05‐0070
NOS 05‐0080
NOS 05‐0090
NOS 05‐0100
AR
SLC10A7
CSGALNACT1
B3GAT3
AR
AR
B4GALT7
B3GALT6
AR
AR
EXOC6B
KIF22
CANT1
CANT1
XYLT1
AR
AD
AR
AR
AR
618363
618870
245600
130070
271640
618395
603546
251450
251450
615777
The phenotype is very variable and has been reported also
as “Larsen‐like” or as “pseudodiastrophic dysplasia”.
Intellectual disability and severe osteopenia with
fractures have been observed. The OMIM entry
includes older descriptions that are probably unrelated.
Formerly known as “EDS, progeroid form”; includes Larsen
syndrome, La Reunion type; see also B3GALT6
deficiency above
Includes MIM 609465—Al‐Gazali syndrome as neonatal
form
Phenotype resembles SEMD‐JL leptodactylic or type Hall
(preceding line)
May have intellectual disability; formerly Desbuquois
dysplasia type 2
Filamins and related disorders
Frontometaphyseal dysplasia, FLNA‐related
Frontometaphyseal dysplasia, MAP3K7‐related
Frontometaphyseal dysplasia, TAB2‐related
NOS 06‐0010
NOS 06‐0020
NOS 06‐0030
AD
AD
XL
TAB2
MAP3K7
FLNA
617137
305620
(Continues)
No MIM entry yet; TAB2 gene also associated with MIM
614980—congenital heart defects, nonsyndromic, 2
FLNA gene also associated with MIM 300049, MIM
300321, MIM 314400, MIM 300048, MIM 300049
(see) and conditions below in this group
5
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Group 6
Note: remarkably, this group contains several disorders of glycosaminoglycan synthesis. In spite of this group being named after a clinical feature (dysplasias with joint dislocations), the
phenotypes in this group are related to those of the preceding Group 4 (sulfation disorders) and of the following Group 6 (filamin disorders) justifying its placement here. See also:
Temtamy type brachydactyly, CHSY1‐related, as well as SEMD with microcephaly, retinal dystrophy and hearing loss, PISD‐related (Liberfarb syndrome), for other conditions with
congenital dislocations, as well as EDSSPD3, SLC39A13‐related, in the SEMD group.
Dysplasias with multiple joint dislocations
NOS 05‐0010
See also filamin disorders (Group 6) and dysplasias with multiple joint dislocations (Group 5) for other conditions with dislocations, as well as brachydactyly, CHSY1‐related, for phalangeal
changes reminiscent of the sulfation disorders.
Developmental delay with corpus callosum, skeletal, and
renal abnormalities, HS2ST1‐related
Name of group/name of disorder
Group 5
NOS 04‐0120
Group number/number of
disorder
TABLE 1
UNGER ET AL.
Cardiospondylocarpofacial syndrome, MAP3K7‐related
Melnick‐Needles syndrome, FLNA‐related
Otopalatodigital syndrome type 1 (OPD1), FLNA‐related
Otopalatodigital syndrome type 2 (OPD2), FLNA‐related
Terminal osseous dysplasia (TOD), FLNA‐related
Larsen syndrome, FLNB‐related
Atelosteogenesis type 1, FLNB‐related
Atelosteogenesis type 3, FLNB‐related
Spondylocarpotarsal synostosis syndrome, FLNB‐related
Spondylocarpotarsal synostosis syndrome, RFLNA‐related
Spondyocarpotarsal synostosis syndrome with
contractures and pterygia, MYH3‐related
Frank‐ter Haar syndrome, SH3PXD2B‐related
NOS 06‐0050
NOS 06‐0060
NOS 06‐0070
NOS 06‐0080
NOS 06‐0090
NOS 06‐0100
NOS 06‐0110
NOS 06‐0120
NOS 06‐0130
NOS 06‐0140
NOS 06‐0150
Inheritance
AR
AD, AR
AR
AR
AD
AD
AD
XL
XL
XL
XL
AD
Gene or locus
SH3PXD2B
MYH3
RFLNA
FLNB
FLNB
FLNB
FLNB
FLNA
FLNA
FLNA
FLNA
MAP3K7
MIM No.
249420
178110, 618469
272460
108721
108720, 112310
150250
300244
304120
311300
309350
157800
Includes previous Borrone dermatocardioskeletal
syndrome
frequently biallelic loss of function variants; monoallelic
missense variants in the MYH3 gene associated with
MIM 193700‐Arthrogryposis 2A, and MIM 618436‐
Arthrogryposis 2B3
Entity proven, no MIM entry yet
Includes Boomerang dysplasia, Piepkorn dysplasia, and
spondylohumerofemoral (giant cell) dysplasia
Includes digitocutaneous dysplasia
Includes osteodysplasty
Notes
Proteoglycan core proteins disorders
Dyssegmental dysplasia, HSPG2‐related
Myotonic chondrodystrophy, HSPG2‐related (Schwartz‐
Jampel syndrome)
Spondylo‐epiphyseal dysplasia, ACAN‐related (dominant,
Kimberley type)
Spondylo‐epi‐metaphyseal dysplasia, ACAN‐related
(recessive, aggrecan type)
Short stature with advanced bone age, ACAN‐related
SEMD, BGN‐related (Camera type)
TRPV4 disorders
Metatropic dysplasia, TRPV4‐related
NOS 07‐0010
NOS 07‐0020
NOS 07‐0030
NOS 07‐0040
NOS 07‐0050
NOS 07‐0060
Group 8
NOS 08‐0010
AD, MOS
XL
AD
AR
AD
AR
AR
TRPV4
BGN
ACAN
ACAN
ACAN
HSPG2
HSPG2
156530
300106
165800
612813
608361
255800
224410, 224400
Includes so‐called “hyperplastic”, lethal, and non‐lethal
forms. Can also result from somatic mosaicism for a
TRPV4 variant.
The BGN gene is also associated with a connective tissue‐
arterial aneurysms disorder (Meester‐Loeys syndrome,
MIM300989)
Sometimes with osteochondritis dissecans; other cases
short stature with no skeletal features and normal bone
age
Variable severity; includes previous Burton dysplasia
Variable severity; Includes both former Silverman‐
Handmaker and Rolland‐Desbuquois types
UNGER ET AL.
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Group 7
See also chondrodysplasia with congenital joint dislocations, CHST3‐related (“recessive Larsen syndrome”) and the group of dysplasias with multiple dislocations, above (Group 5)
Name of group/name of disorder
NOS 06‐0040
(Continued)
Group number/number of
disorder
TABLE 1
6
(Continued)
Spondyloepiphyseal dysplasia, Kozlowski type
Brachyolmia, TRPV4‐related
Familial digital arthropathy with brachydactyly, TRPV4‐
related
NOS 08‐0030
NOS 08‐0040
NOS 08‐0050
Inheritance
AD
AD
AD
AD
Gene or locus
TRPV4
TRPV4
TRPV4
TRPV4
MIM No.
606835
113500
184252
184095
Notes
Previously known as “pseudo‐Morquio syndrome type 2”.
Includes the obsolete MIM 168400‐parastremmatic
dwarfism entry, a phenotypic variant.
Pseudoachondroplasia, COMP‐related
Multiple epiphyseal dysplasia, COMP‐related
Multiple epiphyseal dysplasia, MATN3‐related
Multiple epiphyseal dysplasia, CANT1‐related
Multiple epiphyseal dysplasia, COL9A1‐related
Multiple epiphyseal dysplasia, COL9A2‐related
Multiple epiphyseal dysplasia, COL9A3‐related
Stickler syndrome, recessive type, COL9A1‐related
Stickler syndrome, recessive type, COL9A2‐related
Stickler syndrome, recessive type, COL9A3‐related
Multiple epiphyseal dysplasia with microcephaly and
nystagmus (Lowry‐Wood syndrome), RNU4ATAC‐
related
NOS 09‐0010
NOS 09‐0020
NOS 09‐0030
NOS 09‐0040
NOS 09‐0050
NOS 09‐0060
NOS 09‐0070
NOS 09‐0080
NOS 09‐0090
NOS 09‐0100
NOS 09‐0110
RNU4ATAC
226960
120270
614284
614134
600969
600204
614135
617719
607078
132400
177170
See also Microcephalic osteodysplastic primordial
dwarfism, RNU4ATAC‐related, as well as Roifman
syndrome, RNU4ATAC‐related, both in the primordial
dwarfism group (Group 21), for conditions with
different severity from the RNU4ATAC gene
See also Groups 2 and 3
AR
AR
Short rib–polydactyly syndrome (SRPS), DYNC2H1‐
related
Short rib–polydactyly syndrome (SRPS), IFT80‐related
Short rib–polydactyly syndrome (SRPS), IFT81‐related
Short rib–polydactyly syndrome (SRPS), WDR34‐related
Short rib–polydactyly syndrome (SRPS), WDR60‐related
NOS 10‐0010
NOS 10‐0020
NOS 10‐0030
NOS 10‐0040
NOS 10‐0050
WDR60
WDR34
IFT81
IFT80
DYNC2H1
615503
615633
617895
611263
613091, 263520
(Continues)
There is significant clinical and radiological overlap
between SRP1/3 and ATD. Some forms of both remain
unlinked to the known genes. This gene can also be
responsible for chondroectodermal dysplasia (Ellis‐van
Creveld), see below.
7
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AR
AR
AR
Skeletal disorders caused by abnormalities of cilia or ciliary signaling
Group 10
See also multiple epiphyseal dysplasia, recessive type, SLC26A2‐related, as well as ASPED. Some COL2A1 variants can make a MED‐like phenotype. Some MED or MED‐like phenotypes
remain genetically unclear.
COL9A3
AR
COL9A2
AR
AR
COL9A3
COL9A1
AD
COL9A2
COL9A1
CANT1
MATN3
COMP
COMP
AR
AD
AD
AR
AD
AD
AD
Pseudoachondroplasia and the multiple epiphyseal dysplasias
Group 9
Missense variants in the TRPV4 gene can be responsible for different types of peripheral neuropathies (see under MIM 605427). The TRPV4 skeletal phenotypes can sometimes be
associated with neuropathy.
Spondyloepimetaphyseal dysplasia, TRPV4‐related
(Maroteaux type)
Name of group/name of disorder
NOS 08‐0020
Group number/number of
disorder
TABLE 1
UNGER ET AL.
(Continued)
Short rib–polydactyly syndrome (SRPS), DYNC2LI1‐
related
Short rib–polydactyly syndrome (SRPS), NEK1‐related
Short rib–polydactyly syndrome (SRPS), IFT122‐related
Short rib–polydactyly syndrome (SRPS), WDR19‐related
Short rib‐polydactyly syndrome (SRPS), INTU‐related
Short rib‐polydactyly syndrome (SRPS), TRAF3IP1‐related
Endocrine‐cerebro‐osteo dysplasia (ECO), CILK1‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), DYNC2H1‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), DYNC2LI1‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), WDR34‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), TCTEX1D2‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), WDR60‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), WDR19‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), IFT140‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), TTC21B‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), IFT122‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), WDR35‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), IFT43‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), IFT80‐related
NOS 10‐0070
NOS 10‐0080
NOS 10‐0090
NOS 10‐0100
NOS 10‐0110
NOS 10‐0120
NOS 10‐0130
NOS 10‐0140
NOS 10‐0150
NOS 10‐0160
NOS 10‐0170
NOS 10‐0180
NOS 10‐0190
NOS 10‐0200
NOS 10‐0210
NOS 10‐0220
NOS 10‐0230
NOS 10‐0240
Name of group/name of disorder
Inheritance
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
Gene or locus
IFT80
IFT43
WDR35
IFT122
TTC21B
IFT140
WDR19
WDR60
TCTEX1D2
WDR34
DYNC2LI1
DYNC2H1
CILK1
TRAF3IP1
INTU
WDR19
IFT122
NEK1
DYNC2LI1
MIM No.
611623
617866
614091
See 269860
613819
266920
614376
See 615503
617405
See 615633
See 617088
613091
612651
See 607380
617925
614091
269860
263520
617088
Subsumed under SRPS (MIM 269860)
Gene also known for nephronophthisis (MIM 613820)
WDR19 is associated with MIM 614091, 614376, 614378,
615633 as well as with nephronopthisis (MIM 614377),
Senior‐Loken syndrome (MIM 616307) and Mainzer‐
Saldino syndrome (see below)
TRAF3IP1 also known as IFT154
WDR19 is associated with MIM 614091, 614376, 614378,
615633 as well as with nephronopthisis (MIM 614377),
Senior‐Loken syndrome (MIM 616307) and Mainzer‐
Saldino syndrome (see below)
Possibly also digenic inheritance combining NEK1 with
DYNC2H1 variants
Notes
UNGER ET AL.
15524833, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.63132 by Test, Wiley Online Library on [20/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
NOS 10‐0060
Group number/number of
disorder
TABLE 1
8
(Continued)
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), IFT172‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), IFT81‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), IFT52‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), CFAP410‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), CEP120‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), KIAA0586‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), GRK2‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), TRAF3IP1‐related
Short‐rib thoracic dysplasia (formerly asphyxiating thoracic
dysplasia—Jeune syndrome), KIAA0753‐related
Axial spondylometaphyseal dysplasia, CFAP410‐related
Axial spondylometaphyseal dysplasia, NEK1‐related
Chondroectodermal dysplasia (Ellis‐van Creveld), EVC1‐
related
Chondroectodermal dysplasia (Ellis‐van Creveld), EVC2‐
related
Chondroectodermal dysplasia (Ellis‐van Creveld), WDR35‐
related
Chondroectodermal dysplasia (Ellis‐van Creveld),
DYNC2LI1‐related
Chondroectodermal dysplasia (Ellis‐van Creveld), GLI1‐
related
Chondroectodermal dysplasia (Ellis‐van Creveld), SMO‐
related
Orofaciodigital syndrome type 4 (Mohr‐Majewski),
TCTN3‐related
Orofaciodigital syndrome type 2 (Mohr syndrome), NEK1‐
related
NOS 10‐0260
NOS 10‐0270
NOS 10‐0280
NOS 10‐0290
NOS 10‐0300
NOS 10‐0310
NOS 10‐0320
NOS 10‐0330
NOS 10‐0340
NOS 10‐0350
NOS 10‐0360
NOS 10‐0370
NOS 10‐0380
NOS 10‐0390
NOS 10‐0400
NOS 10‐0410
NOS 10‐0420
NOS 10‐0430
Name of group/name of disorder
Inheritance
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
Gene or locus
NEK1
TCTN3
SMO
GLI1
DYNC2LI1
WDR35
EVC2
EVC1
NEK1
CFAP410
KIAA0753
TRAF3IP1
GRK2
KIAA0586
CEP120
CFAP410
IFT52
IFT81
IFT172
MIM No.
252100
258860
See
See 165220
See 617088
225500
See 252100
602271
619479
See 607380
See 109635
616546
616300
602271
617102
617895
615630
(Continues)
A single case with compound heterozygosity missense
variants reported
See also Weyers acrofacial (acrodental) dysostosis (MIM
193530)
KIAA0753 variants also associated with orofaciodigital
syndrome (MIM 617127) and with Joubert syndrome
(MIM 619476)
TRAF3IP1 also known as IFT154
Gene also associated with Joubert syndrome (MIM
616490)
Described in severe cases resembling SRPS; the CEP120
gene is also associated with Joubert syndrome (MIM
617761)
Notes
9
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NOS 10‐0250
Group number/number of
disorder
TABLE 1
UNGER ET AL.
(Continued)
Cranioectodermal dysplasia (Levin‐Sensenbrenner),
WDR35‐related
Cranioectodermal dysplasia (Levin‐Sensenbrenner),
WDR19‐related
Cranioectodermal dysplasia (Levin‐Sensenbrenner), IFT40‐
related
Cranioectodermal dysplasia (Levin‐Sensenbrenner), IFT43‐
related
Joubert syndrome with short‐rib thoracic dysplasia,
CSPP1‐related
Atrial defects‐polydactyly‐multiple congenital
malformation syndrome, PRKACA‐related
Atrial defects‐polydactyly‐multiple congenital
malformation syndrome, PRKACB‐related
Mainzer‐Saldino syndrome, IFT140‐related
Mainzer‐Saldino syndrome, IFT172‐related
Mainzer‐Saldino syndrome, WDR19‐related
Meckel syndrome, MKS1‐related
Meckel syndrome, TMEM216‐related
Meckel syndrome, TMEM67‐related
Meckel syndrome, CEP290‐related
Meckel syndrome, RPGRIP1L‐related
Meckel syndrome, CC2D2A‐related
Thoracolaryngopelvic dysplasia (Barnes)
NOS 10‐0450
NOS 10‐0460
NOS 10‐0470
NOS 10‐0480
NOS 10‐0490
NOS 10‐0500
NOS 10‐0510
NOS 10‐0520
NOS 10‐0530
NOS 10‐0540
NOS 10‐0550
NOS 10‐0560
NOS 10‐0570
NOS 10‐0580
NOS 10‐0590
NOS 10‐0600
NOS 10‐0610
Inheritance
SP
AR
AR
AR
AR
AR
AR
AR
AR
AR
AD, MOS
AD
AR
AR
AR
AR
AR
AR
Gene or locus
CC2D2A
RPGRIP1L
CEP290
TMEM67
TMEM216
MKS1
WDR19
IFT172
IFT140
PRKACB
PRKACA
CSPP1
IFT43
IFT40
WDR19
WDR35
IFT122
MIM No.
187760
612284
611561
611134
607361
603194
249000
See 614376
266920
619143
619142
615636
614009
see 614620
614378
613610
218330
Dominant transmission reported, but diagnostic criteria
not stringent. The existence pf this entity is disputed.
WDR19 is also associated with MIM 614091, 614376,
614378, 615633 as well as with nephronopthisis (MIM
614377), and Senior‐Loken syndrome (MIM 616307)
IFT172 also associated with Bardet‐Biedl syndrome (MIM
619471) and isolated retinitis pigmentosa (616394)
IFT140 also associated with isolated retinitis pigmentosa
(MIM 617781)
OMIM created the name of “Cardioacrofacial syndrome
2”; one published patient later reclassified as “Ellis‐van
Creveld syndrome”.
OMIM created the name of “Cardioacrofacial syndrome
1”.
In OMIM as “Joubert syndrome type 21”; not all cases
have thoracic dysplasia
see short rib thoracic dysplasia, IFT140‐associated, above
WDR19 is associated with MIM 614091, 614376, 614378,
615633 as well as with nephronopthisis (MIM 614377),
Senior‐Loken syndrome (MIM 616307) and Mainzer‐
Saldino syndrome (see below)
Notes
UNGER ET AL.
15524833, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.63132 by Test, Wiley Online Library on [20/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Given the common genetic basis of several entries in this group and the absence (so far) of clear genotype‐phenotype correlations, the distinction between chondroectodermal dysplasia,
asphyxiating thoracic dystrophy (see below for name change), short rib‐polydactyly syndromes and related conditions is historical and restricted to the clinical phenotypes. We have
followed MIM and used the term “short‐rib thoracic dysplasia” instead of “asphyxiating thoracic dysplasia”, to avoid the negative connotation and inaccuracy of “asphyxiating”. See also
paternal UPD14 and Cerebro‐costo‐mandibular syndrome (rib gap syndrome), SNRPB‐related, both in Group 36. The Bardet‐Biedl syndrome with its large phenotypic spectrum has not
been included in spite of minor skeletal involvement, as the predominant clinical features are non‐skeletal.
Cranioectodermal dysplasia (Levin‐Sensenbrenner),
IFT122‐related
Name of group/name of disorder
NOS 10‐0440
Group number/number of
disorder
TABLE 1
10
Metaphyseal dysplasia Schmid (MCS), COL10A1‐related
Cartilage‐hair hypoplasia (CHH; metaphyseal dysplasia,
McKusick type), RMRP‐related
Metaphyseal dysplasia with short stature (CHH‐like),
POP1‐related
Metaphyseal dysplasia with short stature (CHH‐like),
NEPRO‐related
Metaphyseal dysplasia with pancreatic insufficiency and
cyclic neutropenia (Shwachman‐Bodian‐Diamond
syndrome), SBDS‐related
Metaphyseal dysplasia with pancreatic insufficiency and
cyclic neutropenia (SBDS type 2), EFL1‐related
Metaphyseal dysplasia with pancreatic insufficiency and
cyclic neutropenia, DNAJC21‐related
Shwachman‐Diamond like syndrome, SRP54‐related
Metaphyseal dysplasia Spahr, MMP13‐related
Metaphyseal anadysplasia, MMP13‐related
Metaphyseal anadysplasia, MMP9‐related
Metaphyseal dysplasia with maxillary hypoplasia, RUNX2‐
related
NOS 11‐0010
NOS 11‐0020
NOS 11‐0030
NOS 11‐0040
NOS 11‐0050
NOS 11‐0060
NOS 11‐0070
NOS 11‐0080
NOS 11‐0090
NOS 11‐0100
NOS 11‐0110
NOS 11‐0120
AD
AR
AD
AR
AD
AR
RUNX2
MMP9
MMP13
MMP13
SRP54
DNAJC21
EFL1
SBDS
AR
AR
NEPRO
POP1
RMRP
COL10A1
Gene or locus
AR
AR
AR
AD
Inheritance
156510
613073
602111
250400
618752
617052
617941
260400
618853
617396
250250
156500
MIM No.
AD
Odontochondrodysplasia (ODCD), TRIP11‐related
Spondylometaphyseal dysplasia Sutcliffe (or “corner
fractures” type), FN1‐related
Spondylometaphyseal dysplasia with cone‐rod dystrophy,
PCYT1A‐related
Spondylometaphyseal dysplasia with corneal dystrophy,
PLCB3‐related
NOS 12‐0020
NOS 12‐0030
NOS 12‐0040
NOS 12‐0050
PLCB3
PCYT1A
FN1
TRIP11
ACP5
618961
608940
184255
184260
607944
(Continues)
Some cases are linked to COL2A1 but not the original
family
See also Achondrogenesis, TRIP11‐related (formerly type
1A)
Frequently associated with intragenic duplication of exons
3 to 5 or 3 to 6. See also Cleidocranial dysplasia,
RUNX2‐related (below; MIM 119600), as well as non‐
syndromic midline craniosynostosis, RUNX2‐related,
below
Dominant, monoallelic type; includes SEMD Missouri type
Recessive, biallelic variants
Known in OMIM as Neutropenia, severe congenital, 8
Known in OMIM as Bone Marrow Failure Syndrome 3;
BMFS3
See also severe spondylodysplastic dysplasia, Sedaghatian‐
like
Facial features and hypotrichosis reminiscent of Cartilage‐
Hair Hypoplasia
The clinical spectrum is variable. The denomination of
“anauxetic dysplasia 2” in MIM is confusing as anauxetic
dysplasia is a variant of Cartilage‐Hair Hypoplasia
The phenotype of CHH is variable and includes MIM
607095‐anauxetic dysplasia as well as MIM 250460‐
metaphyseal dysplasia without hypotrichosis
Pathogenic variants are typically located in the C‐terminal
domain of the protein.
Notes
11
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AR
AR
AR
Spondyloenchondrodysplasia with immune dysregulation
(SPENCD), ACP5‐related
NOS 12‐0010
AR
Spondylometaphyseal dysplasias (SMD)
Group 12
See Rhizomelic spondylo‐metaphyseal dysplasia with remission, LBR‐related (Group 13), for another anadysplasia‐like disorder
Name of group/name of disorder
Metaphyseal dysplasias
Group 11
(Continued)
Group number/number of
disorder
TABLE 1
UNGER ET AL.
(Continued)
Inheritance
AR
Gene or locus
HHAT
MIM No.
600092
Notes
Also known as Nivelon‐Nivelon‐Mabille syndrome (sic)
Spondyloepi(meta)physeal dysplasias (SE(M)D)
SED tarda, X‐linked (SED‐XL), TRAPPC2‐related
SED with diabetes mellitus (Wolcott‐Rallison syndrome),
EIF2AK3‐related
Dyggve‐Melchior‐Clausen dysplasia, DYM‐related
Smith‐McCort dysplasia, DYM‐related
Smith‐McCort dysplasia, RAB33B‐related
SEMD, BNIP1‐related
SEMD, MATN3‐related
SEMD, DDRGK1‐related (Shohat type)
SEMD with leucodystrophy, AIFM1‐related
SEMD, RSPRY1‐related
SEMD, TMEM165‐related
SEMD with microcephaly, retinal dystrophy and hearing
loss, PISD‐related (Liberfarb syndrome)
SEMD, UFSP2‐related
SEMD, short limb–abnormal calcification type, DDR2‐
related
Immuno‐osseous dysplasia, SMARCAL1‐related (Schimke
type)
SEMD with immune deficiency and intellectual disability,
EXTL3‐related
SEMD with immune deficiency, PGM3‐related
SEMD with intellectual disability, NANS‐related
SEMD with severe short stature, RPL13‐related
SEMD with elevated lysosomal enzymes, MBTPS1‐related
Short stature, skeletal dysplasia, liver failure, optic nerve
atrophy and Pelger‐Huet anomaly, NBAS‐related
Short stature, skeletal dysplasia and liver failure, RINT1‐
related
NOS 13‐0010
NOS 13‐0020
NOS 13‐0030
NOS 13‐0040
NOS 13‐0050
NOS 13‐0060
NOS 13‐0070
NOS 13‐0080
NOS 13‐0090
NOS 13‐0100
NOS 13‐0110
NOS 13‐0120
NOS 13‐0130
NOS 13‐0140
NOS 13‐0150
NOS 13‐0160
NOS 13‐0170
NOS 13‐0180
NOS 13‐0190
NOS 13‐0200
NOS 13‐0210
NOS 13‐0220
AR
AR
AR
AD
AR
AR
AR
AR
AR
AD
AR
AR
AR
XL
AR
AR
AR
AR
AR
AR
AR
XL
RINT1
NBAS
MBTPS1
RPL13
NANS
PGM3
EXTL3
SMARCAL1
DDR2
UFSP2
PISD
TMEM165
RSPRY1
AIFM1
DDRGK1
MATN3
BNIP1
RAB33B
DYM
DYM
EIF2AK3
TRAPPC2
618641
616483
618392
618728
610442
615816
617425
242900
271665
142669, 617974
618889
614727
616723
300232
602557
608728
see 603291
615222
607326
223800
226980
313400
Combination of clinical features is variable; also known as
infantile liver failure syndrome type 3
Combination of clinical features is variable; also known as
infantile liver failure syndrome type 2
only two unrelated individuals known so far; in OMIM as
“Kondo‐Fu type”; possible role of lysosomal dysfunction
in pathogenesis is unclear
Known in OMIM as “immunodeficiency 23”
Also known as “Immunoskeletal dysplasia with
developmental abnormalities”; includes Omenn
syndrome with chondrodysplasia; see also SMARCAL1,
above
Nephrotic syndrome is an important manifestation; see
also EXTL3 deficiency, below
See also other dysplasias with stippling
Includes Familial hip dysplasia (Beukes)
Phenotypically variable; in some affected individuals
hearing and vision may be unaffected
Congenital disorder of glycosylation type IIk
See also MATN3‐related MED in Group 9
See also SMD Kozlowski, TRPV4‐related, Severe spondylometaphyseal dysplasia (Sedaghatian type), GPX4‐related, as well as Axial spondylometaphyseal dysplasia, CFAP410‐related and
Axial spondylometaphyseal dysplasia, NEK1‐related. In addition, there are many reports of sporadic patients with unclassified SMD variants.
Chondrodysplasia‐pseudohermaphroditism syndrome,
HHAT‐related
Name of group/name of disorder
UNGER ET AL.
15524833, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.63132 by Test, Wiley Online Library on [20/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Group 13
NOS 12‐0060
Group number/number of
disorder
TABLE 1
12
(Continued)
Spondylar and nasal alterations with striated metaphyses
(SPONASTRIME dysplasia), TONSL‐related
Spondyloepiphyseal dysplasia, sensorineural hearing loss,
impaired intellectual development, and Leber congenital
amaurosis (SHILCA) syndrome, NMNAT1‐related
Platyspondyly (brachyolmia) with amelogenesis
imperfecta, LTBP3‐related
Cerebral, ocular, dental, auricular, and skeletal anomalies
(CODAS syndrome), LONP1‐related
Epiphyseal and vertebral dysplasia, microtia, flat nose plus
associated malformation (EVEN‐PLUS syndrome),
HSPA9‐related
Cataracts, growth hormone deficiency, sensory
neuropathy, sensorineural hearing loss, and skeletal
dysplasia (CAGSSS syndrome), IARS2‐related
Steel syndrome, COL27A1‐related
Rhizomelic spondylo‐metaphyseal dysplasia with
remission, LBR‐related
Rhizomelic spondylo‐epi‐metaphyseal dysplasia,
GNPNAT1‐related
NOS 13‐0240
NOS 13‐0250
NOS 13‐0260
NOS 13‐0270
NOS 13‐0280
NOS 13‐0290
NOS 13‐0300
NOS 13‐0310
NOS 13‐0320
Inheritance
Gene or locus
IARS2
AR
AR
AR
GNPNAT1
LBR
COL27A1
HSPA9
AR
AR
LONP1
AR
LTBP3
NMNAT1
AR
AR
TONSL
SLC39A13
AR
AR
MIM No.
619598
618019
615155
616007
616854
600373
601216
619260
271510
612350
Notes
Mitochondrial chaperonopathy
Mitochondrial chaperonopathy
Nonsyndromic Leber congenital amaurosis (LCA9; MIM
608553) is also caused by biallelic NMNAT1 variants
Possibly genetically heterogeneous
SLC39A13/ZIP13 zinc transporter
Achondrogenesis, TRIP11‐related (formerly type 1A)
Schneckenbecken dysplasia, SLC35D1‐related
Severe spondylometaphyseal dysplasia (Sedaghatian type),
GPX4‐related
Severe spondylometaphyseal dysplasia (SMD
Sedaghatian‐like), SBDS‐related
Opsismodysplasia, INPPL1‐related
Spondylometaphyseal dysplasia, PAM16‐ related
Carbohydrate deficient glycoprotein syndrome, ALG9‐
related (ALG9‐CDG; Gillessen‐Kaesbach‐Nishimura
syndrome)
NOS 14‐0010
NOS 14‐0020
NOS 14‐0030
NOS 14‐0040
NOS 14‐0050
NOS 14‐0060
NOS 14‐0070
AR
PAM16
ALG9
AR
INPPL1
SBDS
GPX4
SLC35D1
TRIP11
AR
AR
AR
AR
AR
263210, 608776
613320
258480
260400
250220
269250
200600
Includes lethal and milder cases
13
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(Continues)
See also Thanatophoric dysplasia, FGFR3‐related; achondrogenesis and Torrance dysplasia, COL2A1‐related; Fibrochondrogenesis, COL11A1‐related; Achondrogenesis, SLC26A2‐related;
and Metatropic Dysplasia, TRPV4‐related
Severe spondylodysplastic dysplasias
Group 14
See also: Opsismodysplasia, INPPL1‐related; Mucopolysaccharidosis type 4, GALNS‐related (type 4A; Morquio disease), as well as Progressive pseudorheumatoid dysplasia (PPRD), WISP3‐
related. See also the non‐genetic SEMD phenocopy, “Chondrodysplasia and growth failure following early hematopoietic stem cell transplantation”, ***https://doi.org/10.1002/ajmg.a.
62021, PMID: 33398909.
Spondylodysplastic Ehlers‐Danlos syndrome (SDEDSS
type 3), SLC39A13‐related
Name of group/name of disorder
NOS 13‐0230
Group number/number of
disorder
TABLE 1
UNGER ET AL.
AD
AR
Mesomelic dysplasia (Langer type), SHOX‐related
Omodysplasia, recessive type, GPC6‐related
Omodysplasia, dominant type, FZD2‐related
Robinow syndrome, WNT5A‐related
Robinow syndrome, DVL1‐related
Robinow syndrome, DVL3‐related
Robinow syndrome, FZD2‐related
Robinow syndrome, recessive type, ROR2‐related
Robinow syndrome, recessive type, NXN‐related
Mesomelic dysplasia, HOXD‐related (Kim or Korean type,
Kantaputra type, Fryns type)
Mesomelic dysplasia, Nievergelt type
Mesomelic dysplasia, Kozlowski‐Reardon type
Mesomelic dysplasia with acral synostoses (Verloes‐
David‐Pfeiffer type)
Mesomelic dysplasia (Savarirayan type), ID4‐related
Mesomelic dysplasia with digital anomalies and intellectual
disability (KINSSHIP syndrome), AFF3‐related
Oculo‐skeletal syndrome with rhizomelic shortening,
MAB21L2‐related
NOS 15‐0020
NOS 15‐0030
NOS 15‐0040
NOS 15‐0050
NOS 15‐0060
NOS 15‐0070
NOS 15‐0080
NOS 15‐0090
NOS 15‐0100
NOS 15‐0110
NOS 15‐0120
NOS 15‐0130
NOS 15‐0140
NOS 15‐0150
NOS 15‐0160
NOS 15‐0170
MAB21L2
AFF3
ID4
SULF1,
SLCO5A1
HOXD
NXN
ROR2
FZD2
DVL3
DVL1
WNT5A
FZD2
GPC6
SHOX
SHOX
Gene or locus
615877
619297
605274
600383
249710
163400
156232
268310
616894
616331
180700
164745
258315
249700
127300
MIM No.
In OMIM as “Microphthalmia/Coloboma and skeletal
dysplasia syndrome”. Skeletal involvement not in all
individuals. Two brothers with biallelic variants (AR?)
had ocular but no skeletal involvement.
In spite of the acronym, this condition is quite different
from both Nievergelt and Savarirayan mesomelic
dysplasias
Microdeletions on 6p22.3
Microdeletion syndrome involving two adjacent genes
Duplications at HOXD gene cluster locus; phenotypes is
variable also within families
Includes previous COVESDEM (costo‐vertebral
segmentation defect with mesomelia); see also
brachydactyly type B
Includes Reinhardt‐Pfeiffer dysplasia, MIM 191400.
Clinical continuum with Idiopathic short stature (MIM
300582)
Notes
Acromesomelic dysplasias
Acromesomelic dysplasia (type Maroteaux), NPR2‐related
Acromesomelic dysplasia, PRKG2‐related
NOS 16‐0010
NOS 16‐0020
AR
AR
PRKG2
NPR2
619636, 619638
602875
Condition associated with biallelic loss of function
variants. Three brothers form one family were found to
have a spondylo‐metaphyseal dysplasia phenotype (in
OMIM as “619638 ‐ Spondylometaphyseal dysplasia,
Pagnamenta type”. Needs to be confirmed)
UNGER ET AL.
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Group 16
See also Tibial hemimelia‐polysyndactyly‐triphalangeal thumb, ZRS‐related, also consider: mesomelic dysplasia, Camera type (MIM#611886), the status of which remains unconfirmed
AD
AD
AD
AD
AD
AR
AR
AD
AD
AD
AD
AD
AR
Pseudo‐AR
Pseudo‐AD
Dyschondrosteosis (Leri‐Weill), SHOX‐related
NOS 15‐0010
Inheritance
Name of group/name of disorder
Mesomelic and rhizo‐mesomelic dysplasias
Group 15
(Continued)
Group number/number of
disorder
TABLE 1
14
Grebe dysplasia, GDF5‐related
Grebe dysplasia, BMPR1B‐related
Fibular hypoplasia and complex brachydactyly (Du Pan),
GDF5‐related
Fibular hypoplasia and complex brachydactyly (Du Pan),
BMPR1B‐related
Acromesomelic dysplasia, Osebold‐Remondini type
Acromelic dysplasias
Acrocapitofemoral dysplasia, IHH‐related
Geleophysic dysplasia, ADAMTSL2‐related
Geleophysic dysplasia, FBN1‐related
Geleophysic dysplasia, LTBP3‐related
Acromicric dysplasia, FBN1‐related
Acromicric dysplasia, LTBP3‐related
Weill‐Marchesani syndrome, dominant, FBN1‐related
Weill‐Marchesani syndrome, ADAMTS10‐related
Weill‐Marchesani syndrome, ADAMTS17‐related
Weill‐Marchesani syndrome, LTBP2‐related
Myhre dysplasia, SMAD4‐related
Acrodysostosis, PDE4D‐related
Acrodysostosis, PRKAR1A‐related
Angel‐shaped phalango‐epiphyseal dysplasia (ASPED)
Albright hereditary osteodystrophy, GNAS‐related
Leri Pleonosteosis, linked to 8q22.1
SED with brachydactyly, MIR140‐related
NOS 16‐0040
NOS 16‐0050
NOS 16‐0060
NOS 16‐0070
Group 17
NOS 17‐0010
NOS 17‐0020
NOS 17‐0030
NOS 17‐0040
NOS 17‐0050
NOS 17‐0060
NOS 17‐0070
NOS 17‐0080
NOS 17‐0090
NOS 17‐0100
NOS 17‐0110
NOS 17‐0120
NOS 17‐0130
NOS 17‐0140
NOS 17‐0150
NOS 17‐0160
NOS 17‐0170
Inheritance
AD
AD
AD
AD
AD
AD
AD
AR
AR
AR
AD
AD
AD
AD
AD
AR
AR
AD
AR
AR
AR
AR
Gene or locus
MIR140
8q22.1
GNAS
PRKAR1A
PDE4D
SMAD4
LTBP2
ADAMTS17
ADAMTS10
FBN1
LTBP3
FBN1
LTBP3
FBN1
ADAMTSL2
IHH
BMPR1B
GDF5
BMPR1B
GDF5
MIM No.
618618
151200
103580
105835
101800
614613
139210
614819
613195
277600
608328
See 617809
102370
617809
614185
231050
607778
112910
See 603248
228900
609441
200700
Brachydactylies (isolated)
Brachydactyly type A1, IHH‐related
Brachydactyly type A2, BMPR1B‐related
Brachydactyly type A2, BMP2‐related
NOS 18‐0010
NOS 18‐0020
NOS 18‐0030
AD
BMP2
IHH
BMPR1B
AD
AD
112500
112600
112600
Notes
Duplication of BMP2 enhancer
Brachydactyly with cone‐shaped epiphyses
(Continues)
Duplication at 8q22.1 encompassing GDF6 and SDC2
Overlaps with progressive osseous heteroplasia
Possibly related or allelic to brachydactyly type C
Includes acroscyphodysplasia (see PMID 30006632)
Includes acrolaryngeal dysplasia, previously known as
Fantasy Island dysplasia or Tattoo dysplasia, and
Moore‐Federman syndrome
See other conditions associated with the IHH gene in this
table
See also other GDF5‐related disorders
Includes acromesomelic dysplasia Hunter‐Thompson type
and acromesomelic dysplasia with genital anomalies;
see also see other GDF5‐related disorders
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Group 18
See also Cartilage‐Hair Hypoplasia, RMRP‐related, and the brachdydactyly groups, below (Groups 18 and 19)
Name of group/name of disorder
NOS 16‐0030
(Continued)
Group number/number of
disorder
TABLE 1
UNGER ET AL.
Brachydactyly type A2, GDF5‐related
Brachydactyly type B1, ROR2‐related
Brachydactyly type B2, NOG‐related
Brachydactyly type C, GDF5‐related
Brachydactyly type D, HOXD13‐related
Brachydactyly type E, HOXD13‐related
Brachydactyly with anonychia (Cooks syndrome), KCNJ2‐
related
Preaxial brachydactyly, PAX3 type, linked to 2q35‐36
NOS 18‐0050
NOS 18‐0060
NOS 18‐0070
NOS 18‐0080
NOS 18‐0090
NOS 18‐0100
NOS 18‐0110
Brachydactylies as part of syndromes
Trichorhinophalangeal dysplasia types 1/3
Langer‐Giedion syndrome (Trichorhinophalangeal
dysplasia type 2)
Catel‐Manzke syndrome, TGDS‐related
Deafness, onychodystrophy, osteodystrophy, retardation
and seizures (DOORS) syndrome
Brachydactyly—intellectual disability syndrome, HDAC4‐
related
Hyperphosphatasia with intellectual disability,
brachytelephalangy, and distinct face, PIGV‐related
Brachydactyly‐short stature‐hypertension syndrome,
PDE3A‐related (Bilginturan syndrome)
Brachydactyly, obesity and intellectual disability
syndrome, PRMT7‐related
NOS 19‐0010
NOS 19‐0020
NOS 19‐0030
NOS 19‐0040
NOS 19‐0050
NOS 19‐0060
NOS 19‐0070
NOS 19‐0080
Inheritance
AR
AD
AR
AD
AR
AR
AD
AD
AD
AD
AD
AD
AD
AD
AD
AD
Gene or locus
PRMT7
PDE3A
PIGV
HDAC4
TBC1D24
TGDS
TRPS1, EXT1
TRPS1
2q35‐36
KCNJ2
HOXD13
HOXD13
GDF5
NOG
ROR2
GDF5
MIM No.
617157
112410
239300
600430
220500
616145
150230
190350, 190351
106995
113300
113200
113100
611377
113000
112600
Notes
Phenotype reminiscent of Albright Hereditary
Ostedystrophy (AHO), GNAS‐related (see above) but
recessive. In OMIM as “617157—Short stature,
brachydactyly, intellectual developmental disability, and
seizures”
Several other related defects of GPI synthesis known,
most cases not known for skeletal changes; see for
example, MIM 610293 for a summary
The existence of this entity is questionable. HDAC4
variants alone may not be sufficient to produce either
brachydactyly or intellectual disability. Some patients
have microdeletions involving contiguous genes (2q37
deletion syndrome). HDAC4 variants have been
associated with a developmental disorder (see MIM
619797)
“Osteodystrophy” and “retardation” are misnomers
Microdeletion syndrome; see also multiple cartilaginous
exostoses
TRPS1 and 3 are a phenotypic spectrum
Deletions leading to disruption of TADs and abnormal
expression of PAX3
Duplications of SOX9/KCNJ2 regulatory region
Brachydactyly type D is often a component of
Brachydactyly type E
See other GDF5‐related disorders
See also Robinow syndrome/COVESDEM
See also Grebe dysplasia, GDF5‐related; Fibular
hypoplasia and complex brachydactyly (Du Pan), GDF5‐
related; Brachydactyly type C, GDF5‐related; and
Multiple synostoses syndrome, GDF5‐related
UNGER ET AL.
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Group 19
See also brachdactyly, PTHLH‐related (below)
Name of group/name of disorder
NOS 18‐0040
(Continued)
Group number/number of
disorder
TABLE 1
16
(Continued)
Hand‐foot‐genital syndrome, HOXA13‐related
Rubinstein‐Taybi syndrome, CREBBP‐related
Rubinstein‐Taybi syndrome, EP300‐related
Brachydactyly, Temtamy type, CHSY1‐related
Hyperphalangism, characteristic facies, hallux valgus and
bronchomalacia (Chitayat syndrome), ERF‐related
Hypoacusis with facial an digital anomalies (Keipert
syndrome), GPC4‐related
Christian type brachydactyly
Coffin‐Siris syndrome, ARID1A‐related
Coffin‐Siris syndrome, ARIB1B‐related
Coffin‐Siris syndrome, SMARCB1‐related
Coffin‐Siris syndrome, SMARCA4‐related
Coffin‐Siris syndrome, SMARCE1‐related
Cardiomyopathy and brachydactyly, LMNA‐related (Heart‐
hand syndrome type IV)
NOS 19‐0100
NOS 19‐0110
NOS 19‐0120
NOS 19‐0130
NOS 19‐0140
NOS 19‐0150
NOS 19‐0160
NOS 19‐0170
NOS 19‐0180
NOS 19‐0190
NOS 19‐0200
NOS 19‐0210
NOS 19‐0220
Inheritance
AD
AD
AD
AD
AD
AD
AD
XL
AD
AR
AD
AD
AD
AD
Gene or locus
LMNA
SMARCE1
SMARCA4
SMARCB1
ARID1B
ARID1A
GPC4
ERF
CHSY1
EP300
CREBBP
HOXA13
MYCN
Campomelic dysplasia (CD), SOX9‐related
Stüve‐Wiedemann syndrome, LIFR‐related
Stüve‐Wiedemann syndrome, IL6ST‐related
Kyphomelic dysplasia with facial dysmorphism, KIF5B‐
related
Bent bone dysplasia, FGFR2‐related
Bent bone dysplasia, LAMA5‐related
NOS 20‐0010
NOS 20‐0020
NOS 20‐0030
NOS 20‐0040
NOS 20‐0050
NOS 20‐0060
AR
AD
AD
AR
AR
AD
LAMA5
FGFR2
KIF5B
IL6ST
LIFR
SOX9
MIM No.
614592
211350
619751
601559
114290
610140
616938
614609
614608
135900
614607
112450
301026
617180
605282
613684
180849
140000
164280
Biallelic LAMA5 variants are associated with congenital or
infantile nephrotic syndrome (MIM)
The name “kyphomelic dysplasia” has been applied to
heterogeneous conditions
Includes former neonatal Schwartz‐Jampel syndrome or
SJS type 2
Includes acampomelic campomelic dysplasia (ACD), mild
campomelic dysplasia (MIM 602196); so‐called Ischio‐
pubic‐patellar dysplasia, as well as some cases of
isolated Pierre‐Robin sequence
in OMIM as “Heart‐Hand syndrome, Slovenian type”
Variants in various components of the SWI/SNF complex
have been reported in patients with a diagnosis of
Coffin‐Siris syndrome
Brachytelephalangy is the most consistent skeletal signs
Typically a monoallelic Y89C substitution
Includes Guttmacher syndrome
Notes
17
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(Continues)
Bent bones is an unspecific finding, particularly in a prenatal setting, that can be observed in numerous other conditions, such as those with bone fragility; thus see the OI‐bone fragility
group (group 26) as well as Hypophosphatasia, ALPL‐related.
Bent bones dysplasia group
Group 20
See also CDP, X‐linked recessive, ARSE‐related (brachytelephalangic type; CDPX1)
Microcephaly‐oculo‐digito‐esophageal‐duodenal
syndrome, MYCN‐related (Feingold syndrome)
Name of group/name of disorder
NOS 19‐0090
Group number/number of
disorder
TABLE 1
UNGER ET AL.
Name of group/name of disorder
Primordial dwarfism and slender bones group
3‐M syndrome, CUL7‐related
3‐M syndrome, OBSL1‐related
3‐M syndrome, CCDC8‐related
Sanjad‐Sakati syndrome, recessive, TBCE‐related
Kenny‐Caffey syndrome, dominant, FAM111A‐related
Osteocraniostenosis, FAM111A‐related
Hallermann‐Streiff syndrome
Microcephalic osteodysplastic primordial dwarfism,
RNU4ATAC‐related
Roifman syndrome, RNU4ATAC‐related
Microcephalic osteodysplastic primordial dwarfism, PCNT‐
related
Microcephalic osteodysplastic primordial dwarfism, ATR‐
related
Microcephalic osteodysplastic primordial dwarfism,
RBBP8‐related
Microcephalic osteodysplastic primordial dwarfism,
CEP152‐related
Microcephalic osteodysplastic primordial dwarfism,
DNA2‐related
Microcephalic osteodysplastic primordial dwarfism,
TRAIP‐related
Microcephalic osteodysplastic primordial dwarfism,
NSMCE2‐related
Microcephalic osteodysplastic primordial dwarfism,
CENPE‐related
Microcephalic osteodysplastic primordial dwarfism,
CRIPT‐related
Microcephalic osteodysplastic primordial dwarfism,
XRCC4‐related
Group 21
NOS 21‐0010
NOS 21‐0020
NOS 21‐0030
NOS 21‐0040
NOS 21‐0050
NOS 21‐0060
NOS 21‐0070
NOS 21‐0080
NOS 21‐0090
NOS 21‐0100
NOS 21‐0110
NOS 21‐0120
NOS 21‐0130
NOS 21‐0140
NOS 21‐0150
NOS 21‐0160
NOS 21‐0170
NOS 21‐0180
NOS 21‐0190
(Continued)
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AD
AD
AR
AR
AR
AR
Inheritance
XRCC4
CRIPT
CENPE
NSMCE2
TRAIP
DNA2
CEP152
RBBP8
ATR
PCNT
RNU4ATAC
RNU4ATAC
FAM111A
FAM111A
TBCE
CCDC8
OBSL1
CUL7
Gene or locus
616541
615789
see 616051
617253
616777
615807
613823
606744
210600
210720
616651
210710
234100
602361
127000
241410
614205
612921
273750
MIM No.
In MIM as short stature, microcephaly and endocrine
dysfunction
In MIM as short stature with microcephaly and distinctive
facies
In MIM as autosomal recessive primary microcephaly
In MIM as Seckel syndrome 10
In MIM as Seckel syndrome 9
In MIM as Seckel syndrome 8. The DNA2 gene is also
associated with autosomal dominant progressive
external ophthalmoplegia with mitochondrial DNA
deletions (MIM 615156)
In MIM as Seckel syndrome 5. The CEP152 gene also
causes primary microcephaly (MIM 614852)
In MIM as Seckel syndrome 2. The RBBP8 gene is also
associated with Jawad syndrome (microcephaly with
intellectual disability and digital anomalies; MIM
251255)
In MIM as Seckel syndrome 1
Was MOPD2, Majewski type
See other RNU4ATAC‐related condition in this table
Was MOPD 1/3; usually homozygous variants; includes
Taybi‐Linder cephaloskeletal dysplasia
Usually sporadic; some cases have phenotypic overlap
with osteocraniostenosis, FAM111A‐related
In OMIM as “Kenny‐Caffey type 1” but does not
correspond to the disorder described by Kenny and
Caffey which is the dominant form
Includes dolichospondylic dysplasia and Yakut short
stature syndrome
Notes
UNGER ET AL.
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Group number/number of
disorder
TABLE 1
18
(Continued)
Microcephalic osteodysplastic primordial dwarfism, or
microcephaly‐short stature‐micromelia‐limb
abnormalities, DONSON‐related
IMAGE syndrome (intrauterine growth retardation,
metaphyseal dysplasia, adrenal hypoplasia, and genital
anomalies)
IMAGE syndrome/FILS syndrome, POLE‐related
Saul‐Wilson syndrome, COG4‐related
Short stature, facial dysmorphism, skeletal and dental
anomalies syndrome, SCUBE3‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin), ORC4‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin), ORC4‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin), ORC6‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin), CDT1‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin), CDC6‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin), CDC45‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin), MCM3‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin), MCM5‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin), MCM7‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin), GMNN‐related
Ear‐patella‐primordial short stature syndrome (Meier‐
Gorlin) with craniosynostosis, GINS2‐related
Lysosomal storage diseases with skeletal involvement
Mucopolysaccharidosis type 1, IDUA‐related
Mucopolysaccharidosis type 2, IDS‐related
Mucopolysaccharidosis type 3, SGSH‐related (type 3A)
NOS 21‐0210
NOS 21‐0220
NOS 21‐0230
NOS 21‐0240
NOS 21‐0250
NOS 21‐0260
NOS 21‐0270
NOS 21‐0280
NOS 21‐0290
NOS 21‐0300
NOS 21‐0310
NOS 21‐0320
NOS 21‐0330
NOS 21‐0340
NOS 21‐0350
Group 22
NOS 22‐0010
NOS 22‐0020
NOS 22‐0030
Name of group/name of disorder
AD
AR
XL
AR
AD
AD
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
SGSH
IDS
IDUA
GINS2
GMNN
MCM7
MCM5
MCM3
CDC45
CDC6
CDT1
ORC6
ORC4
ORC1
SCUBE3
COG4
POLE
CDKN1C
AD
AR
Gene or locus
DONSON
Inheritance
AR
MIM No.
252900
309900
607014, 607015, 607016
See 610609
613804
See 600592
602696
See 602693
603465
613805
605525
613803
613800
224690
619184
618150
618336, 615139
614732
251230, 617604
Notes
Known as Sanfilippo A syndrome
Known as Hunter syndrome
(Continues)
Was type 1H‐Hurler syndrome, type 1S‐Scheie syndrome
A single case reported so far
A single case reported so far
in OMIM as “short stature, facial dysmorphism, and
skeletal anomalies with or without cardiac anomalies 2”
The phenotype is variable and may include immune
deficiency (OMIM 615139)
Gene also known to cause Beckwith‐Wiedemann
syndrome (MIM 130650). IMAGE‐associated variants
are clustered in the PCNA‐binding region and are
maternally transmitted (gene is imprinted with
preferential maternal expression)
Milder affected patients may fall into the Meier‐Gorlin
syndrome spectrum
19
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NOS 21‐0200
Group number/number of
disorder
TABLE 1
UNGER ET AL.
Mucolipidosis III (Pseudo‐Hurler polydystrophy),
GNPTAB‐related
Mucolipidosis III (Pseudo‐Hurler polydystrophy), GNPTG‐
related
Mucolipidosis, GCAF‐related
Gaucher disease, GBA‐related
NOS 22‐0230
NOS 22‐0240
NOS 22‐0250
NOS 22‐0260
Inheritance
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
Gene or locus
GBA
CGAF
GNPTG
GNPTAB
GNPTAB
SUMF1
SLC17A5
PPGB
NEU1
GLB1
AGA
MANBA
MAN2B1
FUCA
VPS33A
ARSK
GUSB
ARSB
GLB1
GALNS
GNS
HSGNAT
NAGLU
MIM No.
230800
619345
252605
252600
252500
272200
269920
256540
256550
230500
208400
248510
248500
230000
617303
610011
253220
253200
253010
253000
252940
252930
252920
Notes
Long‐standing Gaucher disease can have bone changes
that are different from the “dysostosis multiplex”
pattern seen in other lysosomal diseases in this group
The gene was previously known as TMEM251 and
encodes for a “GNTAP cleavage and activity factor” (see
GNTAP, above)
In general somewhat milder phenotype than the GNPTAB‐
related form
The old entity of Pacman dysplasia is the prenatal
manifestation of mucolipidosis II with
hyperparathyroidism
Several forms of different severity
Several forms of different severity
Several forms, see also mucopolysaccharidosis type 4B
(Morquio B) above
Known as Sly syndrome
Known as Maroteaux‐Lamy syndrome
Known as Morquio B syndrome
Known as Morquio A syndrome
Known as Sanfilippo D syndrome
Known as Sanfilippo C syndrome
Known as Sanfilippo B syndrome
Chondrodysplasia punctata (CDP) group
CDP, X‐linked recessive, ARSE‐related
(brachytelephalangic type; CDPX1)
NOS 23‐0010
XL
ARSE
302950
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Group 23
See also familial arthritis with hyaluronidase deficiency (“mucopolysaccharidosis type 9”), HYAL1‐related; SEMD with elevated lysosomal enzymes, MBTPS1‐related, above; as well as
Farber disease, ASAH1‐related, below.
Mucolipidosis II (I‐cell disease), GNPTAB‐related
NOS 22‐0220
beta‐Mannosidosis, MANBA‐related
NOS 22‐0150
Multiple sulfatase deficiency, SUMF‐related
alpha‐Mannosidosis, MAN2B1‐related
NOS 22‐0140
Sialic acid storage disease (SIASD), SLC17A5‐related
Fucosidosis, FUCA‐related
NOS 22‐0130
NOS 22‐0210
Mucopolysaccharidosis‐plus syndrome, VPS33A‐related
NOS 22‐0120
NOS 22‐0200
Mucopolysaccharidosis type 10, ARSK‐related
NOS 22‐0110
Galactosialidosis, PPGB‐related
Mucopolysaccharidosis type 7, GUSB‐related
NOS 22‐0100
Sialidosis, NEU1‐related
Mucopolysaccharidosis type 6, ARSB‐related
NOS 22‐0090
NOS 22‐0190
Mucopolysaccharidosis type 4, GLB1‐related (type 4B)
NOS 22‐0080
NOS 22‐0180
Mucopolysaccharidosis type 4, GALNS‐related (type 4A)
NOS 22‐0070
Aspartylglucosaminuria, AGA‐related
Mucopolysaccharidosis type 3, GNS‐related (type 3D)
NOS 22‐0060
Gangliosidosis GM1, GLB1‐related
Mucopolysaccharidosis type 3, HSGNAT‐related (type 3C)
NOS 22‐0050
NOS 22‐0160
Mucopolysaccharidosis type 3, NAGLU‐related (type 3B)
NOS 22‐0170
Name of group/name of disorder
NOS 22‐0040
(Continued)
Group number/number of
disorder
TABLE 1
20
(Continued)
Congenital hemidysplasia, ichthyosis, limb defects (CHILD)
syndrome, NSDHL‐related
Keutel syndrome, MGP‐related
Greenberg dysplasia, LBR‐related
Rhizomelic CDP, PEX7‐related
Rhizomelic CDP, DHPAT‐related
Rhizomelic CDP, AGP5‐related
Rhizomelic CDP, FAR1‐related
Rhizomelic CDP, PEX5‐related
CDP tibial‐metacarpal type
NOS 23‐0030
NOS 23‐0040
NOS 23‐0050
NOS 23‐0060
NOS 23‐0070
NOS 23‐0080
NOS 23‐0090
NOS 23‐0100
NOS 23‐0110
Inheritance
AR
AR
AR
AR
AR
AR
AR
XL
XL
Gene or locus
PEX5
FAR1
AGPS
DHPAT
PEX7
LBR
MGP
NSDHL
EBP
MIM No.
118651
616716
616154
600121
222765
215100
215140
245150
308050
302960
Some cases possibly caused by maternal auto‐immune
disease
MIM calls this entity “peroxisomal fatty acyl‐CoA
reductase 1 disorder”; skeletal phenotype milder than
other rCDP forms. The FAR1 gene is also associated
with cataracts, spastic paraparesis, and speech delay
(MIM 619338, AD)
Includes hydrops‐ectopic calcification‐moth‐eaten
appearance dysplasia (HEM) and dappled diaphyseal
dysplasia; possibly includes also the ultrarare entity
designed as Astley‐Kendall dysplasia. See also the non‐
lethal condition associated with LBR, above
Notes
Osteopetrosis and related osteoclast disorders
Osteopetrosis, neonatal or infantile form, TCIRG1‐related
Osteopetrosis, neonatal or infantile form, CLCN7‐related
Osteopetrosis, neonatal or infantile form, SNX10‐related
Osteopetrosis, infantile form, with nervous system
involvement, OSTM1‐related
Osteopetrosis, infantile form, osteoclast‐poor with
immunoglobulin deficiency, TNFRSF11A‐related
Osteopetrosis, intermediate form, TCIRG1‐related
Osteopetrosis, intermediate form, TNFSF11‐related
Osteopetrosis, intermediate form, PLEKHM‐related
Osteopetrosis, intermediate form, CLCN7‐related
Osteopetrosis, late‐onset, dominant form, CLCN7‐related
NOS 24‐0010
NOS 24‐0020
NOS 24‐0030
NOS 24‐0040
NOS 24‐0050
NOS 24‐0060
NOS 24‐0070
NOS 24‐0080
NOS 24‐0090
NOS 24‐0100
AD
AR
AR
AR
AR
AR
AR
AR
AR
AR
CLCN7
CLCN7
PLEKHM1
166600
259710
611497
259700
259710
TCIRG1
612301
259720
615085
611490
259700
TNFSF11
TNFRSF11A
OSTM1
SNX10
CLCN7
TCIRG1
(Continues)
See also below in this group, dysosteosclerosis,
TNFRSF11A‐related, as well as MIM 602080‐familial
expansile osteolysis
Includes former osteopetrosis with infantile neuraxonal
dysplasia (MIM 600329)
‐
21
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Group 24
Note: stippling can occur in several syndromes such as Zellweger cerebro‐hepato‐renal syndrome (see OMIM for the many genetic types), Smith‐Lemli‐Opitz (MIM 270400), in
Mucolipidosis II (I‐cell disease), GNPTAB‐related, mild forms of Raine dysplasia, FAM20C‐related, and others. See also SEMD short limb‐abnormal calcification type, DDR2‐related.
Stippling in the fetus is also observed as a consequence of maternal auto‐immune disease, sometimes presenting as “CDP tibial‐metacarpal type”.
CDP, X‐linked dominant, EBP‐related (Conradi‐
Hünermann type; CDPX2)
Name of group/name of disorder
NOS 23‐0020
Group number/number of
disorder
TABLE 1
UNGER ET AL.
Osteopetrosis with renal tubular acidosis, CA2‐related
Osteopetrosis with ectodermal dysplasia and immune
defect (OLEDAID), IKBKG‐related
Osteopetrosis, moderate form, SLC4A2‐related
Osteopetrosis, moderate form with defective leucocyte
adhesion, FERMT3‐related
Osteopetrosis, moderate form with defective leucocyte
adhesion, RASGRP2‐related
Osteosclerotic metaphyseal dysplasia, LRKK1‐related
Pyknodysostosis, CTSK‐related
Dysosteosclerosis, SLC29A3‐related
Dysosteosclerosis, TNFRSF11A‐related
Dysosteosclerosis with degenerative encephalopathy and
brain malformation, CSF1R‐related
NOS 24‐0120
NOS 24‐0130
NOS 24‐0140
NOS 24‐0150
NOS 24‐0160
NOS 24‐0170
NOS 24‐0180
NOS 24‐0190
NOS 24‐0200
Inheritance
AR
AR
AR
AR
AR
AR
AR
AR
XL
AR
Gene or locus
CSF1R
TNFRSF11A
SLC29A3
CTSK
LRRK1
RASGRP2
FERMT3
SLC4A2
IKBKG
CA2
MIM No.
618476
224300
224300
265800
615198
615888
612840
See 109280
300301
259730
In OMIM as “Brain abnormalities, neurodegeneration and
dysosteosclerosis (BANDDOS)”; gene also associated
with MIM 221820—leukoencephalopathy with
spheroids.
This entity probably forms a spectrum with Osteopetrosis,
intermediate form, TNFSF11‐related (above)
In some individuals, the features of pyknodyostosis are
absent and the disorder mimics osteopetrosis
The name may be misleading as the condition is best
described as a form of osteopetrosis
OMIM only includes bleeding disorder, platelet type, 18
(MIM 615888) for this gene
In OMIM as Leucocyte Adhesion Deficiency 3 (LAD3)—
MIM 612840
A single adult patient reported, phenotype may evolve
Notes
Osteosclerotic disorders
Desmosterolosis, DHCR4‐related
Raine dysplasia, FAM20C‐related
Caffey disease, COL1A1‐related
Caffey dysplasia (severe variants with prenatal onset)
Dysplastic cortical hyperostosis, Kozlowski‐Tsuruta type
Dysplastic cortical hyperostosis, Al‐Gazali type
Osteopoikilosis, LEMD3‐related
Melorheostosis with osteopoikilosis, LEMD3‐related
Melorheostosis, MAP2K1‐related
NOS 25‐0010
NOS 25‐0020
NOS 25‐0030
NOS 25‐0040
NOS 25‐0050
NOS 25‐0060
NOS 25‐0070
NOS 25‐0080
NOS 25‐0090
SP
AD
AD
AR?
AD
AR
AR
MAP2K1
LEMD3
LEMD3
COL1A1
FAM20C
DHCR24
155950
166700
166700
601356
114000
114000
259775
602398
Possibly locus heterogeneity
Includes mixed sclerosing bone dysplasia
Includes Buschke‐Ollendorff syndrome (same OMIM
entry)
Only a few cases known. Im OMIM as “Lethal short‐limb
skeletal dysplasia, Al Gazali type” . Not to be confused
with “Al‐Gazali syndrome”, a rare variant of B3GALT6
disorders (see above)
A few sporadic cases known, phenotype consistent,
molecular basis unknown
Rare specific variants in COL1A1. See also osteogenesis
imperfecta related to collagen 1 genes.
Variable severity, many cases are perinatal severe, some
cases show survival to adulthood; then often combined
with FGF23 elevation and hypophosphatemic rickets
See also other sterol‐metabolism related conditions
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Group 25
Note: osteomesopyknosis (MIM 166450) may represent a form of osteopetrosis. In a pattern similar to the ciliary disorders, the phenotypes from individual loci are variable and may
overlap with those of other loci.
Name of group/name of disorder
NOS 24‐0110
(Continued)
Group number/number of
disorder
TABLE 1
22
(Continued)
Osteopathia striata with cranial sclerosis (OSCS), AMER1‐
related
Pyle disease, SFRP4‐related
Craniometaphyseal dysplasia, ANKH‐related
Craniometaphyseal dysplasia, GJA1‐related
Diaphyseal dysplasia Camurati‐Engelmann, TGFB1‐related
Hyperostosis‐Hyperphosphatemia syndrome, GALNT3‐
related
Hyperostosis‐Hyperphosphatemia syndrome, FGF23‐
related
Hyperostosis‐Hyperphosphatemia syndrome, KL‐relathed
Cerebellar hypoplasia‐endosteal sclerosis, POLR3B‐related
Hematodiaphyseal dysplasia Ghosal, TBXAS1‐related
Hypertrophic osteoarthropathy, HPGD‐related
Hypertrophic osteoarthropathy, SLCO2A1‐related
Oculodentoosseous dysplasia (ODOD), GJA1‐related,
dominant, mild type
Oculodentoosseous dysplasia (ODOD) GJA1‐related,
recessive, severe type
Osteoectasia with hyperphosphatasia (juvenile Paget
disease), OPG‐related
Osteosclerosis, LRP5‐related
Sclerosteosis, SOST‐related
Sclerosteosis, LRP4‐related
Endosteal hyperostosis, van Buchem type, SOST‐related
Endosteal hyperostosis, Worth type
Craniodiaphyseal dysplasia, SOST‐related
Craniodiaphyseal dysplasia, SP7‐related
Trichodentoosseous dysplasia, DLX3‐related
Diaphyseal medullary stenosis with malignant fibrous
histiocytoma, MTAP‐related
Craniotubular dysplasia, TMEM53‐related
Craniometadiaphyseal dysplasia, Wormian bone type
NOS 25‐0110
NOS 25‐0120
NOS 25‐0130
NOS 25‐0140
NOS 25‐0150
NOS 25‐0160
NOS 25‐0170
NOS 25‐0180
NOS 25‐0190
NOS 25‐0200
NOS 25‐0210
NOS 25‐0220
NOS 25‐0230
NOS 25‐0240
NOS 25‐0250
NOS 25‐0260
NOS 25‐0270
NOS 25‐0280
NOS 25‐0290
NOS 25‐0300
NOS 25‐0310
NOS 25‐0320
NOS 25‐0330
NOS 25‐0340
NOS 25‐0350
Name of group/name of disorder
Inheritance
Gene or locus
AR
TMEM53
MTAP
AD
AR
DLX3
SP7
SOST
LRP5
SOST
LRP4
SOST
LRP5
OPG
GJA1
GJA1
SLCO2A1
HPGD
TBXAS1
POLR3B
KL
AD
AR
AD
AD
AR
AR
AR
AD
AR
AR
AD
AD, AR
AR
AR
AR
AR
FGF23
GALNT3
AR
TGFB1
AD
GJA1
ANKH
SFRP4
AMER1
AR
AR
AD
AR
XL
MIM No.
269300
619727
112250
190320
See 606633
122860
144750
239100
614305
269500
144750, 607634
239000
257850
164200
614441
259100
231095
213002
617994
617993
211900
131300
218400
123000
265900
300373
Also known as Hardcastle disease
(Continues)
One family reported; SP7 variants also associated with
Osteogenesis imperfecta (MIM 613849), see below
Presumed dominant negative variant
Specific 52 kb deletion downstream of SOST
See also sclerosteosis, SOST‐related, below
Includes previous AD osteopetrosis type 1 (OPTA1)
Possibly homozygous form of mild ODOD
Includes cranio‐osteoarthropathy, some cases of recessive
pachydermoperiostosis, as well as recessively inherited
isolated digital clubbing (MIM 119900)
Formerly hyperphosphatemic tumoral calcinosis type 3
Formerly hyperphosphatemic tumoral calcinosis type 2
Formerly hyperphosphatemic tumoral calcinosis type 1
Gain‐of‐function variants
Recessive type
Dominant type
The name “metaphyseal dysplasia, Pyle type” is misleading
(no growth plate dysplasia) and should be avoided
Notes
23
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NOS 25‐0100
Group number/number of
disorder
TABLE 1
UNGER ET AL.
Lenz‐Majewski hyperostotic dysplasia, PTDSS1‐related
Osteochondrodysplasia with hypertrichosis (Cantu
syndrome), ABCC9‐related
Familial Paget disease of bone, SQSTM1‐related
Inclusion body myopathy, Paget disease of bone and
frontotemporal dementia
Endosteal hyperostosis, oligodontia, short stature, facial
dysmorphism and intellectual disability, POLR3GL‐
related
Metaphyseal dysplasia, Braun‐Tinschert type
Trichothiodystrophy with axial osteosclerosis
NOS 25‐0370
NOS 25‐0380
NOS 25‐0390
NOS 25‐0400
NOS 25‐0410
NOS 25‐0420
Inheritance
Gene or locus
POLR3GL
AR
AR
AD
VCP
SQSTM1
ABCC9
PTDSS1
AD
AD
AD
AD
MIM No.
605946
619234
167320
167250
239850
151050
A subset of patients with trichothiodystrophy have
marked osteosclerosis but have not been molecularly
characterized so far
Phenotypic elements will need to be evaluated more
precisely; one patient reported as Wiedemann‐
Rautenstrauch‐syndrome‐like
Monoallelic variants in the VCP gene are also associated
with MIM 616687‐Charcot‐Marie‐Tooth disease 2Y,
and with MIM 613954‐Frontotemporal dementia and/
or amyotrophic lateral sclerosis 6.
Notes
Osteogenesis imperfecta and bone fragility group
Osteogenesis imperfecta, non‐deforming (Sillence type 1),
COL1A1‐related
Osteogenesis imperfecta, non‐deforming (Sillence type 1),
COL1A2‐related
Osteogenesis imperfecta, severe perinatal form (Sillence
type 2) COL1A1‐related
Osteogenesis imperfecta, severe perinatal form (Sillence
type 2), COL1A2‐related
Osteogenesis imperfecta, severe perinatal form (Sillence
type 2), CRTAP‐related
Osteogenesis imperfecta, severe perinatal form (Sillence
type 2), P3H1‐related
Osteogenesis imperfecta, severe perinatal form (Sillence
type 2), PPIB‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), COL1A1‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), COL1A2‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), IFITM5‐related
NOS 26‐0010
NOS 26‐0020
NOS 26‐0030
NOS 26‐0040
NOS 26‐0050
NOS 26‐0060
NOS 26‐0070
NOS 26‐0080
NOS 26‐0090
NOS 26‐0100
AD
AD
AD
AR
AR
AR
AD
AD
AD
AD
IFITM5
COL1A2
COL1A1
PPIB
P3H1
CRTAP
COL1A2
COL1A1
COL1A2
COL1A1
610967
259420
259420
259440
610915
610682
166210
166210
166200
166200
In OMIM OI type III; phenotype is distinct but in some
instances can minimize OI type III
In OMIM as OI type III
In OMIM as OI type III
Formerly “perinatal lethal”; in OMIM as OI type IX
Formerly “perinatal lethal”; in OMIM as OI type VIII
Formerly “perinatal lethal”; in OMIM as OI type VII
Formerly “perinatal lethal”; in OMIM as OI type II
Formerly “perinatal lethal”; in OMIM as OI type II
Usually with persistently blue sclerae, can have signs of
connective tissue weakness (in MIM as OI type I)
Usually with persistently blue sclerae, can have signs of
connective tissue weakness (in MIM as OI type I)
UNGER ET AL.
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Group 26
See also the chondrodysplasia punctata group (group 23); as well as familial expansile osteolysis, TNFRSF11A‐related (below); and trichothiodystrophy with central osteosclerosis (PMID
15148554)
Name of group/name of disorder
NOS 25‐0360
(Continued)
Group number/number of
disorder
TABLE 1
24
(Continued)
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), SERPINF1‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), CRTAP‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), P3H1‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), PPIB‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), SERPINH1‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), FKBP10‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), TMEM38B‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), BMP1‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), WNT1‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), CREB3L1‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), SPARC‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), TENT5A‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), MBTPS2‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), MESD‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3) with neurodevelopmental features,
KDELR2‐related
Osteogenesis imperfecta, progressively deforming
(Sillence type 3), CCD134‐related
Osteogenesis imperfecta, moderate form (Sillence type 4),
COL1A1‐related
Osteogenesis imperfecta, moderate form (Sillence type 4),
COL1A2‐related
Osteogenesis imperfecta, moderate form (Sillence type 4),
WNT1‐related
NOS 26‐0120
NOS 26‐0130
NOS 26‐0140
NOS 26‐0150
NOS 26‐0160
NOS 26‐0170
NOS 26‐0180
NOS 26‐0190
NOS 26‐0200
NOS 26‐0210
NOS 26‐0220
NOS 26‐0230
NOS 26‐0240
NOS 26‐0250
NOS 26‐0260
NOS 26‐0270
NOS 26‐0280
NOS 26‐0290
Name of group/name of disorder
Inheritance
Gene or locus
AR
AD
AD
WNT1
COL1A2
COL1A1
CCD134
KDELR2
AR
AR
MESD
MBTPS2
TENT5A
SPARC
CREB3L1
WNT1
BMP1
TMEM38B
FKBP10
SERPINH1
PPIB
P3H1
CRTAP
SERPINF1
AR
XLR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
MIM No.
see 166220
166220
166220
619795
619131
618644
301014
617952
616507
616229
615220
614856
615066
610968
613848
see 259440
610915
610682
613982
Notes
In OMIM as OI type XV
In OMIM as OI type IV
In OMIM as OI type IV
In OMIM as OI typeXXII
In OMIM as OI type XXI. Frequency of
neurodevelopmental delay not clear yet.
In OMIM as OI type XX
In OMIM as OI type XIX
In OMIM as OI type XVIII
In OMIM as OI type XVII
(Continues)
In OMIM as OI type XVI. Has severe joint laxity and
scoliosis, Ehlers‐Danlos‐like
In OMIM as OI type XV. Biallelic variants; monoallelic
variants may result in AD osteoporosis.
In OMIM OI type XIII
In OMIM OI type XIV
In OMIM OI type XI
In OMIM OI type X
In OMIM OI type IX
In OMIM OI type VIII
In OMIM OI type VII
In OMIM as OI type VI
25
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NOS 26‐0110
Group number/number of
disorder
TABLE 1
UNGER ET AL.
(Continued)
AR
XL
Osteogenesis imperfecta, moderate form (Sillence type 4),
PPIB‐related
Osteogenesis imperfecta, moderate form (Sillence type 4),
FKBP10‐related
Osteogenesis imperfecta, moderate form (Sillence type 4),
SP7‐related
Osteogenesis imperfecta with calcification of interosseous
membranes and/or hypertrophic callus (OI type 5),
IFITM5‐related
Osteogenesis imperfecta with craniosynostosis (Cole‐
Carpenter syndrome), P4HB‐related
Osteogenesis imperfecta with craniosynostosis (Cole‐
Carpenter syndrome), SEC24D‐related
Osteoporosis – X‐linked form, PLS3‐related
Osteoporosis—X‐linked form, MBPTS2‐related
NOS 26‐0320
NOS 26‐0330
NOS 26‐0340
NOS 26‐0350
NOS 26‐0360
NOS 26‐0370
NOS 26‐0380
NOS 26‐0390
Gene or locus
AD
AR
AD
Osteoporosis—AD form, ARHGAP25‐related
Bruck syndrome type 1 (BS1), FKBP10‐related
Bruck syndrome type 2 (BS2), PLOD2‐related
Osteoporosis‐pseudoglioma syndrome, LRP5‐related
Bone fragility with calvarial “doughnut” lesions, SGSM2‐
related
Spondylo‐ocular dysplasia, XYLT2‐related
NOS 26‐0420
NOS 26‐0430
NOS 26‐0440
NOS 26‐0450
NOS 26‐0460
NOS 26‐0470
PLS3
XYLT2
SGMS2
LRP5
PLOD2
FKBP10
ARHGAP25
LRP5
WNT1
MBTPS2
MIM No.
605822
126550
259770
609220
259450
see 610587
166710, 601884
615220
301014
300910
616294
112240
610967
613849
see 610968
see 259440
see 610682
166220
Notes
Overlap with a spondylo‐metaphyseal dysplasia
phenotype
When eye involvement is absent, may mimic progressively
deforming or moderate OI (Sillence types 3 and 4)
See autosomal recessive OI, above; intrafamilial variability
between OI type 3, arthrogryposis and Bruck syndrome
1 is documented
Monoallelic variants; biallelic variants result in MIM
259770 osteoporosis‐pseudoglioma (see below); this
gene is also associated with hyperostotic forms (see
below) as well as with MIM 601813—exudative
vitreoretinopathy, as well as MIM 617875—polycystic
liver disease
OMIM OI type XV
In OMIM as OI type XIX; gene also associated with MIM
300918, MIM308205, MIM 308800
Was Cole‐Carpenter syndrome 2. Possibly misnomer, as
most patients do not have craniosynostosis but rather
large fontanels.
Craniosynostosis is not well documented in this condition
in spite of the name.
When calcification of intraosseous membranes or
hypertrophic callus are not observed, may mimic
progressively deforming or moderate OI (Sillence types
3 and 4)
In OMIM as OI type XII
In OMIM as OI type XI
In OMIM as OI type IX
In OMIM as OI type VII
in OMIM OI type IV
UNGER ET AL.
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AR
AR
AR
AD
AD
Osteoporosis—dominant form, WNT1‐related
Osteoporosis – AD form, LRP5‐related
NOS 26‐0400
NOS 26‐0410
XL
SEC24D
P4HB
IFITM5
AD
AD
SP7
FKBP10
PPIB
CRTAP
IFITM5
AR
AR
AD
AR
Osteogenesis imperfecta, moderate form (Sillence type 4),
CRTAP‐related
NOS 26‐0310
Inheritance
AD
Osteogenesis imperfecta, moderate form (Sillence type 4),
IFITM5‐related
Name of group/name of disorder
NOS 26‐0300
Group number/number of
disorder
TABLE 1
26
Gnathodiaphyseal dysplasia, ANO5‐related
Osteoporosis with developmental delay and microcephaly,
COPB2‐related
Geroderma osteodysplasticum, GORAB‐related
Cutis laxa, PYCR1‐related
Cutis laxa, ATP6V0A2‐related
Wiedemann‐Rautenstrauch syndrome, POLR3A‐related
Singleton‐Merten dysplasia, IFIH‐related
Singleton‐Merten dysplasia, DDX58‐related
NOS 26‐0490
NOS 26‐0500
NOS 26‐0510
NOS 26‐0520
NOS 26‐0530
NOS 26‐0540
NOS 26‐0550
Inheritance
AD
AD
AR
AR
AR
AR
AD
AD
Gene or locus
DDX58
IFIH1
POLR3A
ATP6V0A2
PYCR1
GORAB
COPB2
ANO5
MIM No.
616298
182250
264090
278250, 219200
612940
231070
619884
166260
Notes
Gene also associated with MIM 615846‐Aicardi‐Goutieres
syndrome 7, and OMIM 619773‐Immunodeficiency 95
Gene also associated with MIM 607694‐ Leukodystrophy,
hypomyelinating, with or without oligodontia and/or
hypogonadotropic hypogonadism
Autosomal recessive form, type 2A (ARCL2A); wrinkly skin
syndrome. Skeletal features overlapping with progeroid
EDS and geroderma osteodysplasticum
Autosomal recessive form, type 2B (ARCL2B). Skeletal
features overlapping with progeroid EDS and
geroderma osteodysplasticum
Clinically variable, microcephaly in some cases only
Gene also associated with OMIM 613319‐Miyoshi
muscular dystrophy 3, and OMIM 611307‐recessive
limb‐girdle muscular dystrophy 12
Disorders of bone mineralisation
Hypophosphatasia, ALPL‐related, recessive (biallelic) forms
Hypophosphatasia, ALPL‐related, dominant (monoallelic)
forms
Hypophosphatemic rickets, PHEX‐related
Hypophosphatemic rickets, FGF23‐related
Hypophosphatemic rickets, DMP1‐related
Hypophosphatemic rickets, ENPP1‐related
Hypophosphatemic rickets, SGK3‐related
Hypophosphatemic rickets with hypercalciuria, CLCN5‐
related
Hypophosphatemic rickets with hypercalciuria, SLC34A3‐
related
Vitamin D‐dependent rickets, CYP27B1‐related
Vitamin D‐dependent rickets, CYP2R1‐related
NOS 27‐0010
NOS 27‐0020
NOS 27‐0030
NOS 27‐0040
NOS 27‐0050
NOS 27‐0060
NOS 27‐0070
NOS 27‐0080
NOS 27‐0090
NOS 27‐0100
NOS 27‐0110
AR
AR
AR
AR
XL
AD
AR
AR
AD
XL
AD
CYP2R1
CYP27B1
SLC34A3
CLCN5
SGK3
ENPP1
DMP1
FGF23
PHEX
ALPL
ALPL
600081
264700
241530
300554
see 607591
613312
241520
193100
307800
146300
241500
Formerly type 1B
Formerly type 1A
Autosomal recessive (HHRH)
(Continues)
X‐linked; part of Dent's disease complex (progressive
proximal renal tubulopathy with hypercalciuria, low
molecular weight proteinuria, and nephrocalcinosis;
MIM 300009)
Autosomal dominant
Autosomal recessive (ARHR2)
Autosomal recessive (ARHR1)
Autosomal dominant
X‐linked, most common genetic form of
hypophosphatemic rickets
Includes juvenile and adult forms as well as
odontohypophosphatasia
Includes perinatal, infantile and juvenile forms
27
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Group 27
Note: some of the recently discovered OI variants are still limited to very small numbers of patients; thus, the association with OI “Sillence type 3” is tentative and may be too restrictive
as other phenotypes might emerge in the future. See also: Short stature, skeletal dysplasia, liver failure, optic nerve atrophy and Pelger‐Huet anomaly, NBAS‐related, above (Group 13);
as well as all the Loeys‐Dietz syndrome variants and the Snyder‐Robinson syndrome, SMS‐related (Group 31).
Name of group/name of disorder
NOS 26‐0480
(Continued)
Group number/number of
disorder
TABLE 1
UNGER ET AL.
Vitamin D‐dependent rickets, VDR‐related
Vitamin D‐dependent rickets, CYP3A4‐related
Vitamin D‐dependent rickets, HNRNPC‐related
Familial hyperparathyroidism, CDC73‐related
Familial hyperparathyroidism linked to chromosome 2
Familial hyperparathyroidism, GCM2‐related
Neonatal hyperparathyroidism, CASR‐related
Neonatal hyperparathyroidism, TRPV6‐related
Familial hypocalciuric hypercalcemia with transient
neonatal hyperparathyroidism, CASR‐related
Calcium pyrophosphate deposition disease (familial
chondrocalcinosis), ANKH‐related
Calcium pyrophosphate deposition disease (familial
chondrocalcinosis), TNFRSF11B‐related
Cutaneous skeletal hypophosphatemia syndrome
Cutaneous skeletal hypophosphatemia syndrome
NOS 27‐0130
NOS 27‐0140
NOS 27‐0150
NOS 27‐0160
NOS 27‐0170
NOS 27‐0180
NOS 27‐0190
NOS 27‐0200
NOS 27‐0210
NOS 27‐0220
NOS 27‐0230
NOS 27‐0240
Inheritance
MOS
MOS
AD
AD
AD
AR
AR, AD
AD
AD
AD
AD?
AD
AR
Gene or locus
NRAS
HRAS
TNFRSF11B
ANKH
CASR
TRPV6
CASR
GCM2
2p14‐p13.3
CDC73
HNRNPC
CYP3A4
VDR
MIM No.
see 602643
118600
145980
618188
239200
617343
610071
145000, 145001
see 164020
619073
277440
Notes
Somatic mosaicism for activating variants in NRAS with
elevated FGF23 levels
Somatic mosaicism for activating variants in HRAS with
elevated FGF23 levels
Apparently monoallelic gain‐of‐function variants
Loss‐of‐function variants (see also craniometaphyseal
dysplasia, dominant type)
Other forms of familial hypocalciuric hypercalcemia do not
show significant skeletal phenotypes
Transient form
“Severe” form (but see below, transient form also CASR‐
related). Variants in the CASR gene can also result in
autosomal dominant hypocalcemia (MIM 601198)
Variants in this gene also cause familial isolated
hypoparathyroidism (MIM 618883)
Linkage studies; no gene identified
With or without jaw tumors
Formerly type 2B; molecular basis (supposed HNRNPC
dominant negative) from a single patient
Formerly type 3; specific monoallelic variants that increase
enzyme activity leading to rapid degradation of active
vitamin D
Formerly type 2A
Metaphyseal dysplasia, Jansen type, PTHR1‐related
Metaphyseal dysplasia, Csukasi‐Krakow type, SIK3‐related
Blomstrand dysplasia, PTHR1‐related
Eiken dysplasia, PTHR1‐related
Brachydactyly, PTHLH‐related (brachdactyly type E2)
Osteolysis, PTHLH‐related
NOS 28‐0010
NOS 28‐0020
NOS 28‐0030
NOS 28‐0040
NOS 28‐0050
NOS 28‐0060
PTHLH
PTHLH
PTHR1
PTHR1
SIK3
PTHR1
613382
600002
215045
618162
156400
Duplications of PTHLH causing acro‐osteolysis; see also
Groups 30 and 18
Haploinsufficiency; with or without short stature
Caused by recessive (biallelic) hypomorphic variants
Caused by recessive (biallelic) loss‐of‐function variants
disruption of mTOR signaling downstream of the PTH
receptor
Caused by activating variants
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Note: see also Acrodysostosis, PDE4D‐related and PRKAR1A‐related, above; and Albright hereditary osteodystrophy, GNAS‐related. Monoallelic loss‐of‐function variants in PTHR1 lead to
primary failure of tooth eruption (MIM 125350)
AD
AD
AR
AR
AR
AD
Skeletal disorders of the parathyroid hormone signaling cascade
Group 28
Note: Hyperparathyroidism due to parathyroid adenoma occurs in a number of genetic disorders, for example, in Multiple Endocrine Neoplasias (see MIM for variants). See also Group 28,
below, as well as Raine dysplasia, FAM20C‐related
Name of group/name of disorder
NOS 27‐0120
(Continued)
Group number/number of
disorder
TABLE 1
28
Familial expansile osteolysis, TNFRSF11A‐related
Mandibuloacral dysplasia, LMNA‐related
Mandibuloacral dysplasia, ZMPSTE24‐related
Mandiculoacral dysplasia, MTX2‐related
Progeria, Hutchinson‐Gilford type, LMNA‐related
Multicentric osteolysis, nodulosis and arthropathy
(MONA), MMP2‐related
Multicentric osteolysis, nodulosis and arthropathy
(MONA), MMP14‐related
Hajdu‐Cheney syndrome, NOTCH2‐related
Multicentric carpal‐tarsal osteolysis with and without
nephropathy, MAFB‐related
Penttinen syndrome, PDGFRB‐related
Nestor Guillermo progeria syndrome, BANF1‐related
Farber disease, ASAH1‐related
NOS 29‐0010
NOS 29‐0020
NOS 29‐0030
NOS 29‐0040
NOS 29‐0050
NOS 29‐0060
NOS 29‐0070
NOS 29‐0080
NOS 29‐0090
NOS 29‐0100
NOS 29‐0110
NOS 29‐0120
AR
AR
AD
AD
AD
AR
AR
AD
AR
AR
AR
AD
Inheritance
ASAH1
BANF1
PDGFRB
MAFB
NOTCH2
MMP14
MMP2
LMNA
MTX2
ZMPSTE24
LMNA
TNFRSF11A
Gene or locus
603811
601812
166300
102500
277950
259600
176670
619127
608612
248370
174810, 602080
MIM No.
The chronic, adult form of Farber disease can present as
osteolysis
See also MIM 601812‐Kosaki overgrowth syndrome
Includes the Serpentine fibula‐polycystic kidney syndrome
(SFPKS)
A biallelic homozygous MMP14 variant seen in the original
Winchester syndrome family
Includes Winchester‐Torg syndrome and nodulosis‐
arthropathy‐osteolysis syndrome
See also Progeria (in this group), LMNA‐related
cardiomyopathy and brachydactyly (Group 19) as well
as many other conditions in MIM related to LMNA
Includes early‐onset familial Paget disease of bone. See
other TNFRSF11A‐related phenoytpes in Group 24
Notes
Disorganized development of skeletal components group
Multiple cartilaginous exostoses, EXT1‐related (MCE; or
multiple osteochondromas, MO)
Multiple cartilaginous exostoses, EXT2‐related (MCE; or
multiple osteochondromas, MO)
Cherubism, SH3BP2‐related
Fibrous dysplasia, polyostotic form (McCune‐Albright
syndrome), GNAS‐related
Progressive osseous heteroplasia (POH), GNAS‐related
Metachondromatosis, PTPN11‐related
Osteoglophonic dysplasia, FGFR1‐related
Fibrodysplasia ossificans progressiva (FOP), ACVR1‐
related
Neurofibromatosis type 1, NF1‐related
NOS 30‐0010
NOS 30‐0020
NOS 30‐0030
NOS 30‐0040
NOS 30‐0050
NOS 30‐0060
NOS 30‐0070
NOS 30‐0080
NOS 30‐0090
AD
AD
AD
AD
AD
MOS
AD
AD
AD
NF1
ACVR1
FGFR1
PTPN11
GNAS
GNAS
SH3BP2
EXT2
EXT1
162200
135100
166250
156250
166350
174800
118400
133701
133700
Most cases sporadic but dominant transmission
documented
(Continues)
Craniosynostosis is also an important feature (Group 34)
Loss‐of‐function variants (in contrast to Noonan
syndrome) with loss of heterozygosity in lesional tissue
Germline loss‐of‐function of paternal allele
Somatic mosaicism for gain‐of‐function variants; includes
Mazabraud syndrome with intramuscular myxomas
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Group 30
Note: several neurologic conditions may cause acroosteolysis. See also Osteolysis, PTHLH‐related (above), Pyknodysostosis, CTSK‐related; cleidocranial dysplasia, RUNX2‐related; Keutel
syndrome, MGP‐related; Singleton‐Merten dysplasia, IFIH‐related; and Singleton‐Merten dysplasia, DDX58‐related
Name of group/name of disorder
Osteolysis group
Group 29
(Continued)
Group number/number of
disorder
TABLE 1
UNGER ET AL.
Cherubism with gingival fibromatosis (Ramon syndrome)
Dysplasia epiphysealis hemimelica (Trevor)
Lipomembraneous osteodystrophy with
leukoencephalopathy, TREM2‐related (Nasu‐Hakola)
Lipomembraneous osteodystrophy with
leukoencephalopathy, TYROBP‐related (Nasu‐Hakola)
Enchondromatosis, IDH1‐related (Ollier disease)
Enchondromatosis, IDH2‐related (Ollier disease)
Enchondromatosis with hemangiomas, IDH1‐related
(Maffucci disease)
Enchondromatosis with hemangiomas, IDH2‐related
(Maffucci disease)
Metaphyseal chondromatosis with D‐2‐hydroxyglutaric
aciduria, IDH1‐related
Primary intraosseous vascular malformation, ELMO2‐
related
Osteofibrous dysplasia, MET‐related
Genochondromatosis
Gorham‐Stout disease and familial diffuse angiomatosis of
bone
NOS 30‐0110
NOS 30‐0120
NOS 30‐0130
NOS 30‐0140
NOS 30‐0150
NOS 30‐0160
NOS 30‐0170
NOS 30‐0180
NOS 30‐0190
NOS 30‐0200
NOS 30‐0210
NOS 30‐0220
SP (MOS?),
AD
AD
AD, SP
AR
MOS
MOS
MOS
MOS
MOS
AR
AR
SP
AR
Inheritance
MET
ELMO2
IDH1
IDH2
IDH1
IDH2
IDH1
TYROBP
TREM2
Gene or locus
see 123880
137360
607278
606893
614875
614569
614569
166000
166000
221770
618193
127800
266270
MIM No.
Notes
Severe Gorham‐Stout disease is mostly sporadic. Somatic
KRAS variants have been found in rare cases. In
contrast, milder cases may be familial (“familial diffuse
cystic angiomatosis of bone”; see OMIM 123880).
“Geno” from Greek “knee”, but upper limbs also affected.
Probably includes the condition known as Vaandrager‐
Peña syndrome
Possibly corresponding to the former “Campanacci dysplasia”
Includes so‐called cheirospondyloenchondromatosis.
Somatic mosaicism for IDH1 variants. Possibly also IDH2
variants but not yet well documented
Somatic mosaicism for IDH2 variants; significantly rarer
than IDH1 variants. See also MIM 147650 and 613657,
D‐2‐hydroxyglutaric aciduria 2
Somatic mosaicism for specific IDH1 variants. See also
MIM 147700 and 137800
Somatic mosaicism for IDH2 variants; significantly rarer
than IDH1 variants. See also MIM 147650 and 613657,
D‐2‐hydroxyglutaric aciduria 2
Somatic mosaicism for specific IDH1 variants. See also
MIM 147700 and 137800
Also known as presenile dementia with bone cysts
Also known as presenile dementia with bone cysts
Some familial cases reported (“familial Trevor disease”) but
probably represent a different condition
Some similarities to primary intraosseous vascular
malformation, ELMO2‐related (see below)
Marfan syndrome, FBN1‐related
Congenital contractural arachnodactyly (Beals‐Hecht
syndrome), FBN2‐related
NOS 31‐0010
NOS 31‐0020
FBN2
FBN1
121050
154700
See also as differential diagnosis: homocystinuria and
marfanoid habitus with ID (Lujan Fryns syndrome):
MED12; ZDHHC9; UPF3B
UNGER ET AL.
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AD
AD
Overgrowth (tall stature) syndromes and segmental overgrowth
Group 31
Note: PTEN‐related disorders are not included because the overgrowth is restricted to macrocephaly.‐ See also: Proteus syndrome, AKT1‐related; Spondyloenchondrodysplasia with
immune dysregulation (SPENCD), ACP5‐related; Spondyloepimetaphyseal dysplasia, COL2A1‐related (“SED with marked metaphyseal changes”, including
dysspondyloenchondromatosis); Cutaneous skeletal hypophosphatemia syndrome, HRAS‐ related and NRAS‐related. Some patients with SOX6 variants have osteochondromas.
Name of group/name of disorder
NOS 30‐0100
(Continued)
Group number/number of
disorder
TABLE 1
30
AD
AR
Loeys‐Dietz syndrome, TGFBR2‐related
Loeys‐Dietz syndrome, TGFB2‐related
Loeys‐Dietz syndrome, TGFB3‐related
Loeys‐Dietz syndrome, SMAD2‐related
Loeys‐Dietz syndrome, SMAD3‐related
Weaver syndrome, EZH2‐related
Cohen‐Gibson (Weaver‐like) syndrome, EED‐related
Imagawa‐Matsumoto (Weaver like) syndrome, SUZ12‐related
Sotos syndrome, NSD1‐related
Sotos syndrome, APC2‐related
Malan (Sotos‐like) syndrome, NFIX‐related
Luscan‐Lumish syndrome, SETD2‐related
Tatton‐Brown‐Rahman syndrome, DNMT3A‐related
Marshall‐Smith syndrome, NFIX‐related
Beckwith‐Wiedemann syndrome
Simpson‐Golabi‐Behmel syndrome, GPC3‐related
Proteus syndrome, AKT1‐related
Hypoinsulinemic hypoglycemia with hemihypertrophy
(HIHGHH), AKT2‐related
Congenital ipomatous overgrowth, vascular Malformations,
epidermal Nevi, spinal/skeletal anomalies/scoliosis
(CLOVES) syndrome, PIK3CA‐related
Fibroadipose hyperplasia, PIK3CA‐related
Snyder‐Robinson syndrome (intellectual disability, tall
stature, osteoporosis and fractures), SMS‐related
Overgrowth syndrome with 2q37 translocations
Tall stature with long halluces, NPR2‐related
Tall stature with long halluces, NPR3‐related
Moreno‐Nishimura‐Schmidt syndrome
NOS 31‐0040
NOS 31‐0050
NOS 31‐0060
NOS 31‐0070
NOS 31‐0080
NOS 31‐0090
NOS 31‐0100
NOS 31‐0110
NOS 31‐0120
NOS 31‐0130
NOS 31‐0140
NOS 31‐0150
NOS 31‐0160
NOS 31‐0170
NOS 31‐0180
NOS 31‐0190
NOS 31‐0200
NOS 31‐0210
NOS 31‐0220
NOS 31‐0230
NOS 31‐0240
NOS 31‐0250
NOS 31‐0260
NOS 31‐0270
NOS 31‐0280
Inheritance
Loeys‐Dietz syndrome, TGFBR1‐related
Gene or locus
NPR3
NPR2
NPPC
SMS
MIM No.
608811
619543
615923
see 600296
309583
See 171834
612918
176920
312870
130650
602535
615879
616831
614753
617169
117550
606245
617561
277590
613795
619656
615582
614816
610168
609192
Notes
(Continues)
Biallelic loss‐of‐function variants in NPR3; in OMIM as
Boudin‐Mortier syndrome
Monoallelic gain‐of‐function variants in NPR2; in OMIM as
epiphyseal chondrodysplasia, Miura type
Overgrowth probably caused by overexpression of NPPC
See MIM 171834 for the many conditions associated with
somatic PIK3CA variants
Also named PIK3CA‐related overgrowth syndrome
(PROS); somatic variants; see MIM 171834
Gene also associated with OMIM 125853 diabetes
mellitus type II
Variant or deletion of imprinted genes within the
chromosome 11p15.5 region
See also Malan syndrome. The localization of the
monoallelic variants determine the Malan vs. Marshall‐
Smith phenotype
Some cases reported with NSD1, EED, and SUZ12 variants
Osteopenia with propensity to fractures may be observed
in all variants of the Loeys‐Dietz syndrome
31
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SP
AR
AD
SP
XLR
PIK3CA
PIK3CA
MOS
MOS
AKT2
AKT1
GPC3
11p15.5
region
NFIX
DNMT3A
SETD2
NFIX
APC2
NSD1
SUZ12
EED
EZH2
SMAD3
SMAD2
TGFB3
TGFB2
TGFBR2
TGFBR1
AD
MOS
XL
AD
AD
AD
AD
AD
AD
AD
AD
AD
AD
AD
AD
AD
AD
Name of group/name of disorder
NOS 31‐0030
(Continued)
Group number/number of
disorder
TABLE 1
UNGER ET AL.
(Continued)
Kosaki overgrowth syndrome, PDGFRB‐related
Segmental odontomaxillary dysplasia, ACTB‐related
NOS 31‐0300
NOS 31‐0310
Inheritance
MOS
AR
AD, AR
Gene or locus
ACTB
PDGFRB
FGFR3
MIM No.
see 102630
616592
610474
Notes
See PMID 32585735; see also MIM 243310‐Baraitser‐
Winter syndrome
See also MIM 601812‐Pentinnen syndrome
Original family with monoallelic (dominant negative?)
variant; a second family with biallelic variants (see
Group 1)
Sterile multifocal osteomyelitis, periostitis, and pustulosis
(CINCA/NOMID‐like), IL1RN‐related
Chronic recurrent multifocal osteomyelitis with congenital
dyserythropoietic anemia (CRMO with CDA; Majeed
syndrome), LPIN2‐related
Familial juvenile arthritis with hyaluronidase deficiency,
HYAL1‐related
Hyaline Fibromatosis Syndrome, ANTXR2‐related
NOS 32‐0030
NOS 32‐0040
NOS 32‐0050
NOS 32‐0060
ANTXR2
236490, 228600
601492
609628
See 147679
607115
208230
Previously known as infantile systemic hyalinosis, juvenile
hyaline fibromatosis, and puretic syndrome
Also known as mucopolysaccharidosis type 9, although
clinically no storage
Also known as SED with progressive arthropathy
Cleidocranial dysplasia and related disorders
Cleidocranial dysplasia, RUNX2‐related
Cleidocranial‐like dysplasia, CBFB‐related
CDAGS syndrome (craniosynostosis, delayed fontanel
closure, parietal foramina, imperforate anus, genital
anomalies, skin eruption), RNU12‐related
Yunis‐Varon dysplasia, FIG4‐related
Yunis‐Varon dysplasia, VAC14‐related
Parietal foramina, MSX2‐related
NOS 33‐0010
NOS 33‐0020
NOS 33‐0030
NOS 33‐0040
NOS 33‐0050
NOS 33‐0060
AD
AR
MSX2
VAC14
FIG4
RNU12
AR
AR
CBFB
RUNX2
AD
AD
168500
216340
603116
See 121360
119600
Only one case of VAC14‐related Yunis‐Varon reported so
far, so association needs to be confirmed. Gene also
associated with OMIM 617054 Striatonigral
degeneration, childhood‐onset (several patients
reported)
Gene also causes OMIM 612577 amyotrophic lateral
sclerosis 11, and OMIM 611228 CMT disease 4J
See also MIM 601626, familial leukemia
See also MIM 156510‐metaphyseal dysplasia with
maxillary hypoplasia, as well as non‐syndromic midline
craniosynostosis, RUNX2‐related, below
UNGER ET AL.
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Group 33
Farber disease, ASAH1‐related (osteolysis group 29, and MIM 228000) shows phenotypic overlap with the conditions in this group.
AR
HYAL1
LPIN2
AR
AR
IL1RN
AR
CIAS1
AD
Chronic infantile neurologic cutaneous articular syndrome
(CINCA), CIAS1‐related (neonatal onset multisystem
inflammatory disease (NOMID))
NOS 32‐0020
WISP3
Progressive pseudorheumatoid dysplasia (PPRD), WISP3‐
related
NOS 32‐0010
AR
Genetic inflammatory or rheumatoid‐like osteoarthropathies
Group 32
See also: Shprintzen‐Goldberg syndrome, SKI‐related, in the craniosynostosis group. Note: this group does not include disorders that cause overgrowth secondary to vascular
malformations, such as Klippel‐Trenaunay syndrome, at least until a genetic (somatic) origin will have been demonstrated.
Camptodactyly, tall stature and hearing loss syndrome
(CATSHL), FGFR3‐related
Name of group/name of disorder
NOS 31‐0290
Group number/number of
disorder
TABLE 1
32
Parietal foramina, ALX4‐related
Parietal foramina with cleidocranial dysplasia, MSX2‐
related
NOS 33‐0080
Inheritance
AD
AD
Gene or locus
MSX2
ALX4
MIM No.
168550
609597
Notes
MSX2 variants also cause craniosynostosis Boston type
See also frontonasal dysplasia type 1
Syndromes featuring craniosynostosis
Pfeiffer syndrome, FGFR1‐related
Pfeiffer syndrome, FGFR2‐related
Apert syndrome, FGFR2‐related
Craniosynostosis with cutis gyrata (Beare‐Stevenson),
FGFR2‐related
Crouzon syndrome, FGFR2‐related
Crouzon‐like craniosynostosis with acanthosis nigricans,
FGFR3‐related
Craniosynostosis, Muenke type, FGFR3‐related
Antley‐Bixler syndrome, POR‐related
Craniosynostosis Boston type, MSX2‐related
Saethre‐Chotzen syndrome, TWIST1‐related
Shprintzen‐Goldberg syndrome, SKI‐related
Baller‐Gerold syndrome, RECQL4‐related
Carpenter syndrome, RAB23‐related
Carpenter syndrome, MEGF8‐related
Craniosynostosis, TCF12‐related
Craniosynostosis, SIX1‐related
Complex craniosynostosis, ERF‐related
Non‐syndromic midline (metopic / sagittal)
craniosynostosis, SMAD6‐related
Non‐syndromic midline craniosynostosis, RUNX2‐related
NOS 34‐0010
NOS 34‐0020
NOS 34‐0030
NOS 34‐0040
NOS 34‐0050
NOS 34‐0060
NOS 34‐0070
NOS 34‐0080
NOS 34‐0090
NOS 34‐0100
NOS 34‐0110
NOS 34‐0120
NOS 34‐0130
NOS 34‐0140
NOS 34‐0150
NOS 34‐0160
NOS 34‐0170
NOS 34‐0180
NOS 34‐0190
AD
AD?
AD
AD
AD
AR
AR
AR
AD
AD
AD
AR
AD
AD
AD
AD
AD
AD
AD
RUNX2
SMAD6
ERF
SIX1
TCF12
MEGF8
RAB23
RECQL4
SKI
TWIST1
MSX2
POR
FGFR3
FGFR3
FGFR2
FGFR2
FGFR2
FGFR2
FGFR1
617439
600775
see 601205
615314
614976
201000
218600
182212
101400
604757
201750
602849
612247
123500
123790
101200
101600
101600
(Continues)
Gain‐of‐function variants, duplications, triplications
Rare SMAD6 variants and a common BMP2 polymorphism
may interact to produce craniosynostosis; subject
disputed
Variants in ERF also cause Chitayat hyperphalangism
syndrome (Group 19)
Frequently sagittal and lambdoid synostosis. See also MIM
608389—Branchiootic syndrome 3, and 605192—
deafness, autosomal dominant 23, for other SIX1‐
related phenotypes
Frequently coronal craniosynostosis
See other phenotypes associated with RECQL4 variants,
above
Variants in FGFR3, FGFR2, and TCF12 have been reported
to cause phenotypes resembling Saethre‐Chotzen
syndrome
Heterozygous p.P148H variant in a two families
Defined by specific FGFR3 p.P250R variant
Defined by specific FGFR3 p.A391E variant; also known as
Crouzonodermoskeletal syndrome
Notably p.S372Y or p.Y375C variants
Most have FGFR1 p.P252R variant; Includes Jackson‐
Weiss syndrome (MIM 123150)
33
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Group 34
See also: pyknodysostosis, CTSK‐related; cutis laxa, ATP6V0A2‐related; mandibuloacral dysplasia, LMNA‐related; progeria, Hutchinson‐Gilford type, LMNA‐related; and Hajdu‐Cheney
syndrome, NOTCH2‐related, for similar clavicular defects or osteolysis. See also Crane‐Heise syndrome (MIM 218090), the nosologic status of which remains unclear.
Name of group/name of disorder
NOS 33‐0070
(Continued)
Group number/number of
disorder
TABLE 1
UNGER ET AL.
(Continued)
Craniosynostosis and dental anomalies (CRSDA), IL11RA‐
related
Craniosynostosis, retained deciduous teeth and
intellectual disability, IL6ST‐related
Cutis laxa with craniosynostosis, short stature,
brachydactyly, and syndactyly, LTBP1‐related
Bohring‐Opitz syndrome, ASXL1‐related
Craniosynostosis, radiohumeral fusion and other skeletal
defects, CYP26B1‐related
Cardiac, facial and digital anomalies with developmental
delay (CAFDADD), TRAF7‐related
Craniosynostosis, hypertrichosis, progeroid appearance,
bone dysplasia, characteristic face (Fontaine progeroid
syndrome, Gorlin‐Chaudhry‐Moss syndrome),
SLC25A24‐related
Curry‐Jones syndrome, SMO‐related
3MC syndrome, MASP1‐related
3MC syndrome, COLEC11‐related
3MC syndrome, COLEC10‐related
Weiss‐Kruszka syndrome, ZNF462‐related
Au‐Kline syndrome, HNRNPK‐related
Char syndrome, TFAP2B‐related
Syndrome with developmental and speech delay,
dysmorphic facies, craniosynostosis and T‐cell
abnormalities
NOS 34‐0210
NOS 34‐0220
NOS 34‐0230
NOS 34‐0240
NOS 34‐0250
NOS 34‐0260
NOS 34‐0270
NOS 34‐0280
NOS 34‐0290
NOS 34‐0300
NOS 34‐0310
NOS 34‐0320
NOS 34‐0330
NOS 34‐0340
NOS 34‐0350
Inheritance
Gene or locus
TFAP2B
BCL11B
AD
HNRNPK
ZNF462
COLEC10
COLEC11
MASP1
AD
AD
AD
AR
AR
AR
SMO
SLC25A24
AD
MOS
TRAF7
CYP26B1
ASXL1
LTBP1
IL6ST
IL11RA
ZIC1
AD
AR
AD
AR
AR
AR
AD
MIM No.
618092
169100
616580
618619
248340
265050
257920
601707
612289
618164
614416
605039
619451
see 600694
614188
618736
Craniosynostosis in some affected individuals
Mainly with loss‐of‐function variants
Craniosynostosis and vertebral anomalies in a significant
proportion of cases
Metopic ridging or CSO (metopic, lambdoid, 9/24)
Craniosynostosis in 20%–30%
Craniosynostosis in 20%–30%
Craniosynostosis in 20%–30%
Activating variant c.1234C>T (p.L412F)
Multistructure craniosynostosis is one of the features
CYP26B1 is a retinoid acid‐degrading enzyme,
pathogenesis involves retinoic acid‐associated
morphogenesis
Single case reported, with preserved LIF signaling. See
Stüve‐Wiedemann syndrome, IL6ST‐related (above,
group 24) as well as IL6ST‐MIM 600694 for other
phenotypes associated with IL6ST
Notes
Craniofacial dysostoses
Mandibulofacial dysostosis, TCOF1‐related (Treacher‐
Collins, Franceschetti‐Klein)
NOS 35‐0010
AD
TCOF1
154500
UNGER ET AL.
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Group 35
Craniosynostosis is not rare and may have a non‐genetic pathogenesis in many cases. It can also occur secondarily in any form of rickets. Conditions in which craniosynostosis is an
occasional feature have not been included. See also: cranioectodermal dysplasia (several types in the ciliopathy group); SEMD, RSPRY1‐related; osteocraniostenosis, FAM111A‐related;
Osteogenesis imperfecta with craniosynostosis (Cole‐Carpenter syndrome), P4HB‐related; CDAGS syndrome, RNU12‐related; syndactyly (Lueken type, with or without
craniosynostosis), IHH‐related; and Multiple synostoses syndrome, FGF9‐related. Craniosynostosis can also be present in Loeys‐Dietz syndromes, Meier‐Gorlin syndrome, CDC45‐
related and GINS2‐related; Hypophosphatasia, ALPL‐related; Hypophosphatemic rickets, PHEX‐related; Greig cephalopolysyndactyly syndrome, GLI3‐related; and others.
Structural brain anomalies with impaired ID and
craniosynostosis / craniosynostosis type 6
Name of group/name of disorder
NOS 34‐0200
Group number/number of
disorder
TABLE 1
34
(Continued)
Frontonasal dysplasia, ALX3‐related
Frontonasal dysplasia, ALX4‐related
Frontonasal dysplasia, ALX1‐related
Frontonasal dysplasia, SIX2‐related
Frontonasal dysplasia with additional malformations
(Sweeney‐Cox syndrome), TWIST1‐related
Craniofrontonasal syndrome, EFN1B‐related
Acromelic frontonasal dysostosis, ZSWIM6‐related
Richieri‐Costa‐Pereira syndrome, EIF4A3‐related
Auriculocondylar syndrome, GNAI3‐related (type 1)
Auriculocondylar syndrome, PLCB4‐related (type 2)
Auriculocondylar syndrome, EDN1‐related (type 3)
NOS 35‐0120
NOS 35‐0130
NOS 35‐0140
NOS 35‐0150
NOS 35‐0160
NOS 35‐0170
NOS 35‐0180
NOS 35‐0190
NOS 35‐0200
NOS 35‐0210
NOS 35‐0220
Craniolenticulosutural dysplasia, SEC23A‐related
Agnathia‐Otocephaly complex, PRRX1‐related
NOS 35‐0110
Teebi hypertelorism syndrome, SPECCIL‐related
Acrofacial dysostosis, SF3B4‐related (Nager syndrome)
NOS 35‐0100
NOS 35‐0270
Postaxial acrofacial dysostosis, DHODH‐related (Miller
syndrome)
NOS 35‐0090
NOS 35‐0260
Burns‐McKeown syndrome, TXNL4A‐related
NOS 35‐0080
Weyers acrofacial (acrodental) dysostosis, EVC2‐related
Mandibulofacial dysostosis with alopecia, EDNRA‐related
NOS 35‐0070
NOS 35‐0250
Mandibulofacial dysostosis with microcephaly, EFTUD2‐
related (Guion‐Almeida type)
NOS 35‐0060
Orofaciodigital syndrome type I, OFD1‐related
Mandibulofacial dysostosis with limb deficiencies,
POLR1A‐related (Cincinnati type)
NOS 35‐0050
Weyers acrofacial (acrodental) dysostosis, EVC1‐related
Mandibulofacial dysostosis, POLR1D‐related (Treacher‐
Collins, Franceschetti‐Klein)
NOS 35‐0040
NOS 35‐0230
Mandibulofacial dysostosis, POLR1C‐related (Treacher‐
Collins, Franceschetti‐Klein)
NOS 35‐0030
Inheritance
AR, AD
AD
AD
AD
XL
AR
AR, AD
AD
AR
AD
XL
AD
AD
AR
AR
AR
AD, AR
AD, AR
AR
AR
AD
AD
AD
AD, AR
AR
AD
Gene or locus
SEC23A
SPECC1L
EVC2
EVC1
OFD1
EDN1
PLCB4
GNAI3
EIF4A3
ZSWIM6
EFNB1
TWIST1
SIX2
ALX1
ALX4
ALX3
PRRX1
SF3B4
DHODH
TXNL4A
EDNRA
EFTUD2
POLR1A
POLR1D
POLR1C
POLR1B
MIM No.
607812
145420
193530
193530
311200
615706
614669
602483
268305
603671
304110
617746
See 604994
613456
613451
136760
202650
154400, 201170
263750
608572
616367
610536
616462
613717
248390
618939
Monoallelic and biallelic inheritance observed
See also Group 10
See also Group 10
(Continues)
Results from specific amino acid substitutions in TWIST1
Both monoallelic and biallelic variants are at the basis of a
spectrum that also includes the former “Rodriguez type”
of acrofacial dysostosis
Some pathogenic variants are in the promoter region;
severity is variable
The original description was “acrofacial dysostosis: a
mandibulofacial dysostosis with limb anomalies”. The
limb anomalies are variable
Notes
35
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NOS 35‐0240
Mandibulofacial dysostosis, POLR1B‐related (Treacher‐
Collins, Franceschetti‐Klein)
Name of group/name of disorder
NOS 35‐0020
Group number/number of
disorder
TABLE 1
UNGER ET AL.
(Continued)
Baraitser‐Winter syndrome, ACTB‐related
Baraitser‐Winter syndrome, ACTG1‐related
Cerebrofaciothoracic dysplasia, TMCO1‐related
Opitz GBBB syndrome, MID1‐related
Arhinia microphthalmia syndrome, SMCHD1‐related
(Bosma)
Acrofrontofacionasal dysostosis
Hemifacial microsomia
NOS 35‐0290
NOS 35‐0300
NOS 35‐0310
NOS 35‐0320
NOS 35‐0330
NOS 35‐0340
NOS 35‐0350
Inheritance
SP, AD
AR
AD
XL
AR
AD
AD
XL
Gene or locus
SMCHD1
MID1
TMCO1
ACTG1
ACTB
FGD1
MIM No.
164210
201180
603457
300000
213980
614583
243310
305400
Includes Goldenhar syndrome and Oculo‐Auriculo‐
Vertebral spectrum; genetically heterogeneous; SF3B2
haploinsufficiency identified in ~3% of sporadic and
~25% of familial cases; in some cases a microduplication
on 14q23.1
Notes
Vertebral and costal dysostoses
Currarino syndrome, MNX1‐related
Spondylocostal dysostosis, DLL3‐related
Spondylocostal dysostosis, MESP2‐related
Spondylocostal dysostosis, LFNG‐related
Spondylocostal dysostosis, HES7‐related
Spondylocostal dysostosis, TBX6‐related
Spondylocostal dysostosis, RIPPLY2‐related
Vertebral segmentation defect (congenital scoliosis) with
variable penetrance, MESP2‐related
Vertebral segmentation defect (congenital scoliosis) with
variable penetrance, HES7‐related
Short stature, cervical segmentation defects, and
developmental delay, CDK10‐related
Klippel‐Feil syndrome, GDF6‐related
Klippel‐Feil syndrome, MEOX1‐related
Klippel‐Feil syndrome, GDF3‐related
Klippel‐Feil syndrome, MYO18B‐related
NOS 36‐0010
NOS 36‐0020
NOS 36‐0030
NOS 36‐0040
NOS 36‐0050
NOS 36‐0060
NOS 36‐0070
NOS 36‐0080
NOS 36‐0090
NOS 36‐0100
NOS 36‐0110
NOS 36‐0120
NOS 36‐0130
NOS 36‐0140
AR
AD
AR
AD
AR
AD
AD
AR
AR, AD
AR
AR
AR
AR
AD
MYO18B
GDF3
MEOX1
GDF6
CDK10
HES7
MESP2
RIPPLY2
TBX6
HES7
LFNG
MESP2
DLL3
MNX1
616549
613702
214300
118100
617694
613686
608681
616566
122600
613686
609813
608681
277300
176450
Role of GDF6 variants in Klippel‐Feil syndrome as well as
in AD spondylothoracic dysostosis remains unclear
Possible role of CNVs in TBX6
Possible role of CNVs in TBX6 in modulating the
phenotype?
Possible clinical overlap with caudal regression syndrome
(see MIM 600145; the role of heterozygous variants in
VANGL1 remains to be confirmed)
UNGER ET AL.
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Group 36
See also orofaciodigital syndrome type 4 (Mohr‐Majewski), TCTN3‐related; Endocrine‐cerebro‐osteo dysplasia (ECO), CILK1‐related; the Cerebro‐Costo‐Mandibular syndrome, SNRPB‐
related (group 36, below); and Robinow syndrome (see variants in Group 15)
Faciogenital dysplasia, FGD1‐related (Aarskog‐Scott
syndrome)
Name of group/name of disorder
NOS 35‐0280
Group number/number of
disorder
TABLE 1
36
Cervico‐oculo‐acoustic (Wildervanck) syndrome
Cerebro‐costo‐mandibular syndrome (rib gap syndrome),
SNRPB‐related
Cerebro‐costo‐mandibular‐like syndrome, COG1‐related
Diaphanospondylodysostosis, BMPER‐related
Spondylo‐megaepiphyseal‐metaphyseal dysplasia
(SMMD), NKX3‐2‐related
NAD deficiency syndrome, HAAO‐related
NAD deficiency syndrome, KYNU‐related
NAD deficiency syndrome, NADSYN1‐related
VATER/VACTERL association
VACTERL association with hydrocephalus (VACTERL‐H),
FANCB‐related
VACTERL association with hydrocephalus (VACTERL‐H),
ZIC3‐related
Uniparental disomy, paternal, for chromosome 14
(UPD14; Kagami‐Ogata syndrome)
NOS 36‐0160
NOS 36‐0170
NOS 36‐0180
NOS 36‐0190
NOS 36‐0200
NOS 36‐0210
NOS 36‐0220
NOS 36‐0230
NOS 36‐0240
NOS 36‐0250
NOS 36‐0260
SP
XL
XL
SP
AR
AR
AR
AR
AR
AR
AD
SP
Inheritance
14q32?
ZIC3
FANCB
NADSYN1
KYNU
HAAO
NKX3‐2
BMPER
COG1
SNRPB
Gene or locus
MIM No.
608149
314390
300514
192350
618845
617661
617660
613330
608022
611209
117650
314600
Notes
Imprinted genes at 14q32 may have a role in this complex
phenotype with skeletal malformations such as “coat‐
hanger ribs”
FANCB‐related Fanconi anemia may present in
hemizygous males with the VACTERL‐hydrocephalus
phenotype
In some cases VACTERL‐like
In some cases VACTERL‐like
With associated cardiac, limb and renal defects;
VACTERL‐like
Includes ischiospinal dysostosis, a term that has been used
for milder cases
Also known as CDG IIg
Congenital perceptive deafness, Klippel‐Feil anomaly (see
118100), and abducens palsy with retractio bulbi
Ischiopatellar dysplasia (small patella syndrome), TBX4‐
related
Nail‐patella syndrome, LMX1B‐related
Genitopatellar syndrome, KAT6B‐related
NOS 37‐0010
NOS 37‐0020
NOS 37‐0030
AD
AD
AD
KAT6B
LMX1B
TBX4
606170
161200
147891
See MIM 601360—posterior amelia for the biallelic
phenotype
Limb hypoplasia—reduction defects group
Ulnar‐mammary syndrome, TBX3‐related
Holt‐Oram syndrome, TBX5‐related
Holt‐Oram/Ulnar Mammary blended phenotype
NOS 38‐0010
NOS 38‐0020
NOS 38‐0030
AD
AD
AD
TBX3, TBX5
TBX5
TBX3
142900
181450
(Continues)
CNVs involving both TBX3 and TBX5 may result in
combined phenotype
37
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Group 38
See also Meier‐Gorlin syndromes in the primordial dwarfism group (Group 21), and the pseudoachondroplasia/MED group (Group 9) for conditions with patellar changes; see also ischio‐
pubic‐patellar dysplasia as mild expression of campomelic dysplasia, SOX9‐related; RAPADILINO syndrome, RECQL4‐related. Patellar hypoplasia is variably present in Clubfoot with or
without deficiency of long bones and/or mirror‐image polydactyly, PITX1‐related.
Patellar dysostoses
Group 37
VACTERL is nowadays defined as a “Recurrent Constellation of Embryonic Malformations” (RCEM; see Adam et al, AJMG 2020) without a single genetic basis. It may be mimicked by
NAD deficiency syndrome, Fanconi anemia and others. The diagnosis is supported by negative genetic analysis. See also spondylocarpotarsal synostosis syndrome, FLNB‐related and
RFLNA‐related, Robinow syndrome (variants in Group 15), and cerebrofaciothoracic dysplasia, TMCO1‐related (Group 35)
Name of group/name of disorder
NOS 36‐0150
(Continued)
Group number/number of
disorder
TABLE 1
UNGER ET AL.
Name of group/name of disorder
Posterior Amelia, TBX4‐related
Cornelia de Lange syndrome, NIPBL‐related
Cornelia de Lange syndrome, SMC1A‐related
Cornelia de Lange syndrome, SMC3‐related
Cornelia de Lange syndrome, RAD21‐related
Cornelia de Lange syndrome, HDAC8‐related
Thrombocytopenia‐absent radius (TAR) syndrome,
RBM8A‐related
Thrombocythemia with distal limb defects, THPO‐related
Okihiro syndrome (Duane syndrome with radial ray
anomaly), SALL4‐related
Cousin syndrome, TBX15‐related
Roberts syndrome, ESCO2‐related
Tibial hemimelia‐polysyndactyly‐triphalangeal thumb
(Werner syndrome), ZRS‐related
Clubfoot with or without deficiency of long bones and/or
mirror‐image polydactyly, PITX1‐related
Acheiropodia, LMBR1‐related
Engrailed‐1 related dorsoventral syndrome (ENDOVES),
limb‐brain type
Engrailed‐1 related dorsoventral syndrome (ENDOVES),
limb‐only type
Tetra‐amelia, WNT3‐related
Tetra‐amelia, RSPO2‐related
Limb reduction syndrome, WNT7A‐related
RAPADILINO syndrome, RECQL4‐related
Rothmund‐Thompson syndrome, RECQL4‐related
Rothmund‐Thompson syndrome, ANAPC1‐related
Rothmund‐Thompson syndrome, DNA2‐related
NOS 38‐0040
NOS 38‐0050
NOS 38‐0060
NOS 38‐0070
NOS 38‐0080
NOS 38‐0090
NOS 38‐0100
NOS 38‐0110
NOS 38‐0120
NOS 38‐0130
NOS 38‐0140
NOS 38‐0150
NOS 38‐0160
NOS 38‐0170
NOS 38‐0180
NOS 38‐0190
NOS 38‐0200
NOS 38‐0210
NOS 38‐0220
NOS 38‐0230
NOS 38‐0240
NOS 38‐0250
NOS 38‐0260
(Continued)
Inheritance
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AD
AD
AR
AR
AD
AD
AR
XL
AD
AD
XL
AD
AR
Gene or locus
DNA2
ANAPC1
RECQL4
RECQL4
WNT7A
RSPO2
WNT3
MAENLI
EN1
LMBR1
PITX1
ZRS
ESCO2
TBX15
SALL4
THPO
RBM8A
HDAC8
RAD21
SMC3
SMC1A
NIPBL
TBX4
MIM No.
618625
268400
266280
276820, 228930
618021
273395
619217
619218
200500
119800
188740
268300
260660
607323
187950
274000
300882
614701
610759
300590
122470
601360
Notes
See also Baller‐Gerold syndrome, RECQL4‐related. See
MIM 266280 for explanation of the RAPADILINO
acronym
Includes former Al‐Awadi Raas‐Rothschild limb‐pelvis
hypoplasia‐aplasia as well as Fuhrmann syndrome
MAENLI is a lncRNA regulating EN1 expression
One single patient with a biallelic frameshift variant
described
The Brazilian founder allele is deletion spanning exon 4 of
LMBR1 that probably affects the activity of ZRS, the
limb‐specific enhancer of SHH. In a further patient,
biallelic deletion of exons 1 to 16 of LMBR1, including
the ZRS
In some patients bilateral patellar hypoplasia (see Group
37)
Monoallelic variants in ZRS, a limb‐specific enhancer of
SHH that is located within intron 5 of the LMBR1 gene
Includes IVIC syndrome
Distal limb defects postulated as consequence of vascular
occlusions
Deletion and common SNP on other allele that has
regulatory function
See also ischiopatellar syndrome for the monoallelic
TBX4‐related phenotype
UNGER ET AL.
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Group number/number of
disorder
TABLE 1
38
(Continued)
Hypoglossia‐hypodactylia (Hanhart syndrome)
Poland syndrome
Femoral facial syndrome (FFS)
Femur‐fibula‐ulna syndrome (FFU)
Fibular aplasia, tibial campomelia, and oligosyndactyly
syndrome (FATCO)
NOS 38‐0350
NOS 38‐0360
NOS 38‐0370
NOS 38‐0380
NOS 38‐0390
AR
SP
SP
SP
SP
SP
(several)
TOP2B
AD
AD
NOTCH1
EOGT
DLL4
RBPJ
DOCK6
AD
AD
AR
AD
Gene or locus
ARHGAP31
MIM No.
227650
275220
246570
228200
134780
173800
103300
169550
609296
616028
615297
616589
614814
614219
100300
The complex genetic basis of Fanconi anemia and its
complementation groups and loci is acknowledged but
not further listed in this Nosology; please refer to MIM
or to specialized reviews
Rare cases reported as associated with monoallelic CDX2
variants with variable expressivity
Possibly non‐genetic etiology
Some phenotypic overlap with FFU syndrome (below)
Most commonly sporadic and probably non‐genetic; some
familial cases reported but no specific gene identified so
far
Also known as Hoffmann syndrome (see MIM 609296)
Notes
Split hand/foot with and without other manifestations
Ankyloblepharon‐ectodermal dysplasia‐cleft palate (AEC)
Ectrodactyly‐ectodermal dysplasia cleft‐palate syndrome
Type 3 (EEC3)
NOS 39‐0010
NOS 39‐0020
AD
AD
TP63
TP63
604292
106260
(Continues)
See other TP63‐related disorders in this group (below)
39
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Group 39
There is overlap between this group and the split hand‐foot malformation group. See also Baller‐Gerold syndrome, RECQL4‐related; congenital hemidysplasia, ichthyosis, limb defects
(CHILD) syndrome, NSDHL‐related; as well as the mesomelic and acromesomelic dysplasias groups (above). Some entities in this group (e.g. the Femoral‐facial syndrome and the Femur‐
fibula‐ulna [FFU] syndromes) might be considered (RCEM; see the note to VACTERL in Group 36)
Fanconi anemia
Scapulo‐iliac dysplasia (Kosenow syndrome)
NOS 38‐0340
NOS 38‐0420
B‐cell immunodeficiency‐limb anomaly‐urogenital
malformation syndrome (BILU syndrome), TOP2B‐
related
NOS 38‐0330
Tibial hemimelia (isolated)
Adams‐Oliver syndrome (aplasia cutis congenita and
transverse limb defects), NOTCH1‐related
NOS 38‐0320
Sirenomelia
Adams‐Oliver syndrome (aplasia cutis congenita and
transverse limb defects), EOGT‐related
NOS 38‐0310
NOS 38‐0400
SP
Adams‐Oliver syndrome (aplasia cutis congenita and
transverse limb defects), DLL4‐related
NOS 38‐0300
NOS 38‐0410
SP, AD
Adams‐Oliver syndrome (aplasia cutis congenita and
transverse limb defects), RBPJ‐related
NOS 38‐0290
AR
Adams‐Oliver syndrome (aplasia cutis congenita and
transverse limb defects), DOCK6‐related
NOS 38‐0280
Inheritance
AD
Adams‐Oliver syndrome (aplasia cutis congenita and
transverse limb defects), ARHGAP31‐related
Name of group/name of disorder
NOS 38‐0270
Group number/number of
disorder
TABLE 1
UNGER ET AL.
(Continued)
Ectrodactyly‐ectodermal dysplasia‐macular dystrophy
syndrome (EEM)
Limb‐mammary syndrome (including ADULT syndrome)
Split hand‐foot malformation, isolated form, type 4
(SHFM4)
Split hand‐foot malformation, isolated form, type 1
(SHFM1)
Split hand‐foot malformation, isolated form, type 1
(SHFM1)
Split hand‐foot malformation, isolated form, type 3
(SHFM3)
Split hand‐foot malformation, isolated form, type 6
(SHFM6)
Split‐foot malformation with mesoaxial polydactyly
(SFMMP)
Split‐hand‐foot malformation with or without long bone
deficiency (SHFLD), BHLHA9‐related
Hartsfield syndrome, FGFR1‐related
Split hand‐foot malformation, EPS15L‐related
Aplasia cutis congenita with ectrodactyly, UBA2‐related
Focal dermal hypoplasia (Goltz Syndrome), PORCN‐related
Polydactyly‐Syndactyly‐Triphalangism group
Preaxial polydactyly, SHH‐related
Preaxial polydactyly, GLI1‐related
Preaxial polydactyly, GLI3‐related
Preaxial polydactyly type 3 (PPD3)
Mirror‐image polydactyly of hands and feet (Laurin‐
Sandrow syndrome), SHH‐related
Postaxial polydactyly, GLI1‐related
NOS 39‐0040
NOS 39‐0050
NOS 39‐0060
NOS 39‐0070
NOS 39‐0080
NOS 39‐0090
NOS 39‐0100
NOS 39‐0110
NOS 39‐0120
NOS 39‐0130
NOS 39‐0140
NOS 39‐0150
Group 40
NOS 40‐0010
NOS 40‐0020
NOS 40‐0030
NOS 40‐0040
NOS 40‐0050
NOS 40‐0060
Name of group/name of disorder
Inheritance
AR
AD
AD
AD
AR
AD
XLD
AD
AD
AD
AD
AR
AR
AD
AD
AD
AD
AD
AR
Gene or locus
GLI1
SHH
GLI3
GLI1
SHH
PORCN
UBA2
EPS15L1
FGFR1
BHLHA9
ZAK
WNT10B
10q24
DLX6
DLX5
TP63
TP63
CDH3
MIM No.
618123
135750
174600
174700
174400
174400
305600
615465
612576
616890
225300
246560
183600
220600
605289
603543
225280
Duplication of ZRS (limb enhancer of SHH)
Formerly preaxial polydactyly types 1 and 2 (with
triphalangeal thumb); regulatory domain variant or
duplication of ZRS (limb enhancer of SHH)
19q13.11 deletions may also cause this phenotype. In
OMIM as “aplasia cutis congenita with ectrodactyly
skeletal syndrome” (a redundant name)
Structural variants (deletions) at this locus; one
consanguineous family with homozygous point variant
in EPS15L1 but inheritance still unclear
Duplications at 17p13.3 that include BHLHA9. Phenotypic
penetrance is less than 50% and shows markedly
variable expressivity; includes the so‐called Gollop‐
Wolfgang complex
Duplications at 10q24 encompassing LBX1, BTRC, POLL,
DPCD and FBXW4
Structural variations at locus; also regulatory variants
affecting exons of DYNC1I1 that regulate DLX5;
association with deafness in a single family may be
coincidental; a recessive DLX5 syndrome may exist
Notes
UNGER ET AL.
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NOS 39‐0030
Group number/number of
disorder
TABLE 1
40
Acrocallosal syndrome, KIF7‐related
Acro‐pectoral‐vertebral dysplasia (F‐syndrome), WNT6‐
related
Cenani‐Lenz syndactyly, LRP4‐related
Cenani‐Lenz‐like syndactyly, GREM/FMN1‐related
Oligosyndactyly, radio‐ulnar synostosis, hearing loss and
renal defects syndrome, FMN1‐related
Mesoaxial synostotic syndactyly with phalangeal reduction
(Malik‐Percin), BHLHA9‐related
STAR syndrome (syndactyly of toes, telecanthus, anal and
renal malformations), FAM58A‐related
NOS 40‐0180
NOS 40‐0190
NOS 40‐0200
NOS 40‐0210
NOS 40‐0220
NOS 40‐0230
NOS 40‐0240
Metacarpal 4‐5 fusion, FGF16‐related
Lacrimo‐auriculo‐dento‐digital syndrome (LADD), FGF10‐
related
NOS 40‐0170
NOS 40‐0300
Lacrimo‐auriculo‐dento‐digital syndrome (LADD), FGFR3‐
related
NOS 40‐0160
Syndactyly (Lueken type, with or without
craniosynostosis), IHH‐related
Lacrimo‐auriculo‐dento‐digital syndrome (LADD), FGFR2‐
related
NOS 40‐0150
NOS 40‐0290
Townes‐Brocks syndrome, SALL1‐related
NOS 40‐0140
Syndactyly type 5 (Brachydactyly‐Syndactyly syndrome;
syndactyly with metacarpal and metarsal fusion),
HOXD13‐related
Postaxial polydactyly, isolated (type A10), KIAA0825‐
related
NOS 40‐0130
Syndactyly type 4 (I‐V) Haas type, SHH‐related
Synpolydactyly, HOXD13‐related
NOS 40‐0120
NOS 40‐0280
Synpolydactyly, FBLN1‐related
NOS 40‐0110
NOS 40‐0270
Culler‐Jones syndrome, GLI2‐related
NOS 40‐0100
Syndactyly type 1 (III‐IV)
Hypothalamic hamartomas and polydactyly (Pallister‐Hall‐
like) syndrome, SMO‐related
NOS 40‐0090
Syndactyly type 3 (IV‐V), GJA1‐related
Pallister‐Hall syndrome, GLI3‐related
NOS 40‐0080
NOS 40‐0260
Greig cephalopolysyndactyly syndrome, GLI3‐related
Inheritance
Gene or locus
XLR
FGF16
IHH
HOXD13
AD
SHH
AD
GJA1
FAM58A
BHLHA9
FMN1
GREM1, FMN1
LRP4
WNT6
KIF7
FGF10
FGFR3
FGFR2
SALL1
KIAA0825
HOXD13
FBLN1
AD
AD
AD
XLD
AD
AR
AD
AR
AD
AR
AD
AD
AD
AD
AR
AD
AD
GLI2
SMO
AD
GLI3
AR
GLI3
AD
AD
MIM No.
309630
185900
186300, 610713
186200
186100
185900
300707
609432
see 212780
212780
102510
200990
149730
149730
149730
107480
618498
186000
608180
615849
241800
146510
175700
(Continues)
Duplication of IHH and regulatory region on 2q35;
includes syndactyly with craniosynostosis (Philadelphia
type)
Duplication of ZRS (limb enhancer of SHH)
X‐linked dominant (only affected females known, possibly
lethal in males)
Biallelic deletion of the FMN1 gene (one individual)
Monoallelic duplication of both GREM1 and FMN1 loci
(one individual)
Structural variations of locus resulting in ectopic activation
of WNT6
Hypopituitarism
Notes
41
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NOS 40‐0250
Name of group/name of disorder
NOS 40‐0070
(Continued)
Group number/number of
disorder
TABLE 1
UNGER ET AL.
(Continued)
Synpolydactyly plus syndrome, MAPKAPK5‐related
NOS 40‐0320
Inheritance
AR
AR
Gene or locus
MAPKAPK5
CKAP2L
MIM No.
619869
272440
In OMIM as neurocardiofaciodigital syndrome
Notes
Multiple synostoses syndrome, NOG‐related
Multiple synostoses syndrome, GDF5‐related
Multiple synostoses syndrome, FGF9‐related
Multiple synostoses syndrome, GDF6‐related
Liebenberg syndrome, PITX1‐related
Short stature, auditory atresia, mandibular hypoplasia,
skeletal abnormalities (SAMS) syndrome, GSC‐related
Radio‐ulnar synostosis with amegakaryocytic
thrombocytopenia, HOXA11‐related
Radio‐ulnar synostosis with amegakaryocytic
thrombocytopenia, MECOM‐related
Radio‐ulnar synostosis with microcephaly (Giuffré‐
Tsukahara syndrome)
NOS 41‐0010
NOS 41‐0020
NOS 41‐0030
NOS 41‐0040
NOS 41‐0050
NOS 41‐0060
NOS 41‐0070
NOS 41‐0080
NOS 41‐0090
AD
AD
AR
AD
AD
AD
AD
AD
MECOM
HOXA11
GSC
PITX1
GDF6
FGF9
GDF5
NOG
603438
616738
605432
602471
186550
617898
612961
610017
186500, 186570
X‐linked recessive inheritance suggested
Structural variants encompassing the H2AFY gene
resulting in ectopic activation of PITX1 in upper limb
See other GDF5‐related disorders
Includes: Stapes ankylosis with broad thumbs and toes,
Tarsal‐Carpal coalition syndrome, proximal
Symphalangism 1A; see also Brachydactyly type B2,
NOG‐related, in the brachydactyly group
UNGER ET AL.
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Note: The numbering system (first column) includes “NOS” for “Nosology, skeletal”, followed by the group number and the number of the disorder. The abbreviations are as follows: in the disorder names, SED in spondylo‐
ephyseal dysplasia; SEMD is spondylo‐epi‐metaphyseal dysplasia; MED is multiple epiphyseal dysplasia; CDP is chondrodysplasia punctata. In the “Inheritance” column: AD, autosomal recessive; AR, autosomal recessive; XL,
X‐linked; MOS, somatic mosaicism; SP, sporadic and inheritance unknown. Pseudo‐AD and Pseudo‐AR refers to genes in the pseudoautosomal regions of chromosome X and Y. The “MIM No.” column shows the MIM number
of the disorder; when the number is preceded by “see”, the MIM number is that of the underlying gene.
See also Spondylocarpotarsal synostosis syndrome, FLNB‐related and RFLNA‐related; Cardiospondylocarpofacial syndrome, MAP3K7‐related; mesomelic dysplasia with acral synostoses
(Verloes‐David‐Pfeiffer type); Baller‐Gerold syndrome, RECQL4‐related; and Antley‐Bixler syndrome, POR‐related
Defects in joint formation and synostoses
Group 41
Note: the Smith‐Lemli‐Opitz syndrome can present with polydactyly and/or syndactyly. The different variants of Meckel syndrome can have polydactyly and are included under the
ciliopathies (see there). The Bardet‐Biedl syndromes may have polydactyly as a secondary feature and have not been included in this neither in this group nor in the ciliopathies. See
also Clubfoot with or without deficiency of long bones and/or mirror‐image polydactyly, PITX1‐related. The entity called “Crossed polysyndactyly” not included as unclear whether or
not it is a distinct entity.
Syndactyly with microcephaly and mental retardation
(Filippi syndrome), CKAP2L‐related
Name of group/name of disorder
NOS 40‐0310
Group number/number of
disorder
TABLE 1
42
1 | N A M I N G P RO B L E M S A N D TH E D Y A D I C
A P P R O A C H A S A WA Y F O R W A R D
Smith-McCort dysplasia); while for others the eponymic descriptors are
too similar, leading to diagnostic confusion (e.g., Shprintzen-Goldberg
and Goldberg-Shprintzen syndromes represent distinct disorders). MIM's
Between 2010 and 2020, the technology of massively parallel
choice of these eponyms may not reflect the most significant contribu-
sequencing has taken center stage in medical genetics research and
tion to the delineation of a phenotypic entity. By adopting the dyadic
diagnostics. Among the many lessons learned from next-generation
system, we have elected to describe each disorder with the name of the
sequencing (NGS) results are (1) the large number of previously unrec-
responsible gene rather than with an eponym. While MIM remains the
ognized rare and ultrarare disorders in each domain of genetic medi-
central reference database, the dyadic system allows the Nosology to
cine, (2) the phenotypic heterogeneity arising from a single locus is
group, lump, or dump disorders based on their molecular basis, especially
much greater than previously suspected, and (3) for many dyadic enti-
in the light of the lessons of NGS (see above), and is less bound by his-
ties, individuals who present all the phenotypic criteria as described in
torical constraints. Nevertheless, the Nosology curators have strived to
the textbooks are the exception rather than the rule.
maintain strong bridges to MIM: MIM numbers are included for all disor-
On this background, it has been proposed that the phenotypic
ders when available, and when not available, the MIM number for the
descriptor of a genetic disorder (the “name” of a condition) is no longer
responsible gene is included. Moreover, references are made to the
sufficient to distinguish the disorder unequivocally. Furthermore, the
MIM denomination of individual disorders as well as to other MIM disor-
sequential numbering of conditions with the same name (as applied
ders arising from pathogenic variants in the same gene.
e.g., for osteogenesis imperfecta or ataxias in Mendelian Inheritance in
Man [MIM]) may be unsatisfactory, as a number has no inherent information, making it necessary to consult the numbering reference. As a
consequence, it has been suggested that instead of being attributed by
3 | T H E OR P H A N E T N O M E N C L A T U RE A N D
T H E NO SO L O G Y
a number (or an eponym, see below), the main phenotypic descriptor of
a genetic disorder should best be coupled to the name of the underly-
In the context of a joint collaboration between the International Skel-
ing gene, allowing for more direct and pertinent information, less prone
etal Dysplasia Society (ISDS), the European Reference Network on
to ambiguities and errors; the so-called dyadic approach (Biesecker
Rare Bone Disorders (ERN-BOND) and Orphanet, co-coordinated by
et al., 2021). Of note, the dyadic concept has been pioneered by the
Houda Ali (curator at Orphanet) and Geert Mortier (main curator of
editors of the well-known resource GeneReviews starting in 2020
the 2019 Nosology), a detailed analysis of the Orphanet database in
(Dr. M. Adam, personal communication; and Biesecker et al., 2021).
comparison with the 2019 Nosology, resulted in a list of approxi-
The Nosology has not been immune to the proliferation of num-
mately 248 phenotypic entities that were present in the Orphanet
bered lists, such as, for example, in osteogenesis imperfecta
nomenclature of rare diseases but absent in the 2019 Nosology. To
(Sillence & Rimoin, 1978; Sillence et al., 1979; Van Dijk &
be included in the 2023 Nosology, disorders had to have a recogniz-
Sillence, 2014). In this 2023 revision, the curators have decided to
able phenotype and a clear inheritance pattern or molecular definition.
adopt the dyadic naming approach as it allows for more precision both
Approximately 30 of these disorders met inclusion criteria and have
in the clinic and in the laboratory. However, compromises have been
thus been included in the Nosology. Other disorders in this list had
made in some instances to account for the historic evolution of the
either been described in a single paper without molecular confirma-
Nosology, as well as to maintain congruence and interoperability with
tion, or represent historical descriptions with limited available infor-
what is considered the most important reference database for genetic
mation, reflecting the policy followed by Orphanet to represent all
disorders, MIM (MIM and its online version, OMIM).
disorders fitting the definition of a rare disease to the advantage of
individuals affected by ultrarare presentations, as long as they constitute phenotypically distinct diagnoses (Ref. https://www.orpha.net/
2 | T H E M E N D E LI A N I N H E R I T A N C E I N
M A N CA T A L O G A N D TH E N O S O L O G Y
orphacom/cahiers/docs/GB/eproc_disease_inventory_R1_Nom_Dis_
EP_04.pdf). On the other hand, it became evident that many entries in
the list do not seem to represent distinct phenotypic entities in view
The late Victor McKusick's opus, MIM, remains the single most impor-
of the current knowledge and of the Nosology criteria. This has
tant general reference database for genetic disorders. The way in which
prompted an ongoing revision process by the Orphanet team to
MIM was created and is still curated allows for a detailed documentation
review and identify entries that need to be deactivated and subse-
of the history of each and every disorder. For the same reason, it is less
quently removed from the Orphanet nomenclature of rare diseases.
well-suited to document the changes that occur in the nosography, for
instance when one disorder is subsumed under another; several disorders listed in MIM have been subsumed under other conditions in the
Nosology, or are altogether not recognized as distinct phenotypic enti-
4 | T H E NO SO L O G Y A N D T H E CL I N G E N
CURATION INITIATIVE
ties in the Nosology (e.g., mesomelic dysplasia, Camera type; MIM
611886). Also, MIM makes extensive use of eponyms to distinguish
The ClinGen initiative (https://clinicalgenome.org/affiliation/40065/)
related but distinct disorders (e.g., Dyggve-Melchior-Clausen disease and
is currently working on a set of genes associated with skeletal
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43
UNGER ET AL.
UNGER ET AL.
disorders in order to provide strength of evidence for gene-disease
disorders in the number or function of osteoclasts. The “Osteogenesis
associations, and using strictly verified criteria to assess pathogenicity
Imperfecta and decreased bone density group” was renamed “Osteo-
of variants in genes found to have a definitive association with dis-
genesis Imperfecta and bone fragility group” to reflect the fact that
ease. It has already done so for other groups of genetic disorders,
skeletal fragility is a hallmark of these disorders irrespective of the
such as the cardiomyopathies and others. Several of the present
bone mineral density (as in fact a small subset of osteogenesis imper-
Nosology curators participate in this effort. However, the sheer num-
fecta patients can have high bone mass). The name of the group of
ber of genes involved in constitutional skeletal conditions is such that
“Overgrowth (tall stature) syndromes with skeletal involvement” was
the ClinGen section for skeletal dysplasia genes will take time to be
changed to the more encompassing “Overgrowth (tall stature) syn-
completed. In this context, the Nosology, with its list of curated genes
dromes and segmental overgrowth”. The group of “Craniosynostosis
and disorders (albeit not to the extent set out in the ClinGen initia-
syndromes” was renamed “Syndromes featuring craniosynostosis”, as
tive), will remain the best available resource for the foreseeable
although disorders in this group frequently feature craniosynostosis,
future. Of note, the ClinGen approach is much more “lumping” than
this finding does not always represent the most salient feature. Other
the Nosology, to the extent that phenotypes due to pathogenic vari-
changes in group nomenclature included “Brachydactylies (without
ants at a single locus must have significant qualitative differences to
extraskeletal manifestations)” to “Isolated brachydactylies”; “Brachy-
justify separate nosologic entries (phenotypic entities); a simple quan-
dactylies (with extraskeletal manifestations)” to “Brachydactylies as
titative difference (typically, more or less severe) is not enough to jus-
part of syndromes”; “Ciliopathies with major skeletal involvement” to
tify separation. This may lead us to reflect on what constitutes a
“Skeletal disorders caused by abnormalities of cilia or ciliary signaling”;
“dysplasia” or a “syndrome”. Some of us have also contributed to the
“Abnormal mineralization group” to “Disorders of bone mineraliza-
development of the “Nosology of inborn errors of metabolism” and
tion”; and “Ectrodactyly with and without other manifestations” to
the subsequent “International Classification of Inherited Metabolic
“Split hand/foot with and without other manifestations”.
Disorders” (ICIMD) (Ferreira et al., 2019, 2021). That nosology applies
Some disorders were reassigned. As an example, trichorhinopha-
the “one gene – one condition” principle, unless there are qualitative
langeal dysplasia types 1/3 was moved from the “Acromelic dyspla-
differences. However, it is more difficult to apply this principle to the
sias” group to the group of “Brachydactylies as part of syndromes”.
skeletal conditions. For example, children affected by methylmalonic
The total number of disorders increased from 461 to 771, and the
acidemia may have different urinary concentrations of methylmalonic
number of genes from 437 to 552. Although we are aware of the
acid but will be considered to have the same disorder (MIM 251000).
problems inherent to numeric lists (as discussed above), we have ten-
It would be more difficult to claim that a fetus with achondrogenesis
tatively included a numbering system including the abbreviation
type 1B (MIM 600972) and a child with recessive multiple epiphyseal
“NOS” (for “Nosology, skeletal”), the group number, and a sequential
dysplasia (MIM 226900) have the same disorder, even if the responsi-
number withing the group, taking care to leave gaps that may allow
ble gene is the same and the phenotypes represent opposite ends of
for the inclusion of disorders in the future. Such a numbering system
severity within the same spectrum, as the morphologic features and
might prove helpful in cross-referencing with MIM, Orphanet and
clinical prognosis are so radically distinct.
other databases.
5 | C HA N G E S CO M P A R E D T O P R E V I O U S
REVISIONS
6 | WH A T I S T H E U T I L I TY O F TH E
NO SOL OG Y?
Some changes in the structure of the Nosology deserve to be men-
Since its early revisions, the Nosology has been helpful for pediatri-
tioned. The total number of groups decreased from 42 to 41. This
cians, geneticists, radiologists, and others as a reminder of the differ-
decrease has to do with restructuring of a few groups. Specifically,
ential diagnosis. Its original structure in groups of disorders with
the previous “Perlecan group” and “Aggrecan group” were incorpo-
similar radiographic features reflected the diagnostic approach of the
rated into the new group of “Proteoglycan core protein disorders”,
clinical geneticist and, even more, of the radiologist, to the osteochon-
and the former groups of “Neonatal osteosclerotic dysplasias” and of
drodysplasias. Over the years, the inclusion of brachydactylies, cranio-
“Other sclerosing bone disorders” were fused into the group of (non-
synostoses, craniofacial dysostoses, syndactylies, limb reductions, and
osteopetrotic) “Osteosclerotic disorders”. A new group of “Skeletal
other dysostoses, as well as primordial short stature and overgrowth
disorders of parathyroid hormone signaling cascade” was added to
syndromes has broadened its utility for the differential diagnosis
the current Nosology. The two brachydactylies groups (isolated or as
within these groups of disorders. The 2010 revision stated that “The
part of syndromes; now groups 18 and 19) were found to be more
aim is to provide the Genetics, Pediatrics and Radiology community with
organically placed right after the acromesomelic and acromelic groups
a list of recognized genetic skeletal disorders that can be of help in the
(groups 16 and 17).
diagnosis of individual cases, in the delineation of novel disorders, and in
Several groups were renamed. The group of “Osteopetrosis and
building bridges between clinicians and scientists interested in skeletal
related disorders” is now named “Osteopetrosis and related osteo-
biology. (…) The Nosology should be useful for the diagnosis of patients
clast disorders”, to highlight the fact that the osteopetroses represent
with genetic skeletal diseases, particularly in view of the information flood
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44
expected with the novel sequencing technologies; in the delineation of
DBT/Wellcome Trust India Alliance Grant “Center for Rare Disease
clinical entities and novel disorders, by providing an overview of estab-
Diagnosis, Research and Training number: IA/CRC/20/1/600002”
lished nosologic entities; and for scientists looking for the clinical corre-
(to Katta M. Girisha), the Sigrid Jusélius Foundation (grant to Outi
lates of genes, proteins and pathways involved in skeletal biology.”
Makitie), the National Health and Medical Research Council of
Thirteen years later, the Nosology may have an additional role in molec-
Australia Leadership Fellow Grant #GNT2018081 (to Ravi Savarira-
ular genetic diagnostic testing. In a pre-test setting, the Nosology may
yan), and Curekids New Zealand (support to Stephen P. Robertson).
inform the decision on which genes to include in a diagnostic panel tai-
Open access funding provided by Universite de Lausanne.
lored to a specific clinical situation. Current diagnostic workflows often
involve plausibility verification of variants observed in panel or exome
DATA AVAILABILITY STAT EMEN T
sequencing tests (reverse phenotyping). Also, in the post-test setting,
Data sharing is not applicable to this article as no new data were cre-
the Nosology may be helpful for rapid reference and orientation.
ated or analyzed in this study.
The Nosology is also an illustration of the complexity of the
human genome as demonstrated by the sheer number of genes and
OR CID
gene products required for normal skeletal development and growth.
Débora R. Bertola
The included table with its over 750 entries and its rows and columns
Daniel H. Cohn
is like the musical score for the orchestra of skeletal development and
Katta M. Girisha
https://orcid.org/0000-0002-0139-8239
growth that may be an inspiration to geneticists and basic scientists.
Deborah Krakow
https://orcid.org/0000-0001-9906-4968
Perhaps the hybrid nature of the Nosology, combining clinical, radio-
Outi Makitie
graphic, and molecular criteria, is a strength and not a weakness,
Stephen P. Robertson
https://orcid.org/0000-0002-5181-7809
allowing colleagues with varied backgrounds an approach to the data.
Andrea Superti-Furga
https://orcid.org/0000-0002-3543-7531
https://orcid.org/0000-0002-4701-6777
https://orcid.org/0000-0003-0388-4457
https://orcid.org/0000-0002-4547-001X
It is clear that no nosology in medicine is perfect nor complete.
They are always dynamic and evolving. However, the frequent cita-
RE FE RE NCE S
tions of previous versions of the Nosology suggest that, despite the
A nomenclature for constitutional (intrinsic) diseases of bones. (1971). A
nomenclature for constitutional (intrinsic) diseases of bones. The Journal of Pediatrics, 78(1), 177–179. https://doi.org/10.1016/s00223476(71)80286-x
Beighton, P., Giedion, Z. A., Gorlin, R., Hall, J., Horton, B., Kozlowski, K.,
Lachman, R., Langer, L. O., Maroteaux, P., & Poznanski, A. (1992).
International classification of osteochondrodysplasias. International
working group on constitutional diseases of bone. American Journal of
Medical Genetics, 44(2), 223–229. https://doi.org/10.1002/ajmg.
1320440220
Biesecker, L. G., Adam, M. P., Alkuraya, F. S., Amemiya, A. R.,
Bamshad, M. J., Beck, A. E., Bennett, J. T., Bird, L. M., Carey, J. C.,
Chung, B., Clark, R. D., Cox, T. C., Curry, C., Dinulos, M. B. P.,
Dobyns, W. B., Giampietro, P. F., Girisha, K. M., Glass, I. A.,
Graham, J. M., … Zarate, Y. A. (2021). A dyadic approach to the delineation of diagnostic entities in clinical genomics. American Journal of
Human Genetics, 108(1), 8–15. https://doi.org/10.1016/j.ajhg.2020.
11.013
Bonafe, L., Cormier-Daire, V., Hall, C., Lachman, R., Mortier, G.,
Mundlos, S., Nishimura, G., Sangiorgi, L., Savarirayan, R., Sillence, D.,
Spranger, J., Superti-Furga, A., Warman, M., & Unger, S. (2015). Nosology and classification of genetic skeletal disorders: 2015 revision.
American Journal of Medical Genetics. Part A, 167A(12), 2869–2892.
https://doi.org/10.1002/ajmg.a.37365
Ferreira, C. R., Rahman, S., Keller, M., Zschocke, J., & ICIMD Advisory
Group. (2021). An international classification of inherited metabolic
disorders (ICIMD). Journal of Inherited Metabolic Disease, 44(1), 164–
177. https://doi.org/10.1002/jimd.12348
Ferreira, C. R., van Karnebeek, C. D. M., Vockley, J., & Blau, N. (2019). A
proposed nosology of inborn errors of metabolism. Genetics in Medicine: Official Journal of the American College of Medical Genetics, 21(1),
102–106. https://doi.org/10.1038/s41436-018-0022-8
Hall, C. M. (2002). International nosology and classification of constitutional disorders of bone (2001). American Journal of Medical Genetics,
113(1), 65–77. https://doi.org/10.1002/ajmg.10828
International nomenclature and classification of the osteochondrodysplasias. (1997). International working group on constitutional diseases of
bone (1998). American Journal of Medical Genetics, 79(5), 376–382.
many compromises necessary in its preparation the Nosology has
been useful to, and widely adopted by, the medical and scientific community. Thanks to the continuous progress in delineating genetic conditions, the Nosology starts its obsolescence at the moment it is
published. Nevertheless, may this new version encounter the same
benevolent reception, and also be replaced in time by novel and more
complete versions.
AUTHORS' CONTRIBUTI ON S
All authors conceptualized the revision work, contributed to the revision of several groups of disorders, and participated in the discussion
and decision making. Sheila Unger, Carlos R. Ferreira, and Andrea
Superti-Furga collated the contributions, compiled the final table and
drafted the manuscript. The table and the manuscript were then
revised by all authors and subsequently finalized by Sheila Unger, Carlos R. Ferreira, and Andrea Superti-Furga.
ACKNOWLEDGMENTS
We wish to acknowledge constructive exchanges with Dr. Ada
Hamosh at the McKusick-Nathans Institute of Genetic Medicine,
Johns Hopkins University, Baltimore, USA, concerning the integration
between the Nosology and the MIM catalog, as well as with Dr. Leslie
G. Biesecker, Center for Precision Health Research, NHGRI, Bethesda,
USA, concerning the adoption of the dyadic nomenclature system.
The skillful assistance and graciousness of Mrs. Nathalie Zumstein in
organizing the Nosology sessions in Lausanne (March 2022) is also
gratefully acknowledged. This work was supported by the International Skeletal Dysplasia Society (www.isds.ch) with secretarial logistics, the University of Lausanne (support to Sheila Unger and Andrea
Superti-Furga),
the
NIH/NHGRI
(to
Carlos
R.
Ferreira),
the
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45
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https://doi.org/10.1002/(sici)1096-8628(19981012)79:5<376::aidajmg9>3.0.co;2-h
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How to cite this article: Unger, S., Ferreira, C. R., Mortier,
G. R., Ali, H., Bertola, D. R., Calder, A., Cohn, D. H.,
Cormier-Daire, V., Girisha, K. M., Hall, C., Krakow, D., Makitie,
O., Mundlos, S., Nishimura, G., Robertson, S. P., Savarirayan,
R., Sillence, D., Simon, M., Sutton, V. R., … Superti-Furga, A.
(2023). Nosology of genetic skeletal disorders: 2023 revision.
American Journal of Medical Genetics Part A, 1–46. https://doi.
org/10.1002/ajmg.a.63132
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46