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. 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 NGS results, and providing a basis for novel advances in biology and medicine.
When the first « Nosology » was compiled and published in 1970, few would have predicted that it would gain such an important role in genetics clinics and research to motivate an 11th revision fifty-two years later. Yet, the reasons that stimulated the first Nosology are the same that uphold the present new revision: coping with the wealth of novel information on the growing number and variety of skeletal phenotypes with a genetic basis and trying to assure a common naming system to facilitate diagnosis and communication.
The recognition of chromosomal aneuploidies at the transition between the 50s and the 60s provided a biological foundation to genetics and ushered in a first golden era of clinical genetics. The Birth Defects Conferences between 1969 and 1971 signaled the awareness and importance of clinical genetics throughout the Sixties and initiated a prolific period in disease identification, delineation and description. In this context, it became apparent that « chondrodysplasia » was not a single diagnosis, but that many distinct, true-breeding forms existed; for example, diastrophic dysplasia, spondylo-epiphyseal dysplasia congenita, and the so-called “pseudo-Morquio” disorders were distinguished and clinically described. In addition, biochemistry allowed subtypes of clinically similar disorders to be distinguished, the most notable example at the time being the mucopolysaccharidoses. The contribution of radiologic features and radiologists to the delineation of skeletal dysplasias deserves explicit recognition. In many instances, it was the radiographic features and their time dependent evolution (the “fourth dimension” emphasized by the late Andres Giedion) that permitted not only to discriminate between disorders that had outward similarities but also to recognize a gene’s radiographic signature in phenotypically distinct disorders (e.g. Achondrogenesis type 2 and Spondyloepiphyseal dysplasia congenita) and thus create the first gene families (Spranger, 1985) (and see below).
In 1970, the first prototype of the “Nosology” was drafted (“[International nomenclature of constitutional diseases of bone],” 1970; McKusick & Scott, 1971; “A Nomenclature for Constitutional (Intrinsic) Diseases of Bone,” 1971; “[International nomenclature of constitutional bone diseases. Constitutional bone diseases without known pathogenesis],” 1971). At that time, however, the work was called a “Nomenclature” rather than a Nosology; the goal was to bring all scholars to use the same name for the same condition.
Molecular criteria began to inform the Nosology in the 1980s, first with osteogenesis imperfecta and the discovery of genetic variants in collagen 1. The concept of « bone dysplasia families » originating from different pathogenic variants in a single gene was proposed in the 1980s (Spranger, 1985) and confirmed in the 1990s, with the COL2A1 and FGFR3 disorders being prominent examples. Ever since, the Nosology has straddled the fence between defining disorders based either on their clinical and radiographic features or on the responsible genes (“International Nomenclature of Constitutional Diseases of Bone,” 1979; “International Nomenclature of Constitutional Diseases of Bone. Revision, May, 1983,” 1983; Beighton et al., 1992; Lachman, 1998; “International Nomenclature and Classification of the Osteochondrodysplasias (1997). International Working Group on Constitutional Diseases of Bone,” 1998; Hall, 2002; Superti-Furga & Unger, 2007; Warman et al., 2011; Bonafe et al., 2015; Mortier et al., 2019).
Traditionally, the nosology has been organized into groups of disorders – initially based on radiographic criteria, then by biochemical criteria (metabolic pathways) and subsequently, more and more, by functional and molecular criteria. The organization into groups has been maintained in the current revision as it helps in finding the disorders relevant for a particular patient of finding. On the other hand, Nature has more complexity than can be captured in the Nosology, and our attempt at classification is necessarily both arbitrary and a simplification, as many disorders might warrant classification in more than one group. Thus, we have elected to drop the term “classification” from the title; this is just a “Nosology”.
Naming problems and the dyadic approach as a way forward
Between 2010 and 2020, the technology of massively parallel sequencing has taken center stage in medical genetics research and diagnostics. Among the many lessons learned from next-generation sequencing (NGS) results are (1) the large number of previously unrecognized rare and ultrarare disorders in each domain of genetic medicine, (2) the phenotypic heterogeneity arising from a single locus is much greater than previously suspected, and (3) for many dyadic entities, individuals who present all the phenotypic criteria as described in the textbooks are the exception rather than the rule.
On this background, it has been proposed that the phenotypic descriptor of a genetic disorder (the « name » of a condition) is no longer sufficient to distinguish the disorder unequivocally. Furthermore, the sequential numbering of conditions with the same name (as applied 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 a number (or an eponym, see below), the main phenotypic descriptor of a genetic disorder should best be coupled to the name of the underlying gene, allowing for more direct and pertinent information, less prone to ambiguities and errors; the so-called dyadic approach (Biesecker et al., 2021). Of note, the dyadic concept has been pioneered by the editors of the well-known resource GeneReviews starting in 2020 (Dr. M. Adam, personal communication; and Biesecker et al., 2021).
The Nosology has not been immune to the proliferation of numbered lists, such as, for example, in osteogenesis imperfecta (Sillence & Rimoin, 1978; Sillence et al., 1979; Van Dijk & Sillence, 2014). In this 2023 revision, the curators have decided to adopt the dyadic naming approach as it allows for more precision both in the clinic and in the laboratory. However, compromises have been made in some instances to account for the historic evolution of the Nosology, as well as to maintain congruence and interoperability with what is considered the most important reference database for genetic disorders, Mendelian Inheritance in Man (MIM and its online version, OMIM).
The Mendelian Inheritance in Man (MIM) catalog and the Nosology
The late Victor McKusick’s opus, Mendelian Inheritance in Man, remains the single most important general reference database for genetic disorders. The way in which MIM was created and is still curated allows for a detailed documentation of the history of each and every disorder. For the same reason, it is less 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 entities in the Nosology (e.g., mesomelic dysplasia, Camera type; MIM 611886). Also, MIM makes extensive use of eponyms to distinguish related but distinct disorders (e.g., Dyggve-Melchior-Clausen disease and 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 choice of these eponyms may not reflect the most significant contribution to the delineation of a phenotypic entity. By adopting the dyadic system, we have elected to describe each disorder with the name of the responsible gene rather than with an eponym. While MIM remains the central reference database, the dyadic system allows the Nosology to group, lump, or dump disorders based on their molecular basis, especially in the light of the lessons of NGS (see above), and is less bound by historical constraints. Nevertheless, the Nosology curators have strived to maintain strong bridges to MIM: MIM numbers are included for all disorders when available, and when not available, the MIM number for the responsible gene is included. Moreover, references are made to the MIM denomination of individual disorders as well as to other MIM disorders arising from pathogenic variants in the same gene.
The Orphanet nomenclature and the Nosology
In the context of a joint collaboration between the ISDS, the European Reference Network on Rare Bone Disorders (ERN-BOND) and Orphanet, co-coordinated by Houda Ali (curator at Orphanet) and Geert Mortier (main curator of the 2019 Nosology), a detailed analysis of the Orphanet database in comparison with the 2019 Nosology, resulted in a list of approx. 248 phenotypic entities that were present in the Orphanet nomenclature of rare diseases but absent in the 2019 Nosology. To be included in the 2023 Nosology, disorders had to have a recognizable phenotype and a clear inheritance pattern or molecular definition. Approximately 30 of these disorders met inclusion criteria and have thus been included in the Nosology. Other disorders in this list had either been described in a single paper without molecular confirmation, or represent historical descriptions with limited available information, reflecting the policy followed by Orphanet to represent all 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/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 of the current knowledge and of the Nosology criteria. This has prompted an ongoing revision process by the Orphanet team to review and identify entries that need to be deactivated and subsequently removed from the Orphanet nomenclature of rare diseases.
The Nosology and the ClinGen curation initiative
The ClinGen initiative (https://clinicalgenome.org/affiliation/40065/) is currently working on a set of genes associated with skeletal disorders in order to provide strength of evidence for gene-disease associations, and using strictly verified criteria to assess pathogenicity of variants in genes found to have a definitive association with disease. It has already done so for other groups of genetic disorders, such as the cardiomyopathies and others. Several of the present Nosology curators participate in this effort. However, the sheer number of genes involved in constitutional skeletal conditions is such that the ClinGen section for skeletal dysplasia genes will take time to be completed. In this context, the Nosology, with its list of curated genes and disorders (albeit not to the extent set out in the ClinGen initiative), will remain the best available resource for the foreseeable future. Of note, the ClinGen approach is much more “lumping” than the Nosology, to the extent that phenotypes due to pathogenic variants at a single locus must have significant qualitative differences to justify separate nosologic entries (phenotypic entities); a simple quantitative difference (typically, more or less severe) is not enough to justify separation. This may lead us to reflect on what constitutes a “dysplasia” or a “syndrome”. Some of us have also contributed to the development of the “Nosology of inborn errors of metabolism” and the subsequent “International Classification of Inherited Metabolic Disorders” (ICIMD) (Ferreira et al., 2019, 2021). That nosology applies the “one gene – one condition” principle, unless there are qualitative differences. However, it is more difficult to apply this principle to the skeletal conditions. For example, children affected by methylmalonic acidemia may have different urinary concentrations of methylmalonic acid but will be considered to have the same disorder (MIM 251000). It would be more difficult to claim that a fetus with achondrogenesis type 1B (MIM 600972) and a child with recessive multiple epiphyseal dysplasia (MIM 226900) have the same disorder, even if the responsible gene is the same and the phenotypes represent opposite ends of severity within the same spectrum, as the morphologic features and clinical prognosis are so radically distinct.
Changes compared to previous revisions
Some changes in the structure of the Nosology deserve to be mentioned. The total number of groups decreased from 42 to 41. This decrease has to do with restructuring of a few groups. Specifically, the previous “Perlecan group” and “Aggrecan group” were incorporated into the new group of “Proteoglycan core protein disorders”, and the former groups of “Neonatal osteosclerotic dysplasias” and of “Other sclerosing bone disorders” were fused into the group of (non-osteopetrotic) “Osteosclerotic disorders”. A new group of “Skeletal disorders of parathyroid hormone signaling cascade” was added to the current Nosology. The two brachydactylies groups (isolated or as part of syndromes; now groups 18 and 19) were found to be more organically placed right after the acromesomelic and acromelic groups (groups 16 and 17).
Several groups were renamed. The group of “Osteopetrosis and related disorders” is now named “Osteopetrosis and related osteoclast disorders”, to highlight the fact that the osteopetroses represent disorders in the number or function of osteoclasts. The “Osteogenesis Imperfecta and decreased bone density group” was renamed “Osteogenesis Imperfecta and bone fragility group” to reflect the fact that skeletal fragility is a hallmark of these disorders irrespective of the bone mineral density (as in fact a small subset of osteogenesis imperfecta patients can have high bone mass). The name of the group of “Overgrowth (tall stature) syndromes with skeletal involvement” was changed to the more encompassing “Overgrowth (tall stature) syndromes and segmental overgrowth”. The group of “Craniosynostosis syndromes” was renamed “Syndromes featuring craniosynostosis”, as although disorders in this group frequently feature craniosynostosis, this finding does not always represent the most salient feature. Other changes in group nomenclature included “Brachydactylies (without extraskeletal manifestations)” to “Isolated brachydactylies”; “Brachydactylies (with extraskeletal manifestations)” to “Brachydactylies as part of syndromes”; “Ciliopathies with major skeletal involvement” to “Skeletal disorders caused by abnormalities of cilia or ciliary signaling”; “Abnormal mineralization group” to “Disorders of bone mineralization”; and “Ectrodactyly with and without other manifestations” to “Split hand/foot with and without other manifestations”.
Some disorders were reassigned. As an example, trichorhinophalangeal dysplasia types 1/3 was moved from the “Acromelic dysplasias” group to the group of “Brachydactylies as part of syndromes”.
The total number of disorders increased from 461 to 771, and the number of genes from 437 to 552. Although we are aware of the problems inherent to numeric lists (as discussed above), we have tentatively included a numbering system including the abbreviation “NOS” (for “Nosology, skeletal”), the group number, and a sequential number withing the group, taking care to leave gaps that may allow for the inclusion of disorders in the future. Such a numbering system might prove helpful in cross-referencing with MIM, Orphanet and other databases.
What is the utility of the Nosology?
Since its early revisions, the Nosology has been helpful for pediatricians, geneticists, radiologists, and others as a reminder of the differential diagnosis. Its original structure in groups of disorders with similar radiographic features reflected the diagnostic approach of the clinical geneticist and, even more, of the radiologist, to the osteochondrodysplasias. Over the years, the inclusion of brachydactylies, craniosynostoses, craniofacial dysostoses, syndactylies, limb reductions, and other dysostoses, as well as primordial short stature and overgrowth syndromes has broadened its utility for the differential diagnosis within these groups of disorders. The 2010 revision stated that “The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. (…) The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology.” Thirteen years later, the Nosology may have an additional role in molecular genetic diagnostic testing. In a pre-test setting, the Nosology may inform the decision on which genes to include in a diagnostic panel tailored to a specific clinical situation. Current diagnostic workflows often involve plausibility verification of variants observed in panel or exome sequencing tests (reverse phenotyping). Also, in the post-test setting, the Nosology may be helpful for rapid reference and orientation.
The Nosology is also an illustration of the complexity of the human genome as demonstrated by the sheer number of genes and gene products required for normal skeletal development and growth. The included table with its over 750 entries and its rows and columns is like the musical score for the orchestra of skeletal development and growth that may be an inspiration to geneticists and basic scientists. Perhaps the hybrid nature of the nosology, combining clinical, radiographic, and molecular criteria, is a strength and not a weakness, allowing colleagues with varied backgrounds an approach to the data.
It is clear that no nosology in medicine is perfect nor complete. They are always dynamic and evolving. However, the frequent citations of previous versions of the Nosology suggest that, despite the 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.
| The Nosology of Constitutional Skeletal Disorders: 2023 revision | ||||||
|---|---|---|---|---|---|---|
| Group number/numer of disorder | Name of Group / Name of Disorder | Inheritance | Gene or locus | MIM No. | Notes | |
| Group 1 | FGFR3 chondrodysplasias | |||||
| NOS 01–0010 | Thanatophoric dysplasia (type 1), FGFR3-related | AD | FGFR3 | 187600 | Includes previous “platyspondylyic dysplasia type San Diego” | |
| NOS 01–0020 | Thanatophoric dysplasia (type 2), FGFR3-related | AD | FGFR3 | 187601 | radiographic differences between type 1 and type 2 are correlated to specific FGFR3 variants | |
| NOS 01–0030 | Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), FGFR3-related | AD | FGFR3 | 616482 | ||
| NOS 01–0040 | Achondroplasia, FGFR3-related | AD | FGFR3 | 100800 | ||
| NOS 01–0050 | Hypochondroplasia, FGFR3-related | AD | FGFR3 | 146000 | ||
| 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 | ||||||
| Group 2 | Type 2 collagen disorders | |||||
| NOS 02–0010 | Achondrogenesis, COL2A1-related (formerly type 2, type Langer-Saldino) | AD | COL2A1 | 200610 | Achondrogenesis type 2 and hypochondrogenesis form one phenotypic continuum | |
| NOS 02–0020 | Hypochondrogenesis, COL2A1-related | AD | COL2A1 | 200610 | Achondrogenesis type 2 and hypochondrogenesis form one phenotypic continuum | |
| NOS 02–0030 | Platyspondylic dysplasia, type Torrance, COL2A1-related | AD | COL2A1 | 151210 | Often variants in the C-propeptide of collagen 2 | |
| NOS 02–0040 | Spondyloepiphyseal dysplasia congenita (SEDC), COL2A1-related | AD, AR* | COL2A1 | 183900, 604864 | 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 | |
| NOS 02–0050 | Spondyloepimetaphyseal dysplasia, COL2A1-related | AD | COL2A1 | 184250, 184253, 184255, 616583 | 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 | |
| NOS 02–0060 | Kniest dysplasia, COL2A1-related | AD | COL2A1 | 156550 | ||
| NOS 02–0070 | Spondyloperipheral dysplasia, COL2A1-related | AD | COL2A1 | 271700 | Like Torrance dysplasia, often variants in the C-propeptide of collagen 2 | |
| NOS 02–0080 | SED with metatarsal shortening, COL2A1-related | AD | COL2A1 | 609162 | Often associated with the p.R275C variant; formerly “Czech dysplasia” | |
| NOS 02–0090 | Stickler syndrome, COL2A1-related | AD | COL2A1 | 108300 | Monoallelic loss-of-function variants; See also COL11A1, COL11A2, COL9A1, COL9A2, COL9A3 | |
| NOS 02–0100 | Dysplasia of the proximal femoral epiphyses, COL2A1-related | AD | COL2A1 | 150600, 608805 | 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 | |
| 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 | ||||||
| Group 3 | Type 11 collagen disorders | |||||
| NOS 03–0010 | Stickler syndrome, COL11A1-related | AD, MOS | COL11A1 | 604841 | Can also result from somatic mosaicism for a COL11A1 variant | |
| NOS 03–0020 | Marshall syndrome, COL11A1-related | AD | COL11A1 | 154780 | One report with homozygous p.G901E variant in two affected sibs (PMID 22499343) | |
| NOS 03–0030 | Stickler syndrome, COL11A2-related (non-ocular type) | AD | COL11A2 | 184840 | ||
| NOS 03–0040 | Fibrochondrogenesis, COL11A1-related | AR, AD | COL11A1 | 228520 | ||
| NOS 03–0050 | Fibrochondrogenesis, COL11A2-related | AR, AD | COL11A2 | 614524 | ||
| NOS 03–0060 | Otospondylomegaepiphyseal dysplasia (OSMED), recessive type, COL11A2-related | AR | COL11A2 | 215150 | ||
| NOS 03–0070 | Otospondylomegaepiphyseal dysplasia (OSMED), dominant type, COL11A2-related | AD | COL11A2 | 184840 | Formerly Weissenbacher-Zweymüller syndrome and Stickler syndrome type 3 | |
| 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) | ||||||
| Group 4 | Sulfation disorders | |||||
| NOS 04–0010 | Achondrogenesis, SLC26A2-related (formerly achondrogenesis type 1B, or type Fraccaro) | AR | SLC26A2 | 600972 | Formerly known as achondrogenesis, type Fraccaro | |
| NOS 04–0020 | Atelosteogenesis, SLC26A2-related (formerly atelosteogenesis type 2) | AR | SLC26A2 | 256050 | Includes former entities de la Chapelle dysplasia, McAlister dysplasia, and neonatal osseous dysplasia | |
| NOS 04–0030 | Diastrophic dysplasia, SLC26A2-related | AR | SLC26A2 | 222600 | ||
| NOS 04–0040 | Multiple epiphyseal dysplasia, SLC26A2-related (autosomal recessive type, rMED) | AR | SLC26A2 | 226900 | See also multiple epiphyseal dysplasias and pseudoachondroplasia group (group 9) | |
| NOS 04–0050 | Spondylo-epi-metaphyseal dysplasia, PAPSS2-related | AR | PAPSS2 | 612847 | Formerly “SEMD Pakistani type”; includes the former “recessive brachyolmia, recessive type” as well as the older entities “Toledo brachyolmia” and “Hobaek brachyolmia” | |
| NOS 04–0060 | Chondrodysplasia with congenital joint dislocations, IMPAD1-related | AR | IMPAD1 | 614078 | Some features similar to Catel-Manzke syndrome, TGDS-related, as well as to Desbuquois syndrome, CANT1-related | |
| NOS 04–0070 | Chondrodysplasia with congenital joint dislocations, CHST3-related | AR | CHST3 | 143095 | Includes recessive Larsen syndrome, humero-spinal dysostosis, and SED type Omani | |
| NOS 04–0080 | Chondrodysplasia with hypomyelinating leucodystrophy, SLC35B2-related | AR | SLC35B2 | see 610788 | ||
| NOS 04–0090 | Ehlers-Danlos syndrome, musculocontractural type, CHST14-related | AR | CHST14 | 601776 | Includes adducted thumb-clubfoot syndrome | |
| NOS 04–0100 | Ehlers-Danlos syndrome, musculocontractural type, DSE-related | AR | DSE | 615539 | ||
| NOS 04–0110 | Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD), CHST11-related | AR | CHST11 | 618167 | ||
| NOS 04–0120 | Developmental Delay with Corpus Callosum, Skeletal, and Renal Abnormalities, HS2ST1-related | AR | HS2ST1 | 619194 | ||
| 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. | ||||||
| Group 5 | Dysplasias with multiple joint dislocations | |||||
| NOS 05–0010 | Baratela-Scott syndrome, XYLT1-related | AR | XYLT1 | 615777 | May have intellectual disability; formerly Desbuquois dysplasia type 2 | |
| NOS 05–0020 | Desbuquois dysplasia (with accessory ossification centre in digit 2), CANT1-related | AR | CANT1 | 251450 | ||
| NOS 05–0030 | Desbuquois dysplasia (with short metacarpals and elongated phalanges, Kim type), CANT1-related | AR | CANT1 | 251450 | ||
| NOS 05–0040 | SEMD with joint laxity (Hall type or leptodactylic type), KIF22-related | AD | KIF22 | 603546 | ||
| NOS 05–0050 | SEMD with joint laxity, EXOC6B-related | AR | EXOC6B | 618395 | Phenotype resembles SEMD-JL leptodactylic or type Hall (preceding line) | |
| NOS 05–0060 | SEMD with joint laxity (Beighton type), B3GALT6-related (Ehlers-Danlos syndrome, spondylodysplastic type 2, EDSSPD2) | AR | B3GALT6 | 271640 | Includes MIM 609465 - Al-Gazali syndrome as neonatal form | |
| NOS 05–0070 | Ehlers-Danlos syndrome, spondylodysplastic type 1 (EDSSPD1), B4GALT7-related | AR | B4GALT7 | 130070 | Formerly known as “EDS, progeroid form”; includes Larsen syndrome, La Reunion type; see also B3GALT6 deficiency above | |
| NOS 05–0080 | Multiple joint dislocations, short stature, craniofacial dysmorphisms, and skeletal dysplasia, with or without heart defects, B3GAT3-related | AR | B3GAT3 | 245600 | 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. | |
| NOS 05–0090 | Skeletal dysplasia with joint laxity and advanced bone age (SDJLABA), CSGALNACT1-related | AR | CSGALNACT1 | 618870 | ||
| NOS 05–0100 | Skeletal dysplasia with joint dislocations and amelogenesis imperfecta, SLC10A7-related | AR | SLC10A7 | 618363 | ||
| 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, and EDSSPD3, SLC39A13-related, in the SEMD group. | ||||||
| Group 6 | Filamins and related disorders | |||||
| NOS 06–0010 | Frontometaphyseal dysplasia, FLNA-related | XL | FLNA | 305620 | FLNA gene also associated with MIM 300049, MIM 300321, MIM 314400, MIM 300048, MIM 300049 (see) and conditions below in this group | |
| NOS 06–0020 | Frontometaphyseal dysplasia, MAP3K7-related | AD | MAP3K7 | 617137 | ||
| NOS 06–0030 | Frontometaphyseal dysplasia, TAB2-related | AD | TAB2 | No MIM entry yet; TAB2 gene also associated with MIM 614980 - Congenital heart defects, nonsyndromic, 2 | ||
| NOS 06–0040 | Cardiospondylocarpofacial syndrome, MAP3K7-related | AD | MAP3K7 | 157800 | ||
| NOS 06–0050 | Melnick-Needles syndrome, FLNA-related | XL | FLNA | 309350 | Includes osteodysplasty | |
| NOS 06–0060 | Otopalatodigital syndrome type 1 (OPD1), FLNA-related | XL | FLNA | 311300 | ||
| NOS 06–0070 | Otopalatodigital syndrome type 2 (OPD2), FLNA-related | XL | FLNA | 304120 | ||
| NOS 06–0080 | Terminal osseous dysplasia (TOD), FLNA-related | XL | FLNA | 300244 | Includes digitocutaneous dysplasia | |
| NOS 06–0090 | Larsen syndrome, FLNB-related | AD | FLNB | 150250 | ||
| NOS 06–0100 | Atelosteogenesis type 1, FLNB-related | AD | FLNB | 108720, 112310 | Includes Boomerang dysplasia, Piepkorn dysplasia, and spondylohumerofemoral (giant cell) dysplasia | |
| NOS 06–0110 | Atelosteogenesis type 3, FLNB-related | AD | FLNB | 108721 | ||
| NOS 06–0120 | Spondylocarpotarsal synostosis syndrome, FLNB-related | AR | FLNB | 272460 | ||
| NOS 06–0130 | Spondylocarpotarsal synostosis syndrome, RFLNA-related | AR | RFLNA | Entity proven, no MIM entry yet | ||
| NOS 06–0140 | Spondyocarpotarsal synostosis syndrome with contractures and pterygia, MYH3-related | AD, AR | MYH3 | 178110, 618469 | frequently biallelic loss of function variants; monoallelic missense variants in the MYH3 gene associated with MIM 193700-Arthrogryposis 2A, and MIM 618436-Arthrogryposis 2B3 | |
| NOS 06–0150 | Frank-ter Haar syndrome, SH3PXD2B-related | AR | SH3PXD2B | 249420 | Includes previous Borrone dermatocardioskeletal syndrome | |
| See also Chondrodysplasia with congenital joint dislocations, CHST3-related (“recessive Larsen syndrome”) and the group of dysplasias with multiple dislocations, above (group 5) | ||||||
| Group 7 | Proteoglycan core proteins disorders | |||||
| NOS 07–0010 | Dyssegmental dysplasia, HSPG2-related | AR | HSPG2 | 224410, 224400 | Variable severity; Includes both former Silverman-Handmaker and Rolland-Desbuquois types | |
| NOS 07–0020 | Myotonic chondrodystrophy, HSPG2-related (Schwartz-Jampel syndrome) | AR | HSPG2 | 255800 | Variable severity; includes previous Burton dysplasia | |
| NOS 07–0030 | Spondylo-epiphyseal dysplasia, ACAN-related (dominant, Kimberley type) | AD | ACAN | 608361 | ||
| NOS 07–0040 | Spondylo-epi-metaphyseal dysplasia, ACAN-related (recessive, aggrecan type) | AR | ACAN | 612813 | ||
| NOS 07–0050 | Short stature with advanced bone age, ACAN-related | AD | ACAN | 165800 | Sometimes with osteochondritis dissecans; other cases short stature with no skeletal features and normal bone age | |
| NOS 07–0060 | SEMD, BGN-related (Camera type) | XL | BGN | 300106 | The BGN gene is also associated with a connective tissue- arterial aneurysms disorder (Meester-Loeys syndrome, MIM300989) | |
| Group 8 | TRPV4 disorders | |||||
| NOS 08–0010 | Metatropic dysplasia, TRPV4-related | AD, MOS | TRPV4 | 156530 | Includes “hyperplastic”, lethal and non-lethal forms. Can also result from somatic mosaicism for a TRPV4 variant. | |
| NOS 08–0020 | Spondyloepimetaphyseal dysplasia, TRPV4-related (Maroteaux type) | AD | TRPV4 | 184095 | Previously known as “Pseudo-Morquio syndrome type 2”. Includes MIM 168400-parastremmatic dwarfism, a phenotypic variation | |
| NOS 08–0030 | Spondyloepiphyseal dysplasia, Kozlowski type | AD | TRPV4 | 184252 | ||
| NOS 08–0040 | Brachyolmia, TRPV4-related | AD | TRPV4 | 113500 | ||
| NOS 08–0050 | Familial digital arthropathy with brachydactyly, TRPV4-related | AD | TRPV4 | 606835 | ||
| Missense variants in the TRPV4 gene can be responsible for different types of peripheral neuropathies (see MIM 605427). The TRPV4 skeletal phenotypes can sometimes be associated with neuropathy. | ||||||
| Group 9 | Pseudoachondroplasia and the multiple epiphyseal dysplasias | |||||
| NOS 09–0010 | Pseudoachondroplasia, COMP-related | AD | COMP | 177170 | ||
| NOS 09–0020 | Multiple epiphyseal dysplasia, COMP-related | AD | COMP | 132400 | ||
| NOS 09–0030 | Multiple epiphyseal dysplasia, MATN3-related | AD | MATN3 | 607078 | ||
| NOS 09–0040 | Multiple epiphyseal dysplasia, CANT1-related | AR | CANT1 | 617719 | ||
| NOS 09–0050 | Multiple epiphyseal dysplasia, COL9A1-related | AD | COL9A1 | 614135 | ||
| NOS 09–0060 | Multiple epiphyseal dysplasia, COL9A2-related | AD | COL9A2 | 600204 | ||
| NOS 09–0070 | Multiple epiphyseal dysplasia, COL9A3-related | AD | COL9A3 | 600969 | ||
| NOS 09–0080 | Stickler syndrome, recessive type, COL9A1-related | AR | COL9A1 | 614134 | See also groups 2 and 3 | |
| NOS 09–0090 | Stickler syndrome, recessive type, COL9A2-related | AR | COL9A2 | 614284 | ||
| NOS 09–0100 | Stickler syndrome, recessive type, COL9A3-related | AR | COL9A3 | 120270 | ||
| NOS 09–0110 | Multiple epiphyseal dysplasia with microcephaly and nystagmus (Lowry-Wood syndrome), RNU4ATAC-related | AR | RNU4ATAC | 226960 | 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 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. | ||||||
| Group 10 | Skeletal disorders caused by abnormalities of cilia or ciliary signaling | |||||
| NOS 10–0010 | Short rib–polydactyly syndrome (SRPS), DYNC2H1-related | AR | DYNC2H1 | 613091, 263520 | 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. | |
| NOS 10–0020 | Short rib–polydactyly syndrome (SRPS), IFT80-related | AR | IFT80 | 611263 | ||
| NOS 10–0030 | Short rib–polydactyly syndrome (SRPS), IFT81-related | AR | IFT81 | 617895 | ||
| NOS 10–0040 | Short rib–polydactyly syndrome (SRPS), WDR34-related | AR | WDR34 | 615633 | ||
| NOS 10–0050 | Short rib–polydactyly syndrome (SRPS), WDR60-related | AR | WDR60 | 615503 | ||
| NOS 10–0060 | Short rib–polydactyly syndrome (SRPS), DYNC2LI1-related | AR | DYNC2LI1 | 617088 | ||
| NOS 10–0070 | Short rib–polydactyly syndrome (SRPS), NEK1-related | AR | NEK1 | 263520 | Possibly also digenic inheritance combining NEK1 with DYNC2H1 variants | |
| NOS 10–0080 | Short rib–polydactyly syndrome (SRPS), IFT122-related | AR | IFT122 | 269860 | ||
| NOS 10–0090 | Short rib–polydactyly syndrome (SRPS), WDR19-related | AR | WDR19 | 614091 | 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) | |
| NOS 10–0100 | Short rib-polydactyly syndrome (SRPS), INTU-related | AR | INTU | 617925 | ||
| NOS 10–0110 | Short rib-polydactyly syndrome (SRPS), TRAF3IP1-related | AR | TRAF3IP1 | see 607380 | TRAF3IP1 also known as IFT154 | |
| NOS 10–0120 | Endocrine-cerebro-osteo dysplasia (ECO), CILK1-related | AR | CILK1 | 612651 | ||
| NOS 10–0130 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), DYNC2H1-related | AR | DYNC2H1 | 613091 | ||
| NOS 10–0140 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), DYNC2LI1-related | AR | DYNC2LI1 | see 617088 | ||
| NOS 10–0150 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), WDR34-related | AR | WDR34 | see 615633 | ||
| NOS 10–0160 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), TCTEX1D2-related | AR | TCTEX1D2 | 617405 | ||
| NOS 10–0170 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), WDR60-related | AR | WDR60 | see 615503 | ||
| NOS 10–0180 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), WDR19-related | AR | WDR19 | 614376 | 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) | |
| NOS 10–0190 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), IFT140-related | AR | IFT140 | 266920 | ||
| NOS 10–0200 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), TTC21B-related | AR | TTC21B | 613819 | Gene also known for nephronophthisis (MIM 613820) | |
| NOS 10–0210 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), IFT122-related | AR | IFT122 | see 269860 | Subsumed under SRPS (MIM 269860) | |
| NOS 10–0220 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), WDR35-related | AR | WDR35 | 614091 | ||
| NOS 10–0230 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), IFT43-related | AR | IFT43 | 617866 | ||
| NOS 10–0240 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), IFT80-related | AR | IFT80 | 611623 | ||
| NOS 10–0250 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), IFT172-related | AR | IFT172 | 615630 | ||
| NOS 10–0260 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), IFT81-related | AR | IFT81 | 617895 | ||
| NOS 10–0270 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), IFT52-related | AR | IFT52 | 617102 | ||
| NOS 10–0280 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), CFAP410-related | AR | CFAP410 | 602271 | ||
| NOS 10–0290 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), CEP120-related | AR | CEP120 | 616300 | Described in severe cases resembling SRPS; the CEP120 gene is also associated with Joubert syndrome (MIM 617761) | |
| NOS 10–0300 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), KIAA0586-related | AR | KIAA0586 | 616546 | Gene also associated with Joubert syndrome (MIM 616490) | |
| NOS 10–0310 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), GRK2-related | AR | GRK2 | see 109635 | ||
| NOS 10–0320 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), TRAF3IP1-related | AR | TRAF3IP1 | see 607380 | TRAF3IP1 also known as IFT154 | |
| NOS 10–0330 | Short-rib thoracic dysplasia (formerly asphyxiating thoracic dysplasia - Jeune syndrome), KIAA0753-related | AR | KIAA0753 | 619479 | KIAA0753 variants also associated with orofaciodigital syndrome (MIM 617127) and with Joubert syndrome (MIM 619476) | |
| NOS 10–0340 | Axial spondylometaphyseal dysplasia, CFAP410-related | AR | CFAP410 | 602271 | ||
| NOS 10–0350 | Axial spondylometaphyseal dysplasia, NEK1-related | AR | NEK1 | see 252100 | ||
| NOS 10–0360 | Chondroectodermal dysplasia (Ellis-van Creveld), EVC1-related | AR | EVC1 | 225500 | See also Weyers acrofacial (acrodental) dysostosis (MIM 193530) | |
| NOS 10–0370 | Chondroectodermal dysplasia (Ellis-van Creveld), EVC2-related | AR | EVC2 | |||
| NOS 10–0380 | Chondroectodermal dysplasia (Ellis-van Creveld), WDR35-related | AR | WDR35 | |||
| NOS 10–0390 | Chondroectodermal dysplasia (Ellis-van Creveld), DYNC2LI1-related | AR | DYNC2LI1 | see 617088 | ||
| NOS 10–0400 | Chondroectodermal dysplasia (Ellis-van Creveld), GLI1-related | AR | GLI1 | see 165220 | ||
| NOS 10–0410 | Chondroectodermal dysplasia (Ellis-van Creveld), SMO-related | AR | SMO | see | A single case with compound heterozygosity missense variants reported | |
| NOS 10–0420 | Orofaciodigital syndrome type 4 (Mohr-Majewski), TCTN3-related | AR | TCTN3 | 258860 | ||
| NOS 10–0430 | Orofaciodigital syndrome type 2 (Mohr syndrome), NEK1-related | AR | NEK1 | 252100 | ||
| NOS 10–0440 | Cranioectodermal dysplasia (Levin-Sensenbrenner), IFT122-related | AR | IFT122 | 218330 | ||
| NOS 10–0450 | Cranioectodermal dysplasia (Levin-Sensenbrenner), WDR35-related | AR | WDR35 | 613610 | ||
| NOS 10–0460 | Cranioectodermal dysplasia (Levin-Sensenbrenner), WDR19-related | AR | WDR19 | 614378 | 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) | |
| NOS 10–0470 | Cranioectodermal dysplasia (Levin-Sensenbrenner), IFT40-related | AR | IFT40 | see 614620 | see short rib thoracic dysplasia, IFT140-associated, above | |
| NOS 10–0480 | Cranioectodermal dysplasia (Levin-Sensenbrenner), IFT43-related | AR | IFT43 | 614009 | ||
| NOS 10–0490 | Joubert syndrome with short-rib thoracic dysplasia, CSPP1-related | AR | CSPP1 | 615636 | in OMIM as “Joubert syndrome type 21”; not all cases have thoracic dysplasia | |
| NOS 10–0500 | Atrial defects-polydactyly-multiple congenital malformation syndrome, PRKACA-related | AD | PRKACA | 619142 | OMIM created the name of “Cardioacrofacial syndrome 1”. | |
| NOS 10–0510 | Atrial defects-polydactyly-multiple congenital malformation syndrome, PRKACB-related | AD, MOS | PRKACB | 619143 | OMIM created the name of “Cardioacrofacial syndrome 2”; one published patient later reclassified as “Ellis-van Creveld syndrome”. | |
| NOS 10–0520 | Mainzer-Saldino syndrome, IFT140-related | AR | IFT140 | 266920 | IFT140 also associated with isolated retinitis pigmentosa (MIM 617781) | |
| NOS 10–0530 | Mainzer-Saldino syndrome, IFT172-related | AR | IFT172 | IFT172 also associated with Bardet-Biedl syndrome (MIM 619471) and isolated retinitis pigmentosa (616394) | ||
| NOS 10–0540 | Mainzer-Saldino syndrome, WDR19-related | AR | WDR19 | see 614376 | WDR19 is also associated with MIM 614091, 614376, 614378, 615633 as well as with nephronopthisis (MIM 614377), and Senior-Loken syndrome (MIM 616307) | |
| NOS 10–0550 | Meckel syndrome, MKS1-related | AR | MKS1 | 249000 | ||
| NOS 10–0560 | Meckel syndrome, TMEM216-related | AR | TMEM216 | 603194 | ||
| NOS 10–0570 | Meckel syndrome, TMEM67-related | AR | TMEM67 | 607361 | ||
| NOS 10–0580 | Meckel syndrome, CEP290-related | AR | CEP290 | 611134 | ||
| NOS 10–0590 | Meckel syndrome, RPGRIP1L-related | AR | RPGRIP1L | 611561 | ||
| NOS 10–0600 | Meckel syndrome, CC2D2A-related | AR | CC2D2A | 612284 | ||
| NOS 10–0610 | Thoracolaryngopelvic dysplasia (Barnes) | SP | 187760 | Dominant transmission reported, but diagnostic criteria not stringent. The existence pf this entity is disputed. | ||
| Given the common genetic basis of several disorders 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. Also, the large phenotypic spectrum of the Bardet-Biedl syndrome has not been included in spite of minor skeletal involvement as the predominant clinical features are non-skeletal. | ||||||
| Group 11 | Metaphyseal dysplasias | |||||
| NOS 11–0010 | Metaphyseal dysplasia Schmid (MCS), COL10A1-related | AD | COL10A1 | 156500 | Pathogenic variants are typically located in the C-terminal domain of the protein. | |
| NOS 11–0020 | Cartilage-hair hypoplasia (CHH; metaphyseal dysplasia, McKusick type), RMRP-related | AR | RMRP | 250250 | The phenotype of CHH is variable and includes MIM 607095-anauxetic dysplasia as well as MIM 250460-metaphyseal dysplasia without hypotrichosis | |
| NOS 11–0030 | Metaphyseal dysplasia with short stature (CHH-like), POP1-related | AR | POP1 | 617396 | 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 | |
| NOS 11–0040 | Metaphyseal dysplasia with short stature (CHH-like), NEPRO-related | AR | NEPRO | 618853 | Facial features and hypotrichosis reminiscent of Cartilage-Hair Hypoplasia | |
| NOS 11–0050 | Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia (Shwachman-Bodian-Diamond syndrome), SBDS-related | AR | SBDS | 260400 | See also severe spondylodysplastic dysplasia, Sedaghatian-like | |
| NOS 11–0060 | Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia (SBDS type 2), EFL1-related | AR | EFL1 | 617941 | ||
| NOS 11–0070 | Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia, DNAJC21-related | AR | DNAJC21 | 617052 | Known in OMIM as Bone Marrow Failure Syndrome 3; BMFS3 | |
| NOS 11–0080 | Shwachman-Diamond like syndrome, SRP54-related | AD | SRP54 | 618752 | Known in OMIM as Neutropenia, severe congenital, 8 | |
| NOS 11–0090 | Metaphyseal dysplasia Spahr, MMP13-related | AR | MMP13 | 250400 | Recessive, biallelic variants | |
| NOS 11–0100 | Metaphyseal anadysplasia, MMP13-related | AD | MMP13 | 602111 | Dominant, monoallelic type; includes SEMD Missouri type | |
| NOS 11–0110 | Metaphyseal anadysplasia, MMP9-related | AR | MMP9 | 613073 | ||
| NOS 11–0120 | Metaphyseal dysplasia with maxillary hypoplasia, RUNX2-related | AD | RUNX2 | 156510 | 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 | |
| See Rhizomelic spondylo-metaphyseal dysplasia with remission, LBR-related, for another anadysplasia-like disorder | ||||||
| Group 12 | Spondylometaphyseal dysplasias (SMD) | |||||
| NOS 12–0010 | Spondyloenchondrodysplasia with immune dysregulation (SPENCD), ACP5-related | AR | ACP5 | 607944 | ||
| NOS 12–0020 | Odontochondrodysplasia (ODCD), TRIP11-related | AR | TRIP11 | 184260 | See also Achondrogenesis, TRIP11-related (formerly type 1A) | |
| NOS 12–0030 | Spondylometaphyseal dysplasia Sutcliffe (or “corner fractures” type), FN1-related | AD | FN1 | 184255 | Some cases are linked to COL2A1 but not the original family | |
| NOS 12–0040 | Spondylometaphyseal dysplasia with cone-rod dystrophy, PCYT1A-related | AR | PCYT1A | 608940 | ||
| NOS 12–0050 | Spondylometaphyseal dysplasia with corneal dystrophy, PLCB3-related | AR | PLCB3 | 618961 | ||
| NOS 12–0060 | Chondrodysplasia-pseudohermaphroditism syndrome, HHAT-related | AR | HHAT | 600092 | Also known as Nivelon-Nivelon-Mabille syndrome (sic) | |
| 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. | ||||||
| Group 13 | Spondyloepi(meta)physeal dysplasias (SE(M)D) | |||||
| NOS 13–0010 | SED tarda, X-linked (SED-XL), TRAPPC2-related | XL | TRAPPC2 | 313400 | ||
| NOS 13–0020 | SED with diabetes mellitus (Wolcott-Rallison syndrome), EIF2AK3-related | AR | EIF2AK3 | 226980 | ||
| NOS 13–0030 | Dyggve-Melchior-Clausen dysplasia, DYM-related | AR | DYM | 223800 | ||
| NOS 13–0040 | Smith-McCort dysplasia, DYM-related | AR | DYM | 607326 | ||
| NOS 13–0050 | Smith-McCort dysplasia, RAB33B-related | AR | RAB33B | 615222 | ||
| NOS 13–0060 | SEMD, BNIP1-related | AR | BNIP1 | see 603291 | ||
| NOS 13–0070 | SEMD, MATN3-related | AR | MATN3 | 608728 | See also MATN3-related MED in group 9 | |
| NOS 13–0080 | SEMD, DDRGK1-related (Shohat type) | AR | DDRGK1 | 602557 | ||
| NOS 13–0090 | SEMD with leucodystrophy, AIFM1-related | XL | AIFM1 | 300232 | ||
| NOS 13–0100 | SEMD, RSPRY1-related | AR | RSPRY1 | 616723 | ||
| NOS 13–0110 | SEMD, TMEM165-related | AR | TMEM165 | 614727 | Congenital disorder of glycosylation type IIk | |
| NOS 13–0120 | SEMD with microcephaly, retinal dystrophy and hearing loss, PISD-related (Liberfarb syndrome) | AR | PISD | 618889 | Phenotypically variable; in some affected individuals hearing and vision may be unaffected | |
| NOS 13–0130 | SEMD, UFSP2-related | AD | UFSP2 | 142669, 617974 | Includes Familial hip dysplasia (Beukes) | |
| NOS 13–0140 | SEMD, short limb–abnormal calcification type, DDR2-related | AR | DDR2 | 271665 | See also other dysplasias with stippling | |
| NOS 13–0150 | Immuno-osseous dysplasia, SMARCAL1-related (Schimke type) | AR | SMARCAL1 | 242900 | Nephrotic syndrome is an important manifestation; see also EXTL3 deficiency, below | |
| NOS 13–0160 | SEMD with immune deficiency and intellectual disability, EXTL3-related | AR | EXTL3 | 617425 | Also known as “Immunoskeletal dysplasia with developmental abnormalities”; includes Omenn syndrome with chondrodysplasia; see also SMARCAL1, above | |
| NOS 13–0170 | SEMD with immune deficiency, PGM3-related | AR | PGM3 | 615816 | Known in OMIM as “immunodeficiency 23” | |
| NOS 13–0180 | SEMD with intellectual disability, NANS-related | AR | NANS | 610442 | ||
| NOS 13–0190 | SEMD with severe short stature, RPL13-related | AD | RPL13 | 618728 | ||
| NOS 13–0200 | SEMD with elevated lysosomal enzymes, MBTPS1-related | AR | MBTPS1 | 618392 | only two unrelated individuals known so far; in OMIM as “Kondo-Fu type”; possible role of lysosomal dysfunction in pathogenesis is unclear | |
| NOS 13–0210 | Short stature, skeletal dysplasia, liver failure, optic nerve atrophy and Pelger-Huet anomaly, NBAS-related | AR | NBAS | 616483 | Combination of clinical features is variable; also known as infantile liver failure syndrome type 2 | |
| NOS 13–0220 | Short stature, skeletal dysplasia and liver failure, RINT1-related | AR | RINT1 | 618641 | Combination of clinical features is variable; also known as infantile liver failure syndrome type 3 | |
| NOS 13–0230 | Spondylodysplastic Ehlers-Danlos syndrome (SDEDSS type 3), SLC39A13-related | AR | SLC39A13 | 612350 | SLC39A13 / ZIP13 zinc transporter | |
| NOS 13–0240 | Spondylar and nasal alterations with striated metaphyses (SPONASTRIME dysplasia), TONSL-related | AR | TONSL | 271510 | Possibly genetically heterogeneous | |
| NOS 13–0250 | Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis (SHILCA) syndrome, NMNAT1-related | AR | NMNAT1 | 619260 | Nonsyndromic Leber congenital amaurosis (LCA9; MIM 608553) is also caused by biallelic NMNAT1 variants | |
| NOS 13–0260 | Platyspondyly (brachyolmia) with amelogenesis imperfecta, LTBP3-related | AR | LTBP3 | 601216 | ||
| NOS 13–0270 | Cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS syndrome), LONP1-related | AR | LONP1 | 600373 | Mitochondrial chaperonopathy | |
| NOS 13–0280 | Epiphyseal and vertebral dysplasia, microtia, flat nose plus associated malformation (EVEN-PLUS syndrome), HSPA9-related | AR | HSPA9 | 616854 | Mitochondrial chaperonopathy | |
| NOS 13–0290 | Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia (CAGSSS syndrome), IARS2-related | AR | IARS2 | 616007 | ||
| NOS 13–0300 | Steel syndrome, COL27A1-related | AR | COL27A1 | 615155 | ||
| NOS 13–0310 | Rhizomelic spondylo-metaphyseal dysplasia with remission, LBR-related | AR | LBR | 618019 | ||
| NOS 13–0320 | Rhizomelic spondylo-epi-metaphyseal dysplasia, GNPNAT1-related | AR | GNPNAT1 | 619598 | ||
| See also: Opsismodysplasia, INPPL1-related; Mucopolysaccharidosis type 4, GALNS-related (type 4A; Morquio disease), as well as Progressive pseudorheumatoid dysplasia (PPRD), WISP3-related | ||||||
| Group 14 | Severe spondylodysplastic dysplasias | |||||
| NOS 14–0010 | Achondrogenesis, TRIP11-related (formerly type 1A) | AR | TRIP11 | 200600 | ||
| NOS 14–0020 | Schneckenbecken dysplasia, SLC35D1-related | AR | SLC35D1 | 269250 | ||
| NOS 14–0030 | Severe spondylometaphyseal dysplasia (Sedaghatian type), GPX4-related | AR | GPX4 | 250220 | ||
| NOS 14–0040 | Severe spondylometaphyseal dysplasia (SMD Sedaghatian-like), SBDS-related | AR | SBDS | 260400 | ||
| NOS 14–0050 | Opsismodysplasia, INPPL1-related | AR | INPPL1 | 258480 | Includes lethal and milder cases | |
| NOS 14–0060 | Spondylometaphyseal dysplasia, PAM16- related | AR | PAM16 | 613320 | ||
| NOS 14–0070 | Carbohydrate deficient glycoprotein syndrome, ALG9-related (ALG9-CDG; Gillessen-Kaesbach-Nishimura syndrome) | AR | ALG9 | 263210, 608776 | ||
| See also: Thanatophoric dysplasia, FGFR3-related; achondrogenesis and Torrance dysplasia, COL2A1-related; Fibrochondrogenesis, COL11A1-related; Achondrogenesis, SLC26A2-related; and Metatropic Dysplasia, TRPV4-related | ||||||
| Group 15 | Mesomelic and rhizo-mesomelic dysplasias | |||||
| NOS 15–0010 | Dyschondrosteosis (Leri- Weill), SHOX-related | Pseudo-AD | SHOX | 127300 | Includes Reinhardt-Pfeiffer dysplasia, MIM 191400. Clinical continuum with Idiopathic short stature (MIM 300582) | |
| NOS 15–0020 | Mesomelic dysplasia (Langer type), SHOX-related | Pseudo-AR | SHOX | 249700 | ||
| NOS 15–0030 | Omodysplasia, recessive type, GPC6-related | AR | GPC6 | 258315 | ||
| NOS 15–0040 | Omodysplasia, dominant type, FZD2-related | AD | FZD2 | 164745 | ||
| NOS 15–0050 | Robinow syndrome, WNT5A-related | AD | WNT5A | 180700 | ||
| NOS 15–0060 | Robinow syndrome, DVL1-related | AD | DVL1 | 616331 | ||
| NOS 15–0070 | Robinow syndrome, DVL3-related | AD | DVL3 | 616894 | ||
| NOS 15–0080 | Robinow syndrome, FZD2-related | AD | FZD2 | |||
| NOS 15–0090 | Robinow syndrome, recessive type, ROR2-related | AR | ROR2 | 268310 | Includes previous COVESDEM (costo-vertebral segmentation defect with mesomelia); see also brachydactyly type B | |
| NOS 15–0100 | Robinow syndrome, recessive type, NXN-related | AR | NXN | |||
| NOS 15–0110 | Mesomelic dysplasia, HOXD-related (Kim or Korean type, Kantaputra type, Fryns type) | AD | HOXD | 156232 | Duplications at HOXD gene cluster locus; phenotypes is variable also within families | |
| NOS 15–0120 | Mesomelic dysplasia, Nievergelt type | AD | 163400 | |||
| NOS 15–0130 | Mesomelic dysplasia, Kozlowski-Reardon type | AR | 249710 | |||
| NOS 15–0140 | Mesomelic dysplasia with acral synostoses (Verloes-David-Pfeiffer type) | AD | SULF1, SLCO5A1 | 600383 | Microdeletion syndrome involving two adjacent genes | |
| NOS 15–0150 | Mesomelic dysplasia (Savarirayan type), ID4-related | AD | ID4 | 605274 | Microdeletions on 6p22.3 | |
| NOS 15–0160 | Mesomelic dysplasia with digital anomalies and intellectual disability (KINSSHIP syndrome), AFF3-related | AD | AFF3 | 619297 | In spite of the acronym, this condition is quite different from both Nievergelt and Savarirayan mesomelic dysplasias | |
| NOS 15–0170 | Oculo-skeletal syndrome with rhizomelic shortening, MAB21L2-related | AD | MAB21L2 | 615877 | 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. | |
| See also Tibial hemimelia-polysyndactyly-triphalangeal thumb, ZRS-related, also consider: mesomelic dysplasia, Camera type (MIM#611886), the status of which remains unconfirmed | ||||||
| Group 16 | Acromesomelic dysplasias | |||||
| NOS 16–0010 | Acromesomelic dysplasia (type Maroteaux), NPR2-related | AR | NPR2 | 602875 | ||
| NOS 16–0020 | Acromesomelic dysplasia, PRKG2-related | AR | PRKG2 | 619636, 619638 | 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) | |
| NOS 16–0030 | Grebe dysplasia, GDF5-related | AR | GDF5 | 200700 | Includes acromesomelic dysplasia Hunter-Thompson type and acromesomelic dysplasia with genital anomalies; see also see other GDF5-related disorders | |
| NOS 16–0040 | Grebe dysplasia, BMPR1B-related | AR | BMPR1B | 609441 | ||
| NOS 16–0050 | Fibular hypoplasia and complex brachydactyly (Du Pan), GDF5-related | AR | GDF5 | 228900 | see also other GDF5-related disorders | |
| NOS 16–0060 | Fibular hypoplasia and complex brachydactyly (Du Pan), BMPR1B-related | AR | BMPR1B | see 603248 | ||
| NOS 16–0070 | Acromesomelic dysplasia, Osebold-Remondini type | AD | 112910 | |||
| Group 17 | Acromelic dysplasias | |||||
| NOS 17–0010 | Acrocapitofemoral dysplasia, IHH-related | AR | IHH | 607778 | See other conditions associated with the IHH gene in this table | |
| NOS 17–0020 | Geleophysic dysplasia, ADAMTSL2-related | AR | ADAMTSL2 | 231050 | ||
| NOS 17–0030 | Geleophysic dysplasia, FBN1-related | AD | FBN1 | 614185 | ||
| NOS 17–0040 | Geleophysic dysplasia, LTBP3-related | AD | LTBP3 | 617809 | ||
| NOS 17–0050 | Acromicric dysplasia, FBN1-related | AD | FBN1 | 102370 | Includes acrolaryngeal dysplasia, previously known as Fantasy Island dysplasia or Tattoo dysplasia, and Moore-Federman syndrome | |
| NOS 17–0060 | Acromicric dysplasia, LTBP3-related | AD | LTBP3 | see 617809 | ||
| NOS 17–0070 | Weill-Marchesani syndrome, dominant, FBN1-related | AD | FBN1 | 608328 | ||
| NOS 17–0080 | Weill-Marchesani syndrome, ADAMTS10-related | AR | ADAMTS10 | 277600 | ||
| NOS 17–0090 | Weill-Marchesani syndrome, ADAMTS17-related | AR | ADAMTS17 | 613195 | ||
| NOS 17–0100 | Weill-Marchesani syndrome, LTBP2-related | AR | LTBP2 | 614819 | ||
| NOS 17–0110 | Myhre dysplasia, SMAD4-related | AD | SMAD4 | 139210 | ||
| NOS 17–0120 | Acrodysostosis, PDE4D-related | AD | PDE4D | 614613 | Includes acroscyphodysplasia (see PMID 30006632) | |
| NOS 17–0130 | Acrodysostosis, PRKAR1A-related | AD | PRKAR1A | 101800 | ||
| NOS 17–0140 | Angel-shaped phalango-epiphyseal dysplasia (ASPED) | AD | 105835 | Possibly related or allelic to brachydactyly type C | ||
| NOS 17–0150 | Albright hereditary osteodystrophy, GNAS-related | AD | GNAS | 103580 | Overlaps with progressive osseous heteroplasia | |
| NOS 17–0160 | Leri Pleonosteosis, linked to 8q22.1 | AD | 8q22.1 | 151200 | Duplication at 8q22.1 encompassing GDF6 and SDC2 | |
| NOS 17–0170 | SED with brachydactyly, MIR140-related | AD | MIR140 | 618618 | Brachydactyly with cone-shaped epiphyses | |
| See also Cartilage-Hair Hypoplasia, RMRP-related, and the brachdydactyly groups, below (groups 18 and 19) | ||||||
| Group 18 | Brachydactylies (isolated) | |||||
| NOS 18–0010 | Brachydactyly type A1, IHH-related | AD | IHH | 112500 | ||
| NOS 18–0020 | Brachydactyly type A2, BMPR1B-related | AD | BMPR1B | 112600 | ||
| NOS 18–0030 | Brachydactyly type A2, BMP2-related | AD | BMP2 | 112600 | Duplication of BMP2 enhancer | |
| NOS 18–0040 | Brachydactyly type A2, GDF5-related | AD | GDF5 | 112600 | 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 | |
| NOS 18–0050 | Brachydactyly type B1, ROR2-related | AD | ROR2 | 113000 | see also Robinow syndrome/COVESDEM | |
| NOS 18–0060 | Brachydactyly type B2, NOG-related | AD | NOG | 611377 | ||
| NOS 18–0070 | Brachydactyly type C, GDF5-related | AD | GDF5 | 113100 | see other GDF5-related disorders | |
| NOS 18–0080 | Brachydactyly type D, HOXD13-related | AD | HOXD13 | 113200 | Brachydactyly type D is often a component of Brachydactyly type E | |
| NOS 18–0090 | Brachydactyly type E, HOXD13-related | AD | HOXD13 | 113300 | ||
| NOS 18–0100 | Brachydactyly with anonychia (Cooks syndrome), KCNJ2-related | AD | KCNJ2 | 106995 | Duplications of SOX9/KCNJ2 regulatory region | |
| NOS 18–0110 | Preaxial brachydactyly, PAX3 type, linked to 2q35–36 | AD | 2q35–36 | Deletions leading to disruption of TADs and abnormal expression of PAX3 | ||
| See also brachdactyly, PTHLH-related (below) | ||||||
| Group 19 | Brachydactylies as part of syndromes | |||||
| NOS 19–0010 | Trichorhinophalangeal dysplasia types 1/3 | AD | TRPS1 | 190350, 190351 | TRPS1 and 3 are a phenotypic spectrum | |
| NOS 19–0020 | Langer-Giedion syndrome (Trichorhinophalangeal dysplasia type 2) | AD | TRPS1, EXT1 | 150230 | Microdeletion syndrome; see also multiple cartilaginous exostoses | |
| NOS 19–0030 | Catel-Manzke syndrome, TGDS-related | AR | TGDS | 616145 | ||
| NOS 19–0040 | Deafness, onychodystrophy, osteodystrophy, retardation and seizures (DOORS) syndrome | AR | TBC1D24 | 220500 | “Osteodystrophy” and “retardation” are misnomers | |
| NOS 19–0050 | Brachydactyly - intellectual disability syndrome, HDAC4-related | AD | HDAC4 | 600430 | 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) | |
| NOS 19–0060 | Hyperphosphatasia with intellectual disability, brachytelephalangy, and distinct face, PIGV-related | AR | PIGV | 239300 | Several other related defects of GPI synthesis known, most cases not known for skeletal changes; see e.g., MIM 610293 for a summary | |
| NOS 19–0070 | Brachydactyly-short stature-hypertension syndrome, PDE3A-related (Bilginturan syndrome) | AD | PDE3A | 112410 | ||
| NOS 19–0080 | Brachydactyly, obesity and intelelctual disability syndrome, PRMT7-related | AR | PRMT7 | 617157 | 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” | |
| NOS 19–0090 | Microcephaly-oculo-digito-esophageal-duodenal syndrome, MYCN-related (Feingold syndrome) | AD | MYCN | 164280 | ||
| NOS 19–0100 | Hand-foot-genital syndrome, HOXA13-related | AD | HOXA13 | 140000 | Includes Guttmacher syndrome | |
| NOS 19–0110 | Rubinstein-Taybi syndrome, CREBBP-related | AD | CREBBP | 180849 | ||
| NOS 19–0120 | Rubinstein-Taybi syndrome, EP300-related | AD | EP300 | 613684 | ||
| NOS 19–0130 | Brachydactyly, Temtamy type, CHSY1-related | AR | CHSY1 | 605282 | ||
| NOS 19–0140 | Hyperphalangism, characteristic facies, hallux valgus and bronchomalacia (Chitayat syndrome), ERF-related | AD | ERF | 617180 | typically a monoallelic Y89C substitution | |
| NOS 19–0150 | Hypoacusis with facial an digital anomalies (Keipert syndrome), GPC4-related | XL | GPC4 | 301026 | brachytelephalangy is the most consistent skeletal signs | |
| NOS 19–0160 | Christian type brachydactyly | AD | 112450 | |||
| NOS 19–0170 | Coffin-Siris syndrome, ARID1A-related | AD | ARID1A | 614607 | ||
| NOS 19–0180 | Coffin-Siris syndrome, ARIB1B-related | AD | ARID1B | 135900 | Variants in various components of the SWI/SNF complex have been reported in patients with a diagnosis of Coffin-Siris syndrome | |
| NOS 19–0190 | Coffin-Siris syndrome, SMARCB1-related | AD | SMARCB1 | 614608 | ||
| NOS 19–0200 | Coffin-Siris syndrome, SMARCA4-related | AD | SMARCA4 | 614609 | ||
| NOS 19–0210 | Coffin-Siris syndrome, SMARCE1-related | AD | SMARCE1 | 616938 | ||
| NOS 19–0220 | Cardiomyopathy and brachydactyly, LMNA-related (Heart-hand syndrome type IV) | AD | LMNA | 610140 | in OMIM as “Heart-Hand syndrome, Slovenian type” | |
| See also CDP, X-linked recessive, ARSE-related (brachytelephalangic type; CDPX1) | ||||||
| Group 20 | Bent bones dysplasia group | |||||
| NOS 20–0010 | Campomelic dysplasia (CD), SOX9-related | AD | SOX9 | 114290 | 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 | |
| NOS 20–0020 | Stüve-Wiedemann syndrome, LIFR-related | AR | LIFR | 601559 | Includes former neonatal Schwartz-Jampel syndrome or SJS type 2 | |
| NOS 20–0030 | Stüve-Wiedemann syndrome, IL6ST-related | AR | IL6ST | 619751 | ||
| NOS 20–0040 | Kyphomelic dysplasia with facial dysmorphism, KIF5B-related | AD | KIF5B | 211350 | The name “kyphomelic dysplasia” has been applied to heterogeneous conditions | |
| NOS 20–0050 | Bent bone dysplasia, FGFR2-related | AD | FGFR2 | 614592 | ||
| NOS 20–0060 | Bent bone dysplasia, LAMA5-related | AR | LAMA5 | Biallelic LAMA5 variants are associated with congenital or infantile nephrotic syndrome (MIM | ||
| 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. | ||||||
| Group 21 | Primordial dwarfism and slender bones group | |||||
| NOS 21–0010 | 3-M syndrome, CUL7-related | AR | CUL7 | 273750 | Includes dolichospondylic dysplasia and Yakut short stature syndrome | |
| NOS 21–0020 | 3-M syndrome, OBSL1-related | AR | OBSL1 | 612921 | ||
| NOS 21–0030 | 3-M syndrome, CCDC8-related | AR | CCDC8 | 614205 | ||
| NOS 21–0040 | Sanjad-Sakati syndrome, recessive, TBCE-related | AR | TBCE | 241410 | In OMIM as “Kenny-Caffey type 1” but does not correspond to the disorder described by Kenny and Caffey which is the dominant form | |
| NOS 21–0050 | Kenny-Caffey syndrome, dominant, FAM111A-related | AD | FAM111A | 127000 | ||
| NOS 21–0060 | Osteocraniostenosis, FAM111A-related | AD | FAM111A | 602361 | ||
| NOS 21–0070 | Hallermann-Streiff syndrome | 234100 | Usuall sporadic; some cases have phenotypic overlap with Osteocraniostenosis, FAM111A-related | |||
| NOS 21–0080 | Microcephalic osteodysplastic primordial dwarfism, RNU4ATAC-related | AR | RNU4ATAC | 210710 | Was MOPD 1/3; usually homozygous variants; includes Taybi-Linder cephaloskeletal dysplasia | |
| NOS 21–0090 | Roifman syndrome, RNU4ATAC-related | AR | RNU4ATAC | 616651 | See other RNU4ATAC-related condition in this table | |
| NOS 21–0100 | Microcephalic osteodysplastic primordial dwarfism, PCNT-related | AR | PCNT | 210720 | Was MOPD2, Majewski type | |
| NOS 21–0110 | Microcephalic osteodysplastic primordial dwarfism, ATR-related | AR | ATR | 210600 | In MIM as Seckel syndrome 1 | |
| NOS 21–0120 | Microcephalic osteodysplastic primordial dwarfism, RBBP8-related | AR | RBBP8 | 606744 | In MIM as Seckel syndrome 2. The RBBP8 gene is also associated with Jawad syndrome (microcephaly with intellectual disability and digital anomalies; MIM 251255) | |
| NOS 21–0130 | Microcephalic osteodysplastic primordial dwarfism, CEP152-related | AR | CEP152 | 613823 | In MIM as Seckel syndrome 5. The CEP152 gene also causes primary microcephaly (MIM 614852) | |
| NOS 21–0140 | Microcephalic osteodysplastic primordial dwarfism, DNA2-related | AR | DNA2 | 615807 | In MIM as Seckel syndrome 8. The DNA2 gene is also associated with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (MIM 615156) | |
| NOS 21–0150 | Microcephalic osteodysplastic primordial dwarfism, TRAIP-related | AR | TRAIP | 616777 | In MIM as Seckel syndrome 9 | |
| NOS 21–0160 | Microcephalic osteodysplastic primordial dwarfism, NSMCE2-related | AR | NSMCE2 | 617253 | In MIM as Seckel syndrome 10 | |
| NOS 21–0170 | Microcephalic osteodysplastic primordial dwarfism, CENPE-related | AR | CENPE | see 616051 | In MIM as autosomal recessive primary microcephaly | |
| NOS 21–0180 | Microcephalic osteodysplastic primordial dwarfism, CRIPT-related | AR | CRIPT | 615789 | In MIM as short stature with microcephaly and distinctive facies | |
| NOS 21–0190 | Microcephalic osteodysplastic primordial dwarfism, XRCC4-related | AR | XRCC4 | 616541 | In MIM as short stature, microcephaly and endocrine dysfunction | |
| NOS 21–0200 | Microcephalic osteodysplastic primordial dwarfism, or microcephaly-short stature-micromelia-limb abnormalities, DONSON-related | AR | DONSON | 251230, 617604 | Milder affected patients may fall into the Meier-Gorlin syndrome spectrum | |
| NOS 21–0210 | IMAGE syndrome (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies) | AD | CDKN1C | 614732 | 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) | |
| NOS 21–0220 | IMAGE syndrome / FILS syndrome, POLE-related | AR | POLE | 618336, 615139 | The phenotype is variable and may include immune deficiency (OMIM 615139) | |
| NOS 21–0230 | Saul-Wilson syndrome, COG4-related | AD | COG4 | 618150 | ||
| NOS 21–0240 | Short stature, facial dysmorphism, skeletal and dental anomalies syndrome, SCUBE3-related | AR | SCUBE3 | 619184 | in OMIM as “short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2” | |
| NOS 21–0250 | Ear-patella-primordial short stature syndrome (Meier-Gorlin), ORC4-related | AR | ORC1 | 224690 | ||
| NOS 21–0260 | Ear-patella-primordial short stature syndrome (Meier-Gorlin), ORC4-related | AR | ORC4 | 613800 | ||
| NOS 21–0270 | Ear-patella-primordial short stature syndrome (Meier-Gorlin), ORC6-related | AR | ORC6 | 613803 | ||
| NOS 21–0280 | Ear-patella-primordial short stature syndrome (Meier-Gorlin), CDT1-related | AR | CDT1 | 605525 | ||
| NOS 21–0290 | Ear-patella-primordial short stature syndrome (Meier-Gorlin), CDC6-related | AR | CDC6 | 613805 | A single case reported so far | |
| NOS 21–0300 | Ear-patella-primordial short stature syndrome (Meier-Gorlin), CDC45-related | AR | CDC45 | 603465 | ||
| NOS 21–0310 | Ear-patella-primordial short stature syndrome (Meier-Gorlin), MCM3-related | AR | MCM3 | see 602693 | ||
| NOS 21–0320 | Ear-patella-primordial short stature syndrome (Meier-Gorlin), MCM5-related | AR | MCM5 | 602696 | ||
| NOS 21–0330 | Ear-patella-primordial short stature syndrome (Meier-Gorlin), MCM7-related | AR | MCM7 | see 600592 | ||
| NOS 21–0340 | Ear-patella-primordial short stature syndrome (Meier-Gorlin), GMNN-related | AD | GMNN | 613804 | ||
| NOS 21–0350 | Ear-patella-primordial short stature syndrome (Meier-Gorlin) with craniosynostosis, GINS2-related | AD | GINS2 | see 610609 | A single case reported so far | |
| Group 22 | Lysosomal Storage Diseases with Skeletal Involvement | |||||
| NOS 22–0010 | Mucopolysaccharidosis type 1, IDUA-related | AR | IDUA | 607014, 607015, 607016 | was Type 1H-Hurler syndrome, type 1S-Scheie syndrome | |
| NOS 22–0020 | Mucopolysaccharidosis type 2, IDS-related | XL | IDS | 309900 | known as Hunter syndrome | |
| NOS 22–0030 | Mucopolysaccharidosis type 3, SGSH-related (type 3A) | AR | SGSH | 252900 | known as Sanfilippo A syndrome | |
| NOS 22–0040 | Mucopolysaccharidosis type 3, NAGLU-related (type 3B) | AR | NAGLU | 252920 | known as Sanfilippo B syndrome | |
| NOS 22–0050 | Mucopolysaccharidosis type 3, HSGNAT-related (type 3C) | AR | HSGNAT | 252930 | known as Sanfilippo C syndrome | |
| NOS 22–0060 | Mucopolysaccharidosis type 3, GNS-related (type 3D) | AR | GNS | 252940 | known as Sanfilippo D syndrome | |
| NOS 22–0070 | Mucopolysaccharidosis type 4, GALNS-related (type 4A) | AR | GALNS | 253000 | known as Morquio A syndrome | |
| NOS 22–0080 | Mucopolysaccharidosis type 4, GLB1-related (type 4B) | AR | GLB1 | 253010 | known as Morquio B syndrome | |
| NOS 22–0090 | Mucopolysaccharidosis type 6, ARSB-related | AR | ARSB | 253200 | known as Maroteaux-Lamy syndrome | |
| NOS 22–0100 | Mucopolysaccharidosis type 7, GUSB-related | AR | GUSB | 253220 | known as Sly syndrome | |
| NOS 22–0110 | Mucopolysaccharidosis type 10, ARSK-related | AR | ARSK | 610011 | ||
| NOS 22–0120 | Mucopolysaccharidosis-plus syndrome, VPS33A-related | AR | VPS33A | 617303 | ||
| NOS 22–0130 | Fucosidosis, FUCA-related | AR | FUCA | 230000 | ||
| NOS 22–0140 | alpha-Mannosidosis, MAN2B1-related | AR | MAN2B1 | 248500 | ||
| NOS 22–0150 | beta-Mannosidosis, MANBA-related | AR | MANBA | 248510 | ||
| NOS 22–0160 | Aspartylglucosaminuria, AGA-related | AR | AGA | 208400 | ||
| NOS 22–0170 | Gangliosidosis GM1, GLB1-related | AR | GLB1 | 230500 | Several forms, see also mucopolysaccharidosis type 4B (Morquio B) above | |
| NOS 22–0180 | Sialidosis, NEU1-related | AR | NEU1 | 256550 | Several forms of different severity | |
| NOS 22–0190 | Galactosialidosis, PPGB-related | AR | PPGB | 256540 | Several forms of different severity | |
| NOS 22–0200 | Sialic acid storage disease (SIASD), SLC17A5-related | AR | SLC17A5 | 269920 | ||
| NOS 22–0210 | Multiple sulfatase deficiency, SUMF-related | AR | SUMF1 | 272200 | ||
| NOS 22–0220 | Mucolipidosis II (I-cell disease), GNPTAB-related | AR | GNPTAB | 252500 | the old entity of Pacman dysplasia is the prenatal manifestation of mucolipidosis II with hyperparathyroidism | |
| NOS 22–0230 | Mucolipidosis III (Pseudo-Hurler polydystrophy), GNPTAB-related | AR | GNPTAB | 252600 | ||
| NOS 22–0240 | Mucolipidosis III (Pseudo-Hurler polydystrophy), GNPTG-related | AR | GNPTG | 252605 | in general somewhat milder phenotype than the GNPTAB-related form | |
| NOS 22–0250 | Mucolipidosis, GCAF-related | AR | CGAF | 619345 | The gene was previously known as TMEM251 and encodes for a “GNTAP cleavage and activity factor” (see GNTAP, above) | |
| NOS 22–0260 | Gaucher disease, GBA-related | AR | GBA | 230800 | Long-standing Gaucher disease can have bone changes that are different from the “dysostosis multiplex” pattern seen in other lysosomal diseases in this group | |
| 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. | ||||||
| Group 23 | Chondrodysplasia punctata (CDP) group | |||||
| NOS 23–0010 | CDP, X-linked recessive, ARSE-related (brachytelephalangic type; CDPX1) | XL | ARSE | 302950 | ||
| NOS 23–0020 | CDP, X-linked dominant, EBP-related (Conradi-Hünermann type; CDPX2) | XL | EBP | 302960 | ||
| NOS 23–0030 | Congenital hemidysplasia, ichthyosis, limb defects (CHILD) syndrome, NSDHL-related | XL | NSDHL | 308050 | ||
| NOS 23–0040 | Keutel syndrome, MGP-related | AR | MGP | 245150 | ||
| NOS 23–0050 | Greenberg dysplasia, LBR-related | AR | LBR | 215140 | 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 | |
| NOS 23–0060 | Rhizomelic CDP, PEX7-related | AR | PEX7 | 215100 | ||
| NOS 23–0070 | Rhizomelic CDP, DHPAT-related | AR | DHPAT | 222765 | ||
| NOS 23–0080 | Rhizomelic CDP, AGP5-related | AR | AGPS | 600121 | ||
| NOS 23–0090 | Rhizomelic CDP, FAR1-related | AR | FAR1 | 616154 | 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) | |
| NOS 23–0100 | Rhizomelic CDP, PEX5-related | AR | PEX5 | 616716 | ||
| NOS 23–0110 | CDP tibial-metacarpal type | 118651 | Some cases possibly caused by maternal auto-immune disease | |||
| 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”. | ||||||
| Group 24 | Osteopetrosis and related osteoclast disorders | |||||
| NOS 24–0010 | Osteopetrosis, neonatal or infantile form, TCIRG1-related | AR | TCIRG1 | 259700 | ||
| NOS 24–0020 | Osteopetrosis, neonatal or infantile form, CLCN7-related | AR | CLCN7 | 611490 | ||
| NOS 24–0030 | Osteopetrosis, neonatal or infantile form, SNX10-related | AR | SNX10 | 615085 | ||
| NOS 24–0040 | Osteopetrosis, infantile form, with nervous system involvement, OSTM1-related | AR | OSTM1 | 259720 | Includes former osteopetrosis with infantile neuraxonal dysplasia (MIM 600329) | |
| NOS 24–0050 | Osteopetrosis, infantile form, osteoclast-poor with immunoglobulin deficiency, TNFRSF11A-related | AR | TNFRSF11A | 612301 | See also below in this group, Dysosteosclerosis, TNFRSF11A-related, as well as MIM 602080-familial expansile osteolysis | |
| NOS 24–0060 | Osteopetrosis, intermediate form, TCIRG1-related | AR | TCIRG1 | 259700 | ||
| NOS 24–0070 | Osteopetrosis, intermediate form, TNFSF11-related | AR | TNFSF11 | 259710 | ||
| NOS 24–0080 | Osteopetrosis, intermediate form, PLEKHM-related | AR | PLEKHM1 | 611497 | ||
| NOS 24–0090 | Osteopetrosis, intermediate form, CLCN7-related | AR | CLCN7 | 259710 | ||
| NOS 24–0100 | Osteopetrosis, late-onset, dominant form, CLCN7-related | AD | CLCN7 | 166600 | ||
| NOS 24–0110 | Osteopetrosis with renal tubular acidosis, CA2-related | AR | CA2 | 259730 | ||
| NOS 24–0120 | Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID), IKBKG-related | XL | IKBKG | 300301 | ||
| NOS 24–0130 | Osteopetrosis, moderate form, SLC4A2-related | AR | SLC4A2 | see 109280 | a single adult patient reported, phenotype may evolve | |
| NOS 24–0140 | Osteopetrosis, moderate form with defective leucocyte adhesion, FERMT3-related | AR | FERMT3 | 612840 | In OMIM as Leucocyte Adhesion Deficiency 3 (LAD3) - MIM 612840 | |
| NOS 24–0150 | Osteopetrosis, moderate form with defective leucocyte adhesion, RASGRP2-related | AR | RASGRP2 | 615888 | OMIM only includes Bleeding Disorder, Platelet type, 18 (MIM 615888) for this gene | |
| NOS 24–0160 | Osteosclerotic metaphyseal dysplasia, LRKK1-related | AR | LRRK1 | 615198 | The name may be misleading as the condition is best described as a form of osteopetrosis | |
| NOS 24–0170 | Pyknodysostosis, CTSK-related | AR | CTSK | 265800 | In some individuals, the features of pyknodyostosis are absent and the disorder mimics osteopetrosis | |
| NOS 24–0180 | Dysosteosclerosis, SLC29A3-related | AR | SLC29A3 | 224300 | ||
| NOS 24–0190 | Dysosteosclerosis, TNFRSF11A-related | AR | TNFRSF11A | 224300 | This entity probably forms a spectrum with Osteopetrosis, intermediate form, TNFSF11-related (above) | |
| NOS 24–0200 | Dysosteosclerosis with degenerative encephalopathy and brain malformation, CSF1R-related | AR | CSF1R | 618476 | In OMIM as “Brain abnormalities, neurodegeneration and dysosteosclerosis (BANDDOS)”; gene also associated with MIM 221820 -Leukoencephalopathy with spheroids. | |
| 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. | ||||||
| Group 25 | Osteosclerotic disorders | |||||
| NOS 25–0010 | Desmosterolosis, DHCR4-related | AR | DHCR24 | 602398 | See also other sterol-metabolism related conditions | |
| NOS 25–0020 | Raine dysplasia, FAM20C-related | AR | FAM20C | 259775 | Variable severity, many cases are perinatal severe, some cases show survival to adulthood; then often combined with FGF23 elevation and hypophosphatemic rickets | |
| NOS 25–0030 | Caffey disease, COL1A1-related | AD | COL1A1 | 114000 | Rare specific variants in COL1A1. See also osteogenesis imperfecta related to collagen 1 genes. | |
| NOS 25–0040 | Caffey dysplasia (severe variants with prenatal onset) | AR? | 114000 | |||
| NOS 25–0050 | Dysplastic cortical hyperostosis, Kozlowski-Tsuruta type | A few sporadic cases known, phenotype consistent, molecular basis unknown | ||||
| NOS 25–0060 | Dysplastic cortical hyperostosis, Al-Gazali type | 601356 | 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) | |||
| NOS 25–0070 | Osteopoikilosis, LEMD3-related | AD | LEMD3 | 166700 | Includes Buschke-Ollendorff syndrome (same OMIM entry) | |
| NOS 25–0080 | Melorheostosis with osteopoikilosis, LEMD3-related | AD | LEMD3 | 166700 | Includes mixed sclerosing bone dysplasia | |
| NOS 25–0090 | Melorheostosis, MAP2K1-related | SP | MAP2K1 | 155950 | Possibly locus heterogeneity | |
| NOS 25–0100 | Osteopathia striata with cranial sclerosis (OSCS), AMER1-related | XL | AMER1 | 300373 | ||
| NOS 25–0110 | Pyle disease, SFRP4-related | AR | SFRP4 | 265900 | The name “metaphyseal dysplasia, Pyle type” is misleading (no growth plate dysplasia) and should be avoided | |
| NOS 25–0120 | Craniometaphyseal dysplasia, ANKH-related | AD | ANKH | 123000 | Dominant type | |
| NOS 25–0130 | Craniometaphyseal dysplasia, GJA1-related | AR | GJA1 | 218400 | Recessive type | |
| NOS 25–0140 | Diaphyseal dysplasia Camurati-Engelmann, TGFB1-related | AD | TGFB1 | 131300 | Gain-of-function variants | |
| NOS 25–0150 | Hyperostosis-Hyperphosphatemia syndrome, GALNT3-related | AR | GALNT3 | 211900 | Formerly hyperphosphatemic tumoral calcinosis type 1 | |
| NOS 25–0160 | Hyperostosis-Hyperphosphatemia syndrome, FGF23-related | AR | FGF23 | 617993 | Formerly hyperphosphatemic tumoral calcinosis type 2 | |
| NOS 25–0170 | Hyperostosis-Hyperphosphatemia syndrome, KL-relathed | AR | KL | 617994 | Formerly hyperphosphatemic tumoral calcinosis type 3 | |
| NOS 25–0180 | Cerebellar hypoplasia-endosteal sclerosis, POLR3B-related | AR | POLR3B | 213002 | ||
| NOS 25–0190 | Hematodiaphyseal dysplasia Ghosal, TBXAS1-related | AR | TBXAS1 | 231095 | ||
| NOS 25–0200 | Hypertrophic osteoarthropathy, HPGD-related | AR | HPGD | 259100 | Includes cranio-osteoarthropathy, some cases of recessive pachydermoperiostosis, as well as recessively inherited isolated digital clubbing (MIM 119900) | |
| NOS 25–0210 | Hypertrophic osteoarthropathy, SLCO2A1-related | AD, AR | SLCO2A1 | 614441 | ||
| NOS 25–0220 | Oculodentoosseous dysplasia (ODOD), GJA1-related, dominant, mild type | AD | GJA1 | 164200 | ||
| NOS 25–0230 | Oculodentoosseous dysplasia (ODOD) GJA1-related, recessive, severe type | AR | GJA1 | 257850 | Possibly homozygous form of mild ODOD | |
| NOS 25–0240 | Osteoectasia with hyperphosphatasia (juvenile Paget disease), OPG-related | AR | OPG | 239000 | ||
| NOS 25–0250 | Osteosclerosis, LRP5-related | AD | LRP5 | 144750, 607634 | Includes previous AD osteopetrosis type 1 (OPTA1) | |
| NOS 25–0260 | Sclerosteosis, SOST-related | AR | SOST | 269500 | see also sclerosteosis, SOST-related, below | |
| NOS 25–0270 | Sclerosteosis, LRP4-related | AR | LRP4 | 614305 | ||
| NOS 25–0280 | Endosteal hyperostosis, van Buchem type, SOST-related | AR | SOST | 239100 | Specific 52 kb deletion downstream of SOST | |
| NOS 25–0290 | Endosteal hyperostosis, Worth type | AD | LRP5 | 144750 | ||
| NOS 25–0300 | Craniodiaphyseal dysplasia, SOST-related | AD | SOST | 122860 | Presumed dominant negative variant | |
| NOS 25–0310 | Craniodiaphyseal dysplasia, SP7-related | AR | SP7 | see 606633 | one family reported; SP7 variants also associated with Osteogenesis imperfecta (MIM 613849), see below | |
| NOS 25–0320 | Trichodentoosseous dysplasia, DLX3-related | AD | DLX3 | 190320 | ||
| NOS 25–0330 | Diaphyseal medullary stenosis with malignant fibrous histiocytoma, MTAP-related | AD | MTAP | 112250 | Also known as Hardcastle disease | |
| NOS 25–0340 | Craniotubular dysplasia, TMEM53-related | AR | TMEM53 | 619727 | ||
| NOS 25–0350 | Craniometadiaphyseal dysplasia, Wormian bone type | AR | 269300 | |||
| NOS 25–0360 | Lenz-Majewski hyperostotic dysplasia, PTDSS1-related | AD | PTDSS1 | 151050 | ||
| NOS 25–0370 | Osteochondrodysplasia with hypertrichosis (Cantu syndrome), ABCC9-related | AD | ABCC9 | 239850 | ||
| NOS 25–0380 | Familial Paget disease of bone, SQSTM1-related | AD | SQSTM1 | 167250 | ||
| NOS 25–0390 | Inclusion body myopathy, Paget disease of bone and frontotemporal dementia | AD | VCP | 167320 | 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. | |
| NOS 25–0400 | Endosteal hyperostosis, oligodontia, short stature, facial dysmorphism and intellectual disability, POLR3GL-related | AR | POLR3GL | 619234 | Phenotypic elements will need to be evaluated more precisely; one patient reported as Wiedemann-Rautenstrauch-syndrome-like | |
| NOS 25–0410 | Metaphyseal dysplasia, Braun-Tinschert type | AD | 605946 | |||
| NOS 25–0420 | Trichothiodystrophy with axial osteosclerosis | AR | A subset of patients with trichothiodystrophy have marked osteosclerosis but have not been molecularly characterized so far | |||
| See also the chondrodysplasia punctata group (group 23); as well as familial expansile osteolysis, TNFRSF11A-related (below); and Trichothiodystrophy with central osteosclerosis (PMID 15148554) | ||||||
| Group 26 | Osteogenesis Imperfecta and bone fragility group | |||||
| NOS 26–0010 | Osteogenesis imperfecta, non-deforming (Sillence type 1), COL1A1-related | AD | COL1A1 | 166200 | Usually with persistently blue sclerae, can have signs of connective tissue weakness (in MIM as OI type I) | |
| NOS 26–0020 | Osteogenesis imperfecta, non-deforming (Sillence type 1), COL1A2-related | AD | COL1A2 | 166200 | Usually with persistently blue sclerae, can have signs of connective tissue weakness (in MIM as OI type I) | |
| NOS 26–0030 | Osteogenesis imperfecta, severe perinatal form (Sillence type 2) COL1A1-related | AD | COL1A1 | 166210 | Formerly “perinatal lethal”; in OMIM as OI type II | |
| NOS 26–0040 | Osteogenesis imperfecta, severe perinatal form (Sillence type 2), COL1A2-related | AD | COL1A2 | 166210 | Formerly “perinatal lethal”; in OMIM as OI type II | |
| NOS 26–0050 | Osteogenesis imperfecta, severe perinatal form (Sillence type 2), CRTAP-related | AR | CRTAP | 610682 | Formerly “perinatal lethal”; in OMIM as OI type VII | |
| NOS 26–0060 | Osteogenesis imperfecta, severe perinatal form (Sillence type 2), P3H1-related | AR | P3H1 | 610915 | Formerly “perinatal lethal”; in OMIM as OI type VIII | |
| NOS 26–0070 | Osteogenesis imperfecta, severe perinatal form (Sillence type 2), PPIB-related | AR | PPIB | 259440 | Formerly “perinatal lethal”; in OMIM as OI type IX | |
| NOS 26–0080 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), COL1A1-related | AD | COL1A1 | 259420 | In OMIM as OI type III | |
| NOS 26–0090 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), COL1A2-related | AD | COL1A2 | 259420 | In OMIM as OI type III | |
| NOS 26–0100 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), IFITM5-related | AD | IFITM5 | 610967 | in OMIM OI type III; phenotype is distinct but is some instances can mimin OI type III | |
| NOS 26–0110 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), SERPINF1-related | AR | SERPINF1 | 613982 | In OMIM as OI type VI | |
| NOS 26–0120 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), CRTAP-related | AR | CRTAP | 610682 | In OMIM OI type VII | |
| NOS 26–0130 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), P3H1-related | AR | P3H1 | 610915 | In OMIM OI type VIII | |
| NOS 26–0140 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), PPIB-related | AR | PPIB | see 259440 | In OMIM OI type IX | |
| NOS 26–0150 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), SERPINH1-related | AR | SERPINH1 | 613848 | In OMIM OI type X | |
| NOS 26–0160 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), FKBP10-related | AR | FKBP10 | 610968 | In OMIM OI type XI | |
| NOS 26–0170 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), TMEM38B-related | AR | TMEM38B | 615066 | In OMIM OI type XIV | |
| NOS 26–0180 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), BMP1-related | AR | BMP1 | 614856 | In OMIM OI type XIII | |
| NOS 26–0190 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), WNT1-related | AR | WNT1 | 615220 | In OMIM as OI type XV. Biallelic variants; monoallelic variants may result in AD osteoporosis. | |
| NOS 26–0200 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), CREB3L1-related | AR | CREB3L1 | 616229 | In OMIM as OI type XVI. Has severe joint laxity and scoliosis, Ehlers-Danlos-like | |
| NOS 26–0210 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), SPARC-related | AR | SPARC | 616507 | In OMIM as OI type XVII | |
| NOS 26–0220 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), TENT5A-related | AR | TENT5A | 617952 | In OMIM as OI type XVIII | |
| NOS 26–0230 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), MBTPS2-related | XLR | MBTPS2 | 301014 | In OMIM as OI type XIX | |
| NOS 26–0240 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), MESD-related | AR | MESD | 618644 | In OMIM as OI type XX | |
| NOS 26–0250 | Osteogenesis imperfecta, progressively deforming (Sillence type 3) with neurodevelopmental features, KDELR2-related | AR | KDELR2 | 619131 | In OMIM as OI type XXI. Frequency of neurodevelopmental delay not clear yet. | |
| NOS 26–0260 | Osteogenesis imperfecta, progressively deforming (Sillence type 3), CCD134-related | AR | CCD134 | 619795 | In OMIM as OI typeXXII | |
| NOS 26–0270 | Osteogenesis imperfecta, moderate form (Sillence type 4), COL1A1-related | AD | COL1A1 | 166220 | In OMIM as OI type IV | |
| NOS 26–0280 | Osteogenesis imperfecta, moderate form (Sillence type 4), COL1A2-related | AD | COL1A2 | 166220 | In OMIM as OI type IV | |
| NOS 26–0290 | Osteogenesis imperfecta, moderate form (Sillence type 4), WNT1-related | AR | WNT1 | see 166220 | In OMIM as OI type XV | |
| NOS 26–0300 | Osteogenesis imperfecta, moderate form (Sillence type 4), IFITM5-related | AD | IFITM5 | 166220 | in OMIM OI type IV | |
| NOS 26–0310 | Osteogenesis imperfecta, moderate form (Sillence type 4), CRTAP-related | AR | CRTAP | see 610682 | In OMIM as OI type VII | |
| NOS 26–0320 | Osteogenesis imperfecta, moderate form (Sillence type 4), PPIB-related | AD | PPIB | see 259440 | In OMIM as OI type IX | |
| NOS 26–0330 | Osteogenesis imperfecta, moderate form (Sillence type 4), FKBP10-related | AR | FKBP10 | see 610968 | In OMIM as OI type XI | |
| NOS 26–0340 | Osteogenesis imperfecta, moderate form (Sillence type 4), SP7-related | AR | SP7 | 613849 | In OMIM as OI type XII | |
| NOS 26–0350 | Osteogenesis imperfecta with calcification of interosseous membranes and/or hypertrophic callus (OI type 5), IFITM5-related | AD | IFITM5 | 610967 | When calcification of intraosseous membranes or hypertrophic callus are not observed, may mimic progressively deforming or moderate OI (Sillence types 3 and 4) | |
| NOS 26–0360 | Osteogenesis imperfecta with craniosynostosis (Cole-Carpenter syndrome), P4HB-related | AD | P4HB | 112240 | Craniosynostosis is not well documented in this condition in spite of the name. | |
| NOS 26–0370 | Osteogenesis imperfecta with craniosynostosis (Cole-Carpenter syndrome), SEC24D-related | AR | SEC24D | 616294 | Was Cole-Carpenter syndrome 2. Possibly misnomer, as most patients do not have craniosynostosis but rather large fontanels. | |
| NOS 26–0380 | Osteoporosis – X-linked form, PLS3-related | XL | PLS3 | 300910 | ||
| NOS 26–0390 | Osteoporosis – X-linked form, MBPTS2-related | XL | MBTPS2 | 301014 | In OMIM as OI type XIX; gene also associated with MIM 300918, MIM308205, MIM 308800 | |
| NOS 26–0400 | Osteoporosis – dominant form, WNT1-related | AD | WNT1 | 615220 | OMIM OI type XV | |
| NOS 26–0410 | Osteoporosis – AD form, LRP5-related | AD | LRP5 | 166710, 601884 | 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 | |
| NOS 26–0420 | Osteoporosis -AD form, ARHGAP25-related | AD | ARHGAP25 | see 610587 | ||
| NOS 26–0430 | Bruck syndrome type 1 (BS1), FKBP10-related | AR | FKBP10 | 259450 | See autosomal recessive OI, above; intrafamilial variability between OI type 3, arthrogryposis and Bruck syndrome 1 is documented | |
| NOS 26–0440 | Bruck syndrome type 2 (BS2), PLOD2-related | AR | PLOD2 | 609220 | ||
| NOS 26–0450 | Osteoporosis-pseudoglioma syndrome, LRP5-related | AR | LRP5 | 259770 | When eye involvement is absent, may mimic progressively deforming or moderate OI (Sillence types 3 and 4) | |
| NOS 26–0460 | Bone fragility with calvarial “doughnut” lesions, SGSM2-related | AD | SGMS2 | 126550 | Overlap with a spondylo-metaphyseal dysplasia phenotype | |
| NOS 26–0470 | Spondylo-ocular dysplasia, XYLT2-related | AR | XYLT2 | 605822 | ||
| NOS 26–0480 | Gnathodiaphyseal dysplasia, ANO5-related | AD | ANO5 | 166260 | Gene also associated with OMIM 613319-Miyoshi muscular dystrophy 3, and OMIM 611307-recessive limb-girdle muscular dystrophy 12 | |
| NOS 26–0490 | Osteoporosis with developmental delay and microcephaly, COPB2-related | AD | COPB2 | 619884 | Clinically variable, microcephaly in some cases only | |
| NOS 26–0500 | Geroderma osteodysplasticum, GORAB-related | AR | GORAB | 231070 | ||
| NOS 26–0510 | Cutis laxa, PYCR1-related | AR | PYCR1 | 612940 | Autosomal recessive form, type 2B (ARCL2B). Skeletal features overlapping with progeroid EDS and geroderma osteodysplasticum | |
| NOS 26–0520 | Cutis laxa, ATP6V0A2-related | AR | ATP6V0A2 | 278250, 219200 | Autosomal recessive form, type 2A (ARCL2A); wrinkly skin syndrome. Skeletal features overlapping with progeroid EDS and geroderma osteodysplasticum | |
| NOS 26–0530 | Wiedemann-Rautenstrauch syndrome, POLR3A-related | AR | POLR3A | 264090 | Gene also associated with MIM 607694- Leukodystrophy, hypomyelinating, with or without oligodontia and/or hypogonadotropic hypogonadism | |
| NOS 26–0540 | Singleton-Merten dysplasia, IFIH-related | AD | IFIH1 | 182250 | Gene also associated with MIM 615846-Aicardi-Goutieres syndrome 7, and OMIM 619773-Immunodeficiency 95 | |
| NOS 26–0550 | Singleton-Merten dysplasia, DDX58-related | AD | DDX58 | 616298 | ||
| Note: some of the recently discovered OI variants are limited to very small numbers of patients, so the association with OI “Sillence type 3” is tentative and may be too restrictive as more severe or milder phenotypes will 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, in Group 31. | ||||||
| Group 27 | Disorders of bone mineralisation | |||||
| NOS 27–0010 | Hypophosphatasia, ALPL-related, recessive (biallelic) forms | AR | ALPL | 241500 | Includes perinatal, infantile and juvenile forms | |
| NOS 27–0020 | Hypophosphatasia, ALPL-related, dominant (monoallelic) form | AD | ALPL | 146300 | Includes juvenile and adult forms as well as odontohypophosphatasia | |
| NOS 27–0030 | Hypophosphatemic rickets, PHEX-related | XL | PHEX | 307800 | X-linked, most common form | |
| NOS 27–0040 | Hypophosphatemic rickets, FGF23-related | AD | FGF23 | 193100 | Autosomal dominant | |
| NOS 27–0050 | Hypophosphatemic rickets, DMP1-related | AR | DMP1 | 241520 | Autosomal recessive (ARHR1) | |
| NOS 27–0060 | Hypophosphatemic rickets, ENPP1-related | AR | ENPP1 | 613312 | Autosomal recessive (ARHR2) | |
| NOS 27–0070 | Hypophosphatemic rickets, SGK3-related | AD | SGK3 | see 607591 | Autosomal dominant | |
| NOS 27–0080 | Hypophosphatemic rickets with hypercalciuria, CLCN5-related | XL | CLCN5 | 300554 | X-linked; part of Dent’s disease complex (progressive proximal renal tubulopathy with hypercalciuria, low molecular weight proteinuria, and nephrocalcinosis; MIM 300009) | |
| NOS 27–0090 | Hypophosphatemic rickets with hypercalciuria, SLC34A3-related | AR | SLC34A3 | 241530 | Autosomal recessive (HHRH) | |
| NOS 27–0100 | Vitamin D-dependent rickets, CYP27B1-related | AR | CYP27B1 | 264700 | Formerly type 1A | |
| NOS 27–0110 | Vitamin D-dependent rickets, CYP2R1-related | AR | CYP2R1 | 600081 | Formerly type 1B | |
| NOS 27–0120 | Vitamin D-dependent rickets, VDR-related | AR | VDR | 277440 | Formerly type 2A | |
| NOS 27–0130 | Vitamin D-dependent rickets, CYP3A4-related | AD | CYP3A4 | 619073 | Formerly type 3; specific monoallelic variants that increase enzyme activity leading to rapid degradation of active Vitamin D | |
| NOS 27–0140 | Vitamin D-dependent rickets, HNRNPC-related | AD? | HNRNPC | see 164020 | Formerly type 2B; molecular basis (supposed HNRNPC dominant negative) from a single patient | |
| NOS 27–0150 | Familial hyperparathyroidism, CDC73-related | AD | CDC73 | 145000, 145001 | With or without jaw tumors | |
| NOS 27–0160 | Familial hyperparathyroidism linked to chromosome 2 | AD | 2p14-p13.3 | 610071 | Linkage studies; no gene identified | |
| NOS 27–0170 | Familial hyperparathyroidism, GCM2-related | AD | GCM2 | 617343 | Variants in this gene also cause familial isolated hypoparathyroidism (MIM 618883) | |
| NOS 27–0180 | Neonatal hyperparathyroidism, CASR-related | AR, AD | CASR | 239200 | “Severe” form (but see below, transient form also CASR-related). Variants in the CASR gene can also result in autosomal dominant hypocalcemia (MIM 601198) | |
| NOS 27–0190 | Neonatal hyperparathyroidism, TRPV6-related | AR | TRPV6 | 618188 | Transient form | |
| NOS 27–0200 | Familial hypocalciuric hypercalcemia with transient neonatal hyperparathyroidism, CASR-related | AD | CASR | 145980 | Other forms of familial hypocalciuric hypercalcemia do not show significant skeletal phenotypes | |
| NOS 27–0210 | Calcium pyrophosphate deposition disease (familial chondrocalcinosis), ANKH-related | AD | ANKH | 118600 | Loss-of-function variants (see als craniometaphyseal dysplasia, dominant type) | |
| NOS 27–0220 | Calcium pyrophosphate deposition disease (familial chondrocalcinosis), TNFRSF11B-related | AD | TNFRSF11B | see 602643 | Apparently monoallelic gain-of-function variants | |
| NOS 27–0230 | Cutaneous skeletal hypophosphatemia syndrome | MOS | HRAS | Somatic mosaicism for activating variants in HRAS with elevated FGF23 levels | ||
| NOS 27–0240 | Cutaneous skeletal hypophosphatemia syndrome | MOS | NRAS | Somatic mosaicism for activating variants in NRAS with elevated FGF23 levels | ||
| Note: Hyperparathyroidism due to parathyroid adenoma occurs in a number of genetic disorders, e.g. in Multiple Endocrine Neoplasias (see MIM for variants) - See also Group 28, below, as well as Raine dysplasia, FAM20C-related | ||||||
| Group 28 | Skeletal disorders of parathyroid hormone signaling cascade | |||||
| NOS 28–0010 | Metaphyseal dysplasia, Jansen type, PTHR1-related | AD | PTHR1 | 156400 | Caused by activating variants | |
| NOS 28–0020 | Metaphyseal dysplasia, Csukasi-Krakow type, SIK3-related | AR | SIK3 | 618162 | disruption of mTOR signalling downstream of the PTH receptor | |
| NOS 28–0030 | Blomstrand dysplasia, PTHR1-related | AR | PTHR1 | 215045 | Caused by recessive (biallelic) loss-of-function variants | |
| NOS 28–0040 | Eiken dysplasia, PTHR1-related | AR | PTHR1 | 600002 | Caused by recessive (biallelic) hypomorphic variants | |
| NOS 28–0050 | Brachydactyly, PTHLH-related (brachdactyly type E2) | AD | PTHLH | 613382 | Haploinsufficiency; with or without short stature | |
| NOS 28–0060 | Osteolysis, PTHLH-related | AD | PTHLH | Duplications of PTHLH causing acro-osteolysis; see also group 30 and group 18 | ||
| 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) | ||||||
| Group 29 | Osteolysis group | |||||
| NOS 29–0010 | Familial expansile osteolysis, TNFRSF11A-related | AD | TNFRSF11A | 174810, 602080 | Includes early-onset familial Paget disease of bone. See other TNFRSF11A-related phenoytpes in Group 24 | |
| NOS 29–0020 | Mandibuloacral dysplasia, LMNA-related | AR | LMNA | 248370 | See also Progeria (in this group), LMNA-related cardiomyopathy and brachydactyly (Group 19) as well as many other conditions in MIM related to LMNA | |
| NOS 29–0030 | Mandibuloacral dysplasia, ZMPSTE24-related | AR | ZMPSTE24 | 608612 | ||
| NOS 29–0040 | Mandiculoacral dysplasia, MTX2-related | AR | MTX2 | 619127 | ||
| NOS 29–0050 | Progeria, Hutchinson-Gilford type, LMNA-related | AD | LMNA | 176670 | ||
| NOS 29–0060 | Multicentric osteolysis, nodulosis and arthropathy (MONA), MMP2-related | AR | MMP2 | 259600 | Includes Winchester-Torg syndrome and nodulosis-arthropathy-osteolysis syndrome | |
| NOS 29–0070 | Multicentric osteolysis, nodulosis and arthropathy (MONA), MMP14-related | AR | MMP14 | 277950 | A biallelic homozygous MMP14 variant seen in the original Winchester syndrome family | |
| NOS 29–0080 | Hajdu-Cheney syndrome, NOTCH2-related | AD | NOTCH2 | 102500 | Includes the Serpentine fibula-polycystic kidney syndrome (SFPKS) | |
| NOS 29–0090 | Multicentric carpal-tarsal osteolysis with and without nephropathy, MAFB-related | AD | MAFB | 166300 | ||
| NOS 29–0100 | Penttinen syndrome, PDGFRB-related | AD | PDGFRB | 601812 | See also MIM 601812-Kosaki overgrowth syndrome | |
| NOS 29–0110 | Nestor Guillermo progeria syndrome, BANF1-related | AR | BANF1 | 603811 | ||
| NOS 29–0120 | Farber disease, ASAH1-related | AR | ASAH1 | The chronic, adult form of Farber disease can present as osteolysis | ||
| 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 | ||||||
| Group 30 | Disorganized development of skeletal components group | |||||
| NOS 30–0010 | Multiple cartilaginous exostoses (MCE), EXT1-related (multiple osteochondromas, MO) | AD | EXT1 | 133700 | ||
| NOS 30–0020 | Multiple cartilaginous exostoses (MCE), EXT2-related (multiple osteochondromas, MO) | AD | EXT2 | 133700 | ||
| NOS 30–0030 | Cherubism, SH3BP2-related | AD | SH3BP2 | 118400 | ||
| NOS 30–0040 | Fibrous dysplasia, polyostotic form (McCune-Albright syndrome), GNAS-related | MOS | GNAS | 174800 | Somatic mosaicism for gain-of-function variants; includes Mazabraud syndrome with intramuscular myxomas | |
| NOS 30–0050 | Progressive osseous heteroplasia (POH), GNAS-related | AD | GNAS | 166350 | Germline loss-of-function of paternal allele | |
| NOS 30–0060 | Metachondromatosis, PTPN11-related | AD | PTPN11 | 156250 | Loss-of-function variants (in contrast to Noonan syndrome) with loss of heterozygosity in lesional tissue | |
| NOS 30–0070 | Osteoglophonic dysplasia, FGFR1-related | AD | FGFR1 | 166250 | Craniosynostosis is also an important feature (group 34) | |
| NOS 30–0080 | Fibrodysplasia ossificans progressiva (FOP), ACVR1-related | AD | ACVR1 | 135100 | Most cases sporadic but dominant transmission documented | |
| NOS 30–0090 | Neurofibromatosis type 1, NF1-related | AD | NF1 | 162200 | ||
| NOS 30–0100 | Cherubism with gingival fibromatosis (Ramon syndrome) | AR | 266270 | Some similarities to primary intraosseous vascular malformation, ELMO2-related (see below) | ||
| NOS 30–0110 | Dysplasia epiphysealis hemimelica (Trevor) | SP | 127800 | Some familial cases reported (“familial Trevor disease”) but probably represent a different condition | ||
| NOS 30–0120 | Lipomembraneous osteodystrophy with leukoencephalopathy, TREM2-related (Nasu-Hakola) | AR | TREM2 | 618193 | Also known as presenile dementia with bone cysts | |
| NOS 30–0130 | Lipomembraneous osteodystrophy with leukoencephalopathy, TYROBP-related (Nasu-Hakola) | AR | TYROBP | 221770 | Also known as presenile dementia with bone cysts | |
| NOS 30–0140 | Enchondromatosis, IDH1-related (Ollier disease) | MOS | IDH1 | 166000 | Somatic mosaicism for specific IDH1 variants. See also MIM 147700 and 137800 | |
| NOS 30–0150 | Enchondromatosis, IDH2-related (Ollier disease) | MOS | IDH2 | 166000 | Somatic mosaicism for IDH2 variants; significantly rarer than IDH1 variants. See also MIM 147650 and 613657, D-2-hydroxyglutaric aciduria 2 | |
| NOS 30–0160 | Enchondromatosis with hemangiomas, IDH1-related (Maffucci disease) | MOS | IDH1 | 614569 | Somatic mosaicism for specific IDH1 variants. See also MIM 147700 and 137800 | |
| NOS 30–0170 | Enchondromatosis with hemangiomas, IDH2-related (Maffucci disease) | MOS | IDH2 | 614569 | Somatic mosaicism for IDH2 variants; significantly rarer than IDH1 variants. See also MIM 147650 and 613657, D-2-hydroxyglutaric aciduria 2 | |
| NOS 30–0180 | Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, IDH1-related | MOS | IDH1 | 614875 | Includes so-called cheirospondyloenchondromatosis. Somatic mosaicism for IDH1 variants. Possibly also IDH2 variants but not yet well documented | |
| NOS 30–0190 | Primary intraosseous vascular malformation, ELMO2-related | AR | ELMO2 | 606893 | ||
| NOS 30–0200 | Osteofibrous dysplasia, MET-related | AD, SP | MET | 607278 | Possibly corresponding to the former “Campanacci dysplasia” | |
| NOS 30–0210 | Genochondromatosis | AD | 137360 | “Geno” from Greek “knee”, but upper limbs also affected. Probably includes the condition known as Vaandrager-Peña syndrome | ||
| NOS 30–0220 | Gorham-Stout disease and familial diffuse angiomatosis of bone | SP (MOS?), AD | see 123880 | Gorham-Stout is often severe and 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). | ||
| 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. | ||||||
| Group 31 | Overgrowth (tall stature) syndromes and segmental overgrowth | |||||
| NOS 31–0010 | Marfan syndrome, FBN1-related | AD | FBN1 | 154700 | See also as differential diagnosis: homocystinuria and marfanoid habitus with ID (Lujan Fryns syndrome): MED12; ZDHHC9; UPF3B | |
| NOS 31–0020 | Congenital contractural arachnodactyly (Beals-Hecht syndrome), FBN2-related | AD | FBN2 | 121050 | ||
| NOS 31–0030 | Loeys-Dietz syndrome, TGFBR1-related | AD | TGFBR1 | 609192 | Osteopenia with propensity to fractures may be observed in all variants of the Loeys-Dietz syndrome | |
| NOS 31–0040 | Loeys-Dietz syndrome, TGFBR2-related | AD | TGFBR2 | 610168 | ||
| NOS 31–0050 | Loeys-Dietz syndrome, TGFB2-related | AD | TGFB2 | 614816 | ||
| NOS 31–0060 | Loeys-Dietz syndrome, TGFB3-related | AD | TGFB3 | 615582 | ||
| NOS 31–0070 | Loeys-Dietz syndrome, SMAD2-related | AD | SMAD2 | 619656 | ||
| NOS 31–0080 | Loeys-Dietz syndrome, SMAD3-related | AD | SMAD3 | 613795 | ||
| NOS 31–0090 | Weaver syndrome, EZH2-related | AD | EZH2 | 277590 | Some cases reported with NSD1, EED and SUZ12 variants | |
| NOS 31–0100 | Cohen-Gibson (Weaver-like) syndrome, EED-related | AD | EED | 617561 | ||
| NOS 31–0110 | Imagawa-Matsumoto (Weaver like) syndrome, SUZ12-related | AD | SUZ12 | 606245 | ||
| NOS 31–0120 | Sotos syndrome, NSD1-related | AD | NSD1 | 117550 | ||
| NOS 31–0130 | Sotos syndrome, APC2-related | AR | APC2 | 617169 | ||
| NOS 31–0140 | Malan (Sotos-like) syndrome, NFIX-related | AD | NFIX | 614753 | ||
| NOS 31–0150 | Luscan-Lumish syndrome, SETD2-related | AD | SETD2 | 616831 | ||
| NOS 31–0160 | Tatton-Brown-Rahman syndrome, DNMT3A-related | AD | DNMT3A | 615879 | ||
| NOS 31–0170 | Marshall-Smith syndrome, NFIX-related | AD | NFIX | 602535 | See also Malan syndrome. The localization of the monoallelic variants determine the Malan vs. Marshall-Smith phenotype | |
| NOS 31–0180 | Beckwith-Wiedemann syndrome | AD | 11p15.5 region | 130650 | Variant or deletion of imprinted genes within the chromosome 11p15.5 region | |
| NOS 31–0190 | Simpson-Golabi-Behmel syndrome, GPC3-related | XL | GPC3 | 312870 | ||
| NOS 31–0200 | Proteus syndrome, AKT1-related | MOS | AKT1 | 176920 | ||
| NOS 31–0210 | Hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH), AKT2-related | AD | AKT2 | Gene also associated with OMIM 125853 diabetes mellitus type II | ||
| NOS 31–0220 | Congenital ipomatous overgrowth, vascular Malformations, epidermal Nevi, spinal/skeletal anomalies/scoliosis (CLOVES) syndrome, PIK3CA-related | MOS | PIK3CA | 612918 | Also named PIK3CA-related overgrowth syndrome (PROS); somatic variants; see MIM 171834 | |
| NOS 31–0230 | Fibroadipose hyperplasia, PIK3CA-related | MOS | PIK3CA | see 171834 | See MIM 171834 for the many conditions associated with somatic PIK3CA variants | |
| NOS 31–0240 | Snyder-Robinson syndrome (intellectual disability, tall stature, osteoporosis and fractures), SMS-related | XLR | SMS | 309583 | ||
| NOS 31–0250 | Overgrowth syndrome with 2q37 translocations | SP | NPPC | see 600296 | Overgrowth probably caused by overexpression of NPPC | |
| NOS 31–0260 | Tall stature with long halluces, NPR2-related | AD | NPR2 | 615923 | Monoallelic gain-of-function variants in NPR2; in OMIM as epiphyseal chondrodysplasia, Miura type | |
| NOS 31–0270 | Tall stature with long halluces, NPR3-related | AR | NPR3 | 619543 | Biallelic loss-of-function variants in NPR3; in OMIM as Boudin-Mortier syndrome | |
| NOS 31–0280 | Moreno-Nishimura-Schmidt syndrome | SP | 608811 | |||
| NOS 31–0290 | Camptodactyly, tall stature and hearing loss syndrome (CATSHL), FGFR3-related | AD, AR | FGFR3 | 610474 | Original family with monoallelic (dominant negative?) variant; a second family with biallelic variants (see group 1) | |
| NOS 31–0300 | Kosaki overgrowth syndrome, PDGFRB-related | AR | PDGFRB | 616592 | See also MIM 601812-Pentinnen syndrome | |
| NOS 31–0310 | Segmental odontomaxillary dysplasia, ACTB-related | MOS | ACTB | see 102630 | See PMID 32585735; see also MIM 243310-Baraitser-Winter syndrome | |
| See also: Shprintzen-Goldberg syndrome, SKI-related, in the craniosynostosis group. Note: this category does not include disorders that cause overgrowth secondary to vascular malformations. | ||||||
| Group 32 | Genetic inflammatory or rheumatoid-like osteoarthropathies | |||||
| NOS 32–0010 | Progressive pseudorheumatoid dysplasia (PPRD), WISP3-related | AR | WISP3 | 208230 | Also known as SED with progressive arthropathy | |
| NOS 32–0020 | Chronic infantile neurologic cutaneous articular syndrome (CINCA), CIAS1-related (neonatal onset multisystem inflammatory disease (NOMID)) | AD | CIAS1 | 607115 | ||
| NOS 32–0030 | Sterile multifocal osteomyelitis, periostitis, and pustulosis (CINCA/NOMID-like), IL1RN-related | AR | IL1RN | 147679 | ||
| NOS 32–0040 | Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia (CRMO with CDA; Majeed syndrome), LPIN2-related | AR | LPIN2 | 609628 | ||
| NOS 32–0050 | Familial juvenile arthritis with hyaluronidase deficiency, HYAL1-related | AR | HYAL1 | 601492 | Also known as mucopolysaccharidosis type 9, although clinically no storage | |
| NOS 32–0060 | Hyaline Fibromatosis Syndrome, ANTXR2-related | AR | ANTXR2 | 236490, 228600 | Previously known as Infantile systemic hyalinosis, Juvenile Hyaline Fibromatosis, and Puretic syndrome | |
| Farber disease, ASAH1-related (osteolysis group 29, and MIM 228000) shows phenotypic overlap with the conditions in this group. | ||||||
| Group 33 | Cleidocranial dysplasia and related disorders | |||||
| NOS 33–0010 | Cleidocranial dysplasia, RUNX2-related | AD | RUNX2 | 119600 | See also MIM 156510-metaphyseal dysplasia with maxillary hypoplasia, as well as non-syndromic midline craniosynostosis, RUNX2-related, below | |
| NOS 33–0020 | Cleidocranial-like dysplasia, CBFB-related | AD | CBFB | see 121360 | See also MIM 601626, familial leukemia | |
| NOS 33–0030 | CDAGS syndrome (craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, genital anomalies, skin eruption), RNU12-related | AR | RNU12 | 603116 | ||
| NOS 33–0040 | Yunis-Varon dysplasia, FIG4-related | AR | FIG4 | 216340 | Gene also causes OMIM 612577 amyotrophic lateral sclerosis 11, and OMIM 611228 CMT disease 4J | |
| NOS 33–0050 | Yunis-Varon dysplasia, VAC14-related | AR | VAC14 | 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) | ||
| NOS 33–0060 | Parietal foramina, MSX2-related | AD | MSX2 | 168500 | ||
| NOS 33–0070 | Parietal foramina, ALX4-related | AD | ALX4 | 609597 | See also Frontonasal dysplasia type 1 | |
| NOS 33–0080 | Parietal foramina with cleidocranial dysplasia, MSX2-related | AD | MSX2 | 168550 | MSX2 variants also cause craniosynostosis Boston type | |
| 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. | ||||||
| Group 34 | Syndromes featuring craniosynostosis | |||||
| NOS 34–0010 | Pfeiffer syndrome, FGFR1-related | AD | FGFR1 | 101600 | Most have FGFR1 p.P252R variant; Includes Jackson-Weiss syndrome (MIM 123150) | |
| NOS 34–0020 | Pfeiffer syndrome, FGFR2-related | AD | FGFR2 | 101600 | ||
| NOS 34–0030 | Apert syndrome, FGFR2-related | AD | FGFR2 | 101200 | ||
| NOS 34–0040 | Craniosynostosis with cutis gyrata (Beare-Stevenson), FGFR2-related | AD | FGFR2 | 123790 | Notably p.S372Y or p.Y375C variants | |
| NOS 34–0050 | Crouzon syndrome, FGFR2-related | AD | FGFR2 | 123500 | ||
| NOS 34–0060 | Crouzon-like craniosynostosis with acanthosis nigricans, FGFR3-related | AD | FGFR3 | 612247 | Defined by specific FGFR3 p.A391E variant; also known as Crouzonodermoskeletal syndrome | |
| NOS 34–0070 | Craniosynostosis, Muenke type, FGFR3-related | AD | FGFR3 | 602849 | Defined by specific FGFR3 p.P250R variant | |
| NOS 34–0080 | Antley-Bixler syndrome, POR-related | AR | POR | 201750 | ||
| NOS 34–0090 | Craniosynostosis Boston type, MSX2-related | AD | MSX2 | 604757 | Heterozygous p.P148H variant in a two families | |
| NOS 34–0100 | Saethre-Chotzen syndrome, TWIST1-related | AD | TWIST1 | 101400 | Variants in FGFR3, FGFR2 and TCF12 have been reported to cause phenotypes resembling Saethre-Chotzen syndrome | |
| NOS 34–0110 | Shprintzen-Goldberg syndrome, SKI-related | AD | SKI | 182212 | ||
| NOS 34–0120 | Baller-Gerold syndrome, RECQL4-related | AR | RECQL4 | 218600 | see other phenotypes associated with RECQL4 variants, above | |
| NOS 34–0130 | Carpenter syndrome, RAB23-related | AR | RAB23 | 201000 | ||
| NOS 34–0140 | Carpenter syndrome, MEGF8-related | AR | MEGF8 | 614976 | ||
| NOS 34–0150 | Craniosynostosis, TCF12-related | AD | TCF12 | 615314 | Frequently coronal craniosynostosis | |
| NOS 34–0160 | Craniosynostosis, SIX1-related | AD | SIX1 | see 601205 | Frequently sagittal and lambdoid synostosis. See also MIM 608389 - Branchiootic syndrome 3, and 605192- Deafness, autosomal dominant 23, for other SIX1-related phenotypes | |
| NOS 34–0170 | Complex craniosynostosis, ERF-related | AD | ERF | 600775 | Variants in ERF also cause Chitayat hyperphalangism syndrome (Group 19) | |
| NOS 34–0180 | Non-syndromic midline (metopic / sagittal) craniosynostosis, SMAD6-related | AD? | SMAD6 | 617439 | Rare SMAD6 variants and a common BMP2 polymorphism may interact to produce craniosynostosis; subject disputed | |
| NOS 34–0190 | Non-syndromic midline craniosynostosis, RUNX2-related | AD | RUNX2 | Gain-of-function variants, duplications, triplications | ||
| NOS 34–0200 | Structural brain anomalies with impaired ID and craniosynostosis / craniosynostosis type 6 | AD | ZIC1 | 618736 | ||
| NOS 34–0210 | Craniosynostosis and dental anomalies (CRSDA), IL11RA-related | AR | IL11RA | 614188 | ||
| NOS 34–0220 | Craniosynostosis, retained deciduous teeth and intellectual disability, IL6ST-related | AR | IL6ST | see 600694 | 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 | |
| NOS 34–0230 | Cutis laxa with craniosynostosis, short stature, brachydactyly, and syndactyly, LTBP1-related | AR | LTBP1 | 619451 | ||
| NOS 34–0240 | Bohring-Opitz syndrome, ASXL1-related | AD | ASXL1 | 605039 | ||
| NOS 34–0250 | Craniosynostosis, radiohumeral fusion and other skeletal defects, CYP26B1-related | AR | CYP26B1 | 614416 | CYP26B1 is a retinoid acid-degrading enzyme, pathogenesis involves retinoic acid-associated morphogenesis | |
| NOS 34–0260 | Cardiac, facial and digital anomalies with developmental delay (CAFDADD), TRAF7-related | AD | TRAF7 | 618164 | Multisuture craniosynostosis is one of the features | |
| NOS 34–0270 | Craniosynostosis, hypertrichosis, progeroid appearance, bone dysplasia, characteristic face (Fontaine progeroid syndrome, Gorlin-Chaudhry-Moss syndrome), SLC25A24-related | AD | SLC25A24 | 612289 | ||
| NOS 34–0280 | Curry-Jones syndrome, SMO-related | MOS | SMO | 601707 | Activating variant c.1234C>T (p.L412F) | |
| NOS 34–0290 | 3MC syndrome, MASP1-related | AR | MASP1 | 257920 | Craniosynostosis in 20–30% | |
| NOS 34–0300 | 3MC syndrome, COLEC11-related | AR | COLEC11 | 265050 | Craniosynostosis in 20–30% | |
| NOS 34–0310 | 3MC syndrome, COLEC10-related | AR | COLEC10 | 248340 | Craniosynostosis in 20–30% | |
| NOS 34–0320 | Weiss-Kruszka syndrome, ZNF462-related | AD | ZNF462 | 618619 | Metopic ridging or CSO (metopic, lambdoid, 9/24) | |
| NOS 34–0330 | Au-Kline syndrome, HNRNPK-related | AD | HNRNPK | 616580 | Craniosynostosis and vertebral anomalies in a significant proportion of cases | |
| NOS 34–0340 | Char syndrome, TFAP2B-related | AD | TFAP2B | 169100 | Mainly with loss-of-function variants | |
| NOS 34–0350 | Syndrome with developmental and speech delay, dysmorphic facies, craniosynostosis and T-cell abnormalities | AD | BCL11B | 618092 | Craniosynostosis in some affected individuals | |
| 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. | ||||||
| Group 35 | Craniofacial Dysostoses | |||||
| NOS 35–0010 | Mandibulofacial dysostosis, TCOF1-related (Treacher-Collins, Franceschetti-Klein) | AD | TCOF1 | 154500 | ||
| NOS 35–0020 | Mandibulofacial dysostosis, POLR1B-related (Treacher-Collins, Franceschetti-Klein) | AD | POLR1B | 618939 | ||
| NOS 35–0030 | Mandibulofacial dysostosis, POLR1C-related (Treacher-Collins, Franceschetti-Klein) | AR | POLR1C | 248390 | ||
| NOS 35–0040 | Mandibulofacial dysostosis, POLR1D-related (Treacher-Collins, Franceschetti-Klein) | AD, AR | POLR1D | 613717 | ||
| NOS 35–0050 | Mandibulofacial dysostosis with limb deficiencies, POLR1A-related (Cincinnati type) | AD | POLR1A | 616462 | The original description was “acrofacial dysostosis: a mandibulofacial dysostosis with limb anomalies”. The limb anomalies are variable | |
| NOS 35–0060 | Mandibulofacial dysostosis with microcephaly, EFTUD2-related (Guion-Almeida type) | AD | EFTUD2 | 610536 | ||
| NOS 35–0070 | Mandibulofacial dysostosis with alopecia, EDNRA-related | AD | EDNRA | 616367 | ||
| NOS 35–0080 | Burns-McKeown syndrome, TXNL4A-related | AR | TXNL4A | 608572 | Some pathogenic variants are in the promoter region; severity is variable | |
| NOS 35–0090 | Postaxial acrofacial dysostosis, DHODH-related (Miller syndrome) | AR | DHODH | 263750 | ||
| NOS 35–0100 | Acrofacial dysostosis, SF3B4-related (Nager syndrome) | AD, AR | SF3B4 | 154400, 201170 | Both monoallelic and biallelic variants are at the basis of a spectrum that also includes the former “Rodriguez type” of acrofacial dysostosis | |
| NOS 35–0110 | Agnathia-Otocephaly complex, PRRX1-related | AD, AR | PRRX1 | 202650 | ||
| NOS 35–0120 | Frontonasal dysplasia, ALX3-related | AR | ALX3 | 136760 | ||
| NOS 35–0130 | Frontonasal dysplasia, ALX4-related | AR | ALX4 | 613451 | ||
| NOS 35–0140 | Frontonasal dysplasia, ALX1-related | AR | ALX1 | 613456 | ||
| NOS 35–0150 | Frontonasal dysplasia, SIX2-related | AD | SIX2 | see 604994 | ||
| NOS 35–0160 | Frontonasal dysplasia with additional malformations (Sweeney-Cox syndrome), TWIST1-related | AD | TWIST1 | 617746 | Results from specific amino acid substitutions in TWIST1 | |
| NOS 35–0170 | Craniofrontonasal syndrome, EFN1B-related | XL | EFNB1 | 304110 | ||
| NOS 35–0180 | Acromelic frontonasal dysostosis, ZSWIM6-related | AD | ZSWIM6 | 603671 | ||
| NOS 35–0190 | Richieri-Costa-Pereira syndrome, EIF4A3-related | AR | EIF4A3 | 268305 | ||
| NOS 35–0200 | Auriculocondylar syndrome, GNAI3-related (type 1) | AD | GNAI3 | 602483 | ||
| NOS 35–0210 | Auriculocondylar syndrome, PLCB4-related (type 2) | AR, AD | PLCB4 | 614669 | ||
| NOS 35–0220 | Auriculocondylar syndrome, EDN1-related (type 3) | AR | EDN1 | 615706 | ||
| NOS 35–0230 | Orofaciodigital syndrome type I, OFD1-related | XL | OFD1 | 311200 | ||
| NOS 35–0240 | Weyers acrofacial (acrodental) dysostosis, EVC1-related | AD | EVC1 | 193530 | See also group 10 | |
| NOS 35–0250 | Weyers acrofacial (acrodental) dysostosis, EVC2-related | AD | EVC2 | 193530 | See also group 10 | |
| NOS 35–0260 | Teebi hypertelorism syndrome, SPECCIL-related | AD | SPECC1L | 145420 | ||
| NOS 35–0270 | Craniolenticulosutural dysplasia, SEC23A-related | AR, AD | SEC23A | 607812 | Monoallelic and biallelic inheritance observed | |
| NOS 35–0280 | Faciogenital dysplasia, FGD1-related (Aarskog-Scott syndrome) | XL | FGD1 | 305400 | ||
| NOS 35–0290 | Baraitser-Winter syndrome, ACTB-related | AD | ACTB | 243310 | ||
| NOS 35–0300 | Baraitser-Winter syndrome, ACTG1-related | AD | ACTG1 | 614583 | ||
| NOS 35–0310 | Cerebrofaciothoracic dysplasia, TMCO1-related | AR | TMCO1 | 213980 | ||
| NOS 35–0320 | Opitz GBBB syndrome, MID1-related | XL | MID1 | 300000 | ||
| NOS 35–0330 | Arhinia microphthalmia syndrome, SMCHD1-related (Bosma) | AD | SMCHD1 | 603457 | ||
| NOS 35–0340 | Acrofrontofacionasal dysostosis | AR | 201180 | |||
| NOS 35–0350 | Hemifacial microsomia | SP, AD | 164210 | 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 | ||
| 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) | ||||||
| Group 36 | Vertebral and costal dysostoses | |||||
| NOS 36–0010 | Currarino syndrome, MNX1-related | AD | MNX1 | 176450 | Possible clinical o)verlap with caudal regression syndrome (see MIM 600145; the role of heterozygous variants in VANGL1 remains to be confirmed) | |
| NOS 36–0020 | Spondylocostal dysostosis, DLL3-related | AR | DLL3 | 277300 | Possible role of CNVs in TBX6 in modulating the phenotype? | |
| NOS 36–0030 | Spondylocostal dysostosis, MESP2-related | AR | MESP2 | 608681 | ||
| NOS 36–0040 | Spondylocostal dysostosis, LFNG-related | AR | LFNG | 609813 | ||
| NOS 36–0050 | Spondylocostal dysostosis, HES7-related | AR | HES7 | 613686 | ||
| NOS 36–0060 | Spondylocostal dysostosis, TBX6-related | AR, AD | TBX6 | 122600 | Possible role of CNVs in TBX6 | |
| NOS 36–0070 | Spondylocostal dysostosis, RIPPLY2-related | AR | RIPPLY2 | 616566 | ||
| NOS 36–0080 | Vertebral segmentation defect (congenital scoliosis) with variable penetrance, MESP2-related | AD | MESP2 | 608681 | ||
| NOS 36–0090 | Vertebral segmentation defect (congenital scoliosis) with variable penetrance, HES7-related | AD | HES7 | 613686 | ||
| NOS 36–0100 | Short stature, cervical segmentation defects, and developmental delay, CDK10-related | AR | CDK10 | 617694 | ||
| NOS 36–0110 | Klippel-Feil syndrome, GDF6-related | AD | GDF6 | 118100 | Role of GDF6 variants in Klippel-Feil syndrome as well as in AD spondylothoracic dysostosis remains unclear | |
| NOS 36–0120 | Klippel-Feil syndrome, MEOX1-related | AR | MEOX1 | 214300 | ||
| NOS 36–0130 | Klippel-Feil syndrome, GDF3-related | AD | GDF3 | 613702 | ||
| NOS 36–0140 | Klippel-Feil syndrome, MYO18B-related | AR | MYO18B | 616549 | ||
| NOS 36–0150 | Cervico-oculo-acoustic (Wildervanck) syndrome | SP | 314600 | Congenital perceptive deafness, Klippel-Feil anomaly (see 118100), and abducens palsy with retractio bulbi | ||
| NOS 36–0160 | Cerebro-costo-mandibular syndrome (rib gap syndrome), SNRPB-related | AD | SNRPB | 117650 | ||
| NOS 36–0170 | Cerebro-costo-mandibular-like syndrome, COG1-related | AR | COG1 | 611209 | Also known as CDG IIg | |
| NOS 36–0180 | Diaphanospondylodysostosis, BMPER-related | AR | BMPER | 608022 | Includes ischiospinal dysostosis, a term that has been used for milder cases | |
| NOS 36–0190 | Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD), NKX3–2-related | AR | NKX3–2 | 613330 | ||
| NOS 36–0200 | NAD deficiency syndrome, HAAO-related | AR | HAAO | 617660 | With associated cardiac, limb and renal defects; VACTERL-like | |
| NOS 36–0210 | NAD deficiency syndrome, KYNU-related | AR | KYNU | 617661 | In some cases VACTERL-like | |
| NOS 36–0220 | NAD deficiency syndrome, NADSYN1-related | AR | NADSYN1 | 618845 | In some cases VACTERL-like | |
| NOS 36–0230 | VATER/VACTERL association | SP | 192350 | |||
| NOS 36–0240 | VACTERL association with hydrocephalus (VACTERL-H), FANCB-related | XL | FANCB | 300514 | FANCB-related Fanconi anemia may present in hemizygous males with the VACTERL-hydrocephalus phenotype | |
| NOS 36–0250 | VACTERL association with hydrocephalus (VACTERL-H), ZIC3-related | XL | ZIC3 | 314390 | ||
| NOS 36–0260 | Uniparental disomy, paternal, for chromosome 14 (UPD14; Kagami-Ogata syndrome) | SP | 14q32? | 608149 | Imprinted genes at 14q32 may have a role in this complex phenotype with skeletal malformations such as “coat-hanger ribs” | |
| 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) | ||||||
| Group 37 | Patellar dysostoses | |||||
| NOS 37–0010 | Ischiopatellar dysplasia (small patella syndrome), TBX4-related | AD | TBX4 | 147891 | See MIM 601360 - posterior amelia for the biallelic phenotype | |
| NOS 37–0020 | Nail-patella syndrome, LMX1B-related | AD | LMX1B | 161200 | ||
| NOS 37–0030 | Genitopatellar syndrome, KAT6B-related | AD | KAT6B | 606170 | ||
| 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. | ||||||
| Group 38 | Limb hypoplasia – reduction defects group | |||||
| NOS 38–0010 | Ulnar-mammary syndrome, TBX3-related | AD | TBX3 | 181450 | ||
| NOS 38–0020 | Holt-Oram syndrome, TBX5-related | AD | TBX5 | 142900 | ||
| NOS 38–0030 | Holt-Oram/Ulnar Mammary blended phenotype | AD | TBX3, TBX5 | CNVs involving both TBX3 and TBX5 may result in combined phenotype | ||
| NOS 38–0040 | Posterior Amelia, TBX4-related | AR | TBX4 | 601360 | See also ischiopatellar syndrome for the monoallelic TBX4-related phenotype | |
| NOS 38–0050 | Cornelia de Lange syndrome, NIPBL-related | AD | NIPBL | 122470 | ||
| NOS 38–0060 | Cornelia de Lange syndrome, SMC1A-related | XL | SMC1A | 300590 | ||
| NOS 38–0070 | Cornelia de Lange syndrome, SMC3-related | AD | SMC3 | 610759 | ||
| NOS 38–0080 | Cornelia de Lange syndrome, RAD21-related | AD | RAD21 | 614701 | ||
| NOS 38–0090 | Cornelia de Lange syndrome, HDAC8-related | XL | HDAC8 | 300882 | ||
| NOS 38–0100 | Thrombocytopenia-absent radius (TAR) syndrome, RBM8A-related | AR | RBM8A | 274000 | Deletion and common SNP on other allele that has regulatory function | |
| NOS 38–0110 | Thrombocythemia with distal limb defects, THPO-related | AD | THPO | 187950 | Distal limb defects postulated as consequence of vascular occlusions | |
| NOS 38–0120 | Okihiro syndrome (Duane syndrome with radial ray anomaly), SALL4-related | AD | SALL4 | 607323 | Includes IVIC syndrome | |
| NOS 38–0130 | Cousin syndrome, TBX15-related | AR | TBX15 | 260660 | ||
| NOS 38–0140 | Roberts syndrome, ESCO2-related | AR | ESCO2 | 268300 | ||
| NOS 38–0150 | Tibial hemimelia-polysyndactyly-triphalangeal thumb (Werner syndrome), ZRS-related | AD | ZRS | 188740 | Monoallelic variants in ZRS, a limb-specific enhancer of SHH that is located within intron 5 of the LMBR1 gene | |
| NOS 38–0160 | Clubfoot with or without deficiency of long bones and/or mirror-image polydactyly, PITX1-related | AD | PITX1 | 119800 | In some patients bilateral patellar hypoplasia (see group 37) | |
| NOS 38–0170 | Acheiropodia, LMBR1-related | AR | LMBR1 | 200500 | 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 | |
| NOS 38–0180 | Engrailed-1 related dorsoventral syndrome (ENDOVES), limb-brain type | AR | EN1 | 619218 | One single patient with a biallelic frameshift variant described | |
| NOS 38–0190 | Engrailed-1 related dorsoventral syndrome (ENDOVES), limb-only type | AR | MAENLI | 619217 | MAENLI is a lncRNA regulating EN1 expression | |
| NOS 38–0200 | Tetra-amelia, WNT3-related | AR | WNT3 | 273395 | ||
| NOS 38–0210 | Tetra-amelia, RSPO2-related | AR | RSPO2 | 618021 | ||
| NOS 38–0220 | Limb reduction syndrome, WNT7A-related | AR | WNT7A | 276820, 228930 | Includes former Al-Awadi Raas-Rothschild limb-pelvis hypoplasia-aplasia as well as Fuhrmann syndrome | |
| NOS 38–0230 | RAPADILINO syndrome, RECQL4-related | AR | RECQL4 | 266280 | See also Baller-Gerold syndrome, RECQL4-related. See MIM 266280 for explanation of the RAPADILINO acronym | |
| NOS 38–0240 | Rothmund-Thompson syndrome, RECQL4-related | AR | RECQL4 | 268400 | ||
| NOS 38–0250 | Rothmund-Thompson syndrome, ANAPC1-related | AR | ANAPC1 | 618625 | ||
| NOS 38–0260 | Rothmund-Thompson syndrome, DNA2-related | AR | DNA2 | |||
| NOS 38–0270 | Adams-Oliver syndrome (aplasia cutis congenita and transverse limb defects), ARHGAP31-related | AD | ARHGAP31 | 100300 | ||
| NOS 38–0280 | Adams-Oliver syndrome (aplasia cutis congenita and transverse limb defects), DOCK6-related | AR | DOCK6 | 614219 | ||
| NOS 38–0290 | Adams-Oliver syndrome (aplasia cutis congenita and transverse limb defects), RBPJ-related | AD | RBPJ | 614814 | ||
| NOS 38–0300 | Adams-Oliver syndrome (aplasia cutis congenita and transverse limb defects), DLL4-related | AR | DLL4 | 616589 | ||
| NOS 38–0310 | Adams-Oliver syndrome (aplasia cutis congenita and transverse limb defects), EOGT-related | AD | EOGT | 615297 | ||
| NOS 38–0320 | Adams-Oliver syndrome (aplasia cutis congenita and transverse limb defects), NOTCH1-related | AD | NOTCH1 | 616028 | ||
| NOS 38–0330 | B-cell immunodeficiency-limb anomaly-urogenital malformation syndrome (BILU syndrome), TOP2B-related | AD | TOP2B | 609296 | Also known as Hoffmann syndrome (see MIM 609296) | |
| NOS 38–0340 | Scapulo-iliac dysplasia (Kosenow syndrome) | AD | 169550 | |||
| NOS 38–0350 | Hypoglossia-hypodactylia (Hanhart syndrome) | SP | 103300 | |||
| NOS 38–0360 | Poland syndrome | SP, AD | 173800 | Most commonly sporadic and probably non-genetic; some familial cases reported but no specific gene identified so far | ||
| NOS 38–0370 | Femoral facial syndrome (FFS) | SP | 134780 | Some phenotypic overlap with FFU syndrome (below) | ||
| NOS 38–0380 | Femur-fibula-ulna syndrome (FFU) | SP | 228200 | |||
| NOS 38–0390 | Fibular aplasia, tibial campomelia, and oligosyndactyly syndrome (FATCO) | SP | 246570 | |||
| NOS 38–0400 | Tibial hemimelia (isolated) | SP | 275220 | Possibly non-genetic etiology | ||
| NOS 38–0410 | Sirenomelia | SP | Rare cases reported as associated with monoallelic CDX2 variants with variable expressivity | |||
| NOS 38–0420 | Fanconi anemia | AR | (several) | 227650 | 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 | |
| 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) | ||||||
| Group 39 | Split hand/foot with and without other manifestations | |||||
| NOS 39–0010 | Ankyloblepharon-ectodermal dysplasia-cleft palate (AEC) | AD | TP63 | 106260 | see other TP63-related disorders in this group (below) | |
| NOS 39–0020 | Ectrodactyly-ectodermal dysplasia cleft-palate syndrome Type 3 (EEC3) | AD | TP63 | 604292 | ||
| NOS 39–0030 | Ectrodactyly-ectodermal dysplasia-macular dystrophy syndrome (EEM) | AR | CDH3 | 225280 | ||
| NOS 39–0040 | Limb-mammary syndrome (including ADULT syndrome) | AD | TP63 | 603543 | ||
| NOS 39–0050 | Split hand-foot malformation, isolated form, type 4 (SHFM4) | AD | TP63 | 605289 | ||
| NOS 39–0060 | Split hand-foot malformation, isolated form, type 1 (SHFM1) | AD | DLX5 | 220600 | 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 | |
| NOS 39–0070 | Split hand-foot malformation, isolated form, type 1 (SHFM1) | AD | DLX6 | 183600 | ||
| NOS 39–0080 | Split hand-foot malformation, isolated form, type 3 (SHFM3) | AD | 10q24 | 246560 | Duplications at 10q24 encompassing LBX1, BTRC, POLL, DPCD and FBXW4 | |
| NOS 39–0090 | Split hand-foot malformation, isolated form, type 6 (SHFM6) | AR | WNT10B | 225300 | ||
| NOS 39–0100 | Split-foot malformation with mesoaxial polydactyly (SFMMP) | AR | ZAK | 616890 | ||
| NOS 39–0110 | Split-hand-foot malformation with or without long bone deficiency (SHFLD), BHLHA9-related | AD | BHLHA9 | 612576 | 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 | |
| NOS 39–0120 | Hartsfield syndrome, FGFR1-related | AD | FGFR1 | 615465 | ||
| NOS 39–0130 | Split hand-foot malformation, EPS15L-related | AD | EPS15L1 | Structural variants (deletions) at this locus; one consanguineous family with homozygous point variant in EPS15L1 but inheritance still unclear | ||
| NOS 39–0140 | Aplasia cutis congenita with ectrodactyly, UBA2-related | AD | UBA2 | 19q13.11 deletions may also cause this phenotype. In OMIM as “aplasia cutis congenita with ectrodactyly skeletal syndrome” (a redundant name) | ||
| NOS 39–0150 | Focal dermal hypoplasia (Goltz Syndrome), PORCN-related | XLD | PORCN | 305600 | ||
| Group 40 | Polydactyly-Syndactyly-Triphalangism group | |||||
| NOS 40–0010 | Preaxial polydactyly, SHH-related | AD | SHH | 174400 | Formerly preaxial polydactyly type 1 and type 2 (with triphalangeal thumb); regulatory domain variant or duplication of ZRS (limb enhancer of SHH) | |
| NOS 40–0020 | Preaxial polydactyly, GLI1-related | AR | GLI1 | 174400 | ||
| NOS 40–0030 | Preaxial polydactyly, GLI3-related | AD | GLI3 | 174700 | ||
| NOS 40–0040 | Preaxial polydactyly type 3 (PPD3) | AD | 174600 | |||
| NOS 40–0050 | Mirror-image polydactyly of hands and feet (Laurin-Sandrow syndrome), SHH-related | AD | SHH | 135750 | Duplication of ZRS (limb enhancer of SHH) | |
| NOS 40–0060 | Postaxial polydactyly, GLI1-related | AR | GLI1 | 618123 | ||
| NOS 40–0070 | Greig cephalopolysyndactyly syndrome, GLI3-related | AD | GLI3 | 175700 | ||
| NOS 40–0080 | Pallister-Hall syndrome, GLI3-related | AD | GLI3 | 146510 | ||
| NOS 40–0090 | Hypothalamic hamartomas and polydactyly (Pallister-Hall-like) syndrome, SMO-related | AR | SMO | 241800 | ||
| NOS 40–0100 | Culler-Jones syndrome, GLI2-related | AD | GLI2 | 615849 | Hypopituitarism | |
| NOS 40–0110 | Synpolydactyly, FBLN1-related | AD | FBLN1 | 608180 | ||
| NOS 40–0120 | Synpolydactyly, HOXD13-related | AD | HOXD13 | 186000 | ||
| NOS 40–0130 | Postaxial polydactyly, isolated (type A10), KIAA0825-related | AR | KIAA0825 | 618498 | ||
| NOS 40–0140 | Townes-Brocks syndrome, SALL1-related | AD | SALL1 | 107480 | ||
| NOS 40–0150 | Lacrimo-auriculo-dento-digital syndrome (LADD), FGFR2-related | AD | FGFR2 | 149730 | ||
| NOS 40–0160 | Lacrimo-auriculo-dento-digital syndrome (LADD), FGFR3-related | AD | FGFR3 | 149730 | ||
| NOS 40–0170 | Lacrimo-auriculo-dento-digital syndrome (LADD), FGF10-related | AD | FGF10 | 149730 | ||
| NOS 40–0180 | Acrocallosal syndrome, KIF7-related | AR | KIF7 | 200990 | ||
| NOS 40–0190 | Acro-pectoral-vertebral dysplasia (F-syndrome), WNT6-related | AD | WNT6 | 102510 | Structural variations of locus resulting in ectopic activation of WNT6 | |
| NOS 40–0200 | Cenani-Lenz syndactyly, LRP4-related | AR | LRP4 | 212780 | ||
| NOS 40–0210 | Cenani-Lenz-like syndactyly, GREM/FMN1-related | AD | GREM1, FMN1 | see 212780 | Monoallelic duplication of both GREM1 and FMN1 loci (one individual) | |
| NOS 40–0220 | Oligosyndactyly, radio-ulnar synostosis, hearing loss and renal defects syndrome, FMN1-related | AR | FMN1 | Biallelic deletion of the FMN1 gene (one individual) | ||
| NOS 40–0230 | Mesoaxial synostotic syndactyly with phalangeal reduction (Malik-Percin), BHLHA9-related | AD | BHLHA9 | 609432 | ||
| NOS 40–0240 | STAR syndrome (syndactyly of toes, telecanthus, anal and renal malformations), FAM58A-related | XLD | FAM58A | 300707 | X-linked dominant (only affected females known, possibly lethal in males) | |
| NOS 40–0250 | Syndactyly type 1 (III-IV) | AD | 185900 | |||
| NOS 40–0260 | Syndactyly type 3 (IV-V), GJA1-related | AD | GJA1 | 186100 | ||
| NOS 40–0270 | Syndactyly type 4 (I-V) Haas type, SHH-related | AD | SHH | 186200 | Duplication of ZRS (limb enhancer of SHH) | |
| NOS 40–0280 | Syndactyly type 5 (Brachydactyly-Syndactyly syndrome; syndactyly with metacarpal and metarsal fusion), HOXD13-related | AD | HOXD13 | 186300, 610713 | ||
| NOS 40–0290 | Syndactyly (Lueken type, with or without craniosynostosis), IHH-related | AD | IHH | 185900 | Duplication of IHH and regulatory region on 2q35; includes syndactyly with craniosynostosis (Philadelphia type) | |
| NOS 40–0300 | Metacarpal 4–5 fusion, FGF16-related | XLR | FGF16 | 309630 | ||
| NOS 40–0310 | Syndactyly with microcephaly and mental retardation (Filippi syndrome), CKAP2L-related | AR | CKAP2L | 272440 | ||
| NOS 40–0320 | Synpolydactyly plus syndrome, MAPKAPK5-related | AR | MAPKAPK5 | 619869 | In OMIM as neurocardiofaciodigital syndrome | |
| 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. | ||||||
| Group 41 | Defects in joint formation and synostoses | |||||
| NOS 41–0010 | Multiple synostoses syndrome, NOG-related | AD | NOG | 186500, 186570 | 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 | |
| NOS 41–0020 | Multiple synostoses syndrome, GDF5-related | AD | GDF5 | 610017 | see other GDF5-related disorders | |
| NOS 41–0030 | Multiple synostoses syndrome, FGF9-related | AD | FGF9 | 612961 | ||
| NOS 41–0040 | Multiple synostoses syndrome, GDF6-related | AD | GDF6 | 617898 | ||
| NOS 41–0050 | Liebenberg syndrome, PITX1-related | AD | PITX1 | 186550 | Structural variants encompassing the H2AFY gene resulting in ectopic activation of PITX1 in upper limb | |
| NOS 41–0060 | Short stature, auditory atresia, mandibular hypoplasia, skeletal abnormalities (SAMS) syndrome, GSC-related | AR | GSC | 602471 | ||
| NOS 41–0070 | Radio-ulnar synostosis with amegakaryocytic thrombocytopenia, HOXA11-related | AD | HOXA11 | 605432 | ||
| NOS 41–0080 | Radio-ulnar synostosis with amegakaryocytic thrombocytopenia, MECOM-related | AD | MECOM | 616738 | ||
| NOS 41–0090 | Radio-ulnar synostosis with microcephaly (Giuffré-Tsukahara syndrome) | 603438 | X-linked recessive inheritance suggested | |||
| 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 |
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.
Acknowledgements. –
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 DBT/Wellcome Trust India Alliance Grant ‘Center for Rare Disease Diagnosis, Research and Training number: IA/CRC/20/1/600002” (to Katta M. Girisha), the Sigrid Jusélius Foundation (grant to Outi Makitie), the National Health and Medical Research Council of Australia Leadership Fellow Grant #GNT2018081 (to Ravi Savarirayan), and Curekids New Zealand (support to Stephen P. Robertson).
References
- A nomenclature for constitutional (intrinsic) diseases of bones. (1971). The Journal of Pediatrics, 78(1), 177–179. 10.1016/s0022-3476(71)80286-x [DOI] [PubMed] [Google Scholar]
- Beighton P, Giedion ZA, Gorlin R, Hall J, Horton B, Kozlowski K, Lachman R, Langer LO, 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. 10.1002/ajmg.1320440220 [DOI] [PubMed] [Google Scholar]
- Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, Bennett JT, Bird LM, Carey JC, Chung B, Clark RD, Cox TC, Curry C, Dinulos MBP, Dobyns WB, Giampietro PF, Girisha KM, Glass IA, Graham JM, … Zarate YA (2021). A dyadic approach to the delineation of diagnostic entities in clinical genomics. American Journal of Human Genetics, 108(1), 8–15. 10.1016/j.ajhg.2020.11.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1002/ajmg.a.37365 [DOI] [PubMed] [Google Scholar]
- Ferreira CR, 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. 10.1002/jimd.12348 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ferreira CR, van Karnebeek CDM, 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. 10.1038/s41436-018-0022-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hall CM (2002). International nosology and classification of constitutional disorders of bone (2001). American Journal of Medical Genetics, 113(1), 65–77. 10.1002/ajmg.10828 [DOI] [PubMed] [Google Scholar]
- 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. 10.1002/(sici)1096-8628(19981012)79:5<376::aid-ajmg9>3.0.co;2-h [DOI] [PubMed] [Google Scholar]
- [International nomenclature of constitutional bone diseases. Constitutional bone diseases without known pathogenesis]. (1971). Archives Francaises De Pediatrie, 28(5), 553–557. [PubMed] [Google Scholar]
- International Nomenclature of Constitutional Diseases of Bone. Revision, May, 1983. (1983). Annales De Radiologie, 26(6), 457–462. [PubMed] [Google Scholar]
- International nomenclature of Constitutional Diseases of bone: Revision--May 1977. (1979). American Journal of Medical Genetics, 3(1), 21–26. 10.1002/ajmg.1320030107 [DOI] [PubMed] [Google Scholar]
- [International nomenclature of constitutional diseases of bones]. (1970). Annales De Radiologie, 13(7), 455–464. [PubMed] [Google Scholar]
- Lachman RS (1998). International nomenclature and classification of the osteochondrodysplasias (1997). Pediatric Radiology, 28(10), 737–744. 10.1007/s002470050458 [DOI] [PubMed] [Google Scholar]
- McKusick VA, & Scott CI (1971). A nomenclature for constitutional disorders of bone. The Journal of Bone and Joint Surgery. American Volume, 53(5), 978–986. [PubMed] [Google Scholar]
- Mortier GR, Cohn DH, Cormier-Daire V, Hall C, Krakow D, Mundlos S, Nishimura G, Robertson S, Sangiorgi L, Savarirayan R, Sillence D, Superti-Furga A, Unger S, & Warman ML (2019). Nosology and classification of genetic skeletal disorders: 2019 revision. American Journal of Medical Genetics. Part A, 179(12), 2393–2419. 10.1002/ajmg.a.61366 [DOI] [PubMed] [Google Scholar]
- Sillence DO, & Rimoin DL (1978). Classification of osteogenesis imperfecta. Lancet (London, England), 1(8072), 1041–1042. 10.1016/s0140-6736(78)90763-8 [DOI] [PubMed] [Google Scholar]
- Sillence DO, Rimoin DL, & Danks DM (1979). Clinical variability in osteogenesis imperfecta-variable expressivity or genetic heterogeneity. Birth Defects Original Article Series, 15(5B), 113–129. [PubMed] [Google Scholar]
- Spranger J (1985). Pattern recognition in bone dysplasias. Progress in Clinical and Biological Research, 200, 315–342. [PubMed] [Google Scholar]
- Superti-Furga A, & Unger S (2007). Nosology and classification of genetic skeletal disorders: 2006 revision. American Journal of Medical Genetics. Part A, 143A(1), 1–18. 10.1002/ajmg.a.31483 [DOI] [PubMed] [Google Scholar]
- Van Dijk FS, & Sillence DO (2014). Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment. American Journal of Medical Genetics. Part A, 164A(6), 1470–1481. 10.1002/ajmg.a.36545 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabel B, & Superti-Furga A (2011). Nosology and classification of genetic skeletal disorders: 2010 revision. American Journal of Medical Genetics. Part A, 155A(5), 943–968. 10.1002/ajmg.a.33909 [DOI] [PMC free article] [PubMed] [Google Scholar]