Nosology and classification of genetic skeletal disorders : 2010 revision
Howard Hughes Medical Institute1, Necker-Enfants Malades Hospital2, University of London3, University of California, Los Angeles4, Cedars-Sinai Medical Center5, University of Antwerp6, Max Planck Society7, University of Otago8, Royal Children's Hospital9, Children's Hospital at Westmead10, University of Freiburg11, University Hospital of Lausanne12
01 May 2011-American Journal of Medical Genetics Part A (Wiley-Blackwell)-Vol. 155, Iss: 5, pp 943-968
TL;DR: The Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene.
Abstract: Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel 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. © 2011 Wiley-Liss, Inc.
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TL;DR: The new OI nomenclature and the pre‐and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI.
Abstract: Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution–NonCommercial–NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
518 citations
University of Lausanne1, Necker-Enfants Malades Hospital2, Great Ormond Street Hospital3, University of California, Los Angeles4, University of Antwerp5, Charité6, Max Planck Society7, Children's Medical Center of Dallas8, University of Melbourne9, Children's Hospital at Westmead10, Boston Children's Hospital11
TL;DR: The nosology can also serve as a reference for the creation of locus‐specific databases that are expected to help in delineating genotype–phenotype correlations and to harbor the information that will be gained by combining clinical observations and next generation sequencing results.
Abstract: The purpose of the nosology is to serve as a "master" list of the genetic disorders of the skeleton to facilitate diagnosis and to help delineate variant or newly recognized conditions. This is the 9th edition of the nosology and in comparison with its predecessor there are fewer conditions but many new genes. In previous editions, diagnoses that were phenotypically indistinguishable but genetically heterogenous were listed separately but we felt this was an unnecessary distinction. Thus the overall number of disorders has decreased from 456 to 436 but the number of groups has increased to 42 and the number of genes to 364. The nosology may become increasingly important today and tomorrow in the era of big data when the question for the geneticist is often whether a mutation identified by next generation sequencing technology in a particular gene can explain the clinical and radiological phenotype of their patient. This can be particularly difficult to answer conclusively in the prenatal setting. Personalized medicine emphasizes the importance of tailoring diagnosis and therapy to the individual but for our patients with rare skeletal disorders, the importance of tapping into a resource where genetic data can be centralized and made available should not be forgotten or underestimated. The nosology can also serve as a reference for the creation of locus-specific databases that are expected to help in delineating genotype-phenotype correlations and to harbor the information that will be gained by combining clinical observations and next generation sequencing results.
458 citations
Cites background or methods from "Nosology and classification of gene..."
...The criteria used for inclusion of disorders are unchanged from the previous revision [Warman et al., 2011]....
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...…[1970, 1971a,b, 1979, 1983, 1998; Hall, 2002; Lachman, 1998;McKusick and Scoot, 1971; Rimoin, 1979; Spranger, 1992; Superti-Furga and Unger, 2007; Warman et al., 2011] The current nosology revision took place in Bologna, Italy just prior to the 11th International Skeletal Dysplasia Society…...
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University of Antwerp1, University of California, Los Angeles2, Necker-Enfants Malades Hospital3, Great Ormond Street Hospital4, Charité5, Children's Medical Center of Dallas6, University of Otago7, University of Melbourne8, Children's Hospital at Westmead9, University of Lausanne10, Boston Children's Hospital11
TL;DR: This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes and remarkable, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders.
Abstract: The application of massively parallel sequencing technology to the field of skeletal disorders has boosted the discovery of the underlying genetic defect for many of these diseases. It has also resulted in the delineation of new clinical entities and the identification of genes and pathways that had not previously been associated with skeletal disorders. These rapid advances have prompted the Nosology Committee of the International Skeletal Dysplasia Society to revise and update the last (2015) version of the Nosology and Classification of Genetic Skeletal Disorders. This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes. Remarkably, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders. By providing a reference list of recognized entities and their causal genes, the Nosology should help clinicians achieve accurate diagnoses for their patients and help scientists advance research in skeletal biology.
403 citations
Cites background from "Nosology and classification of gene..."
...Previously, the percentages of disorders that had been “solved” genetically were 58% (215/372) for the 2006 revision, 69% (316/456) for the 2010 revision, and 88% (385/436) for the 2015 revision (Bonafe et al., 2015; Superti-Furga & Unger, 2007; Warman et al., 2011)....
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...The first ISDS revision was published in 2002 and thereafter at regular intervals (Bonafe et al., 2015; Hall, 2002; Superti-Furga & Unger, 2007; Warman et al., 2011)....
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TL;DR: The ways in which temporal and spatial activation of transforming growth factor-β (TGF-β), a multi-functional signaling molecule, are needed for proper tissue development and regulation of stem cells throughout the body are reviewed.
Abstract: TGF-β 1-3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix (ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.
245 citations
TL;DR: In the last decade, the primary cilia machinery has been implicated in more than a dozen disorders united as ciliopathies, including skeletal dysplasias, such as Jeune syndrome and short rib-polydactyly type III as discussed by the authors.
Abstract: In the last 10 years, the primary cilia machinery has been implicated in more than a dozen disorders united as ciliopathies, including skeletal dysplasias, such as Jeune syndrome and short rib-polydactyly type III. Indeed, primary cilia play a vital role in transduction of signals in the hedgehog pathway that is especially important in skeletal development. In this review, we focus on skeletal conditions belonging to the ciliopathy group: the short rib-polydactyly group (SRPs) that includes Verma-Naumoff syndrome (SRP type III), Majewski syndrome (SRP type II), Jeune syndrome (ATD), as well as Ellis-van Creveld syndrome (EVC), the Sensenbrenner syndrome, and, finally, Weyers acrofacial dysostosis. Today, 10 different genes have been identified as responsible for seven "skeletal" ciliopathies. Mutations have been identified in dynein motor (DYNC2H1), in intraflagellar transport (IFT) complexes (IFT80, IFT122, IFT43, WDR35, WDR19, and TTC21B) as well as in genes responsible for the basal body (NEK1, EVC, and EVC2). The wide clinical variability observed for an individual ciliopathy gene supports the development of exome strategy specifically dedicated to cilia genes to identify mutations in this particularly heterogeneous group of disorders.
223 citations
Cites background from "Nosology and classification of gene..."
...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....
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...Thiel C, Kessler K, Giessl A, Dimmler A, Shalev SA, von derHaar S, ZenkerM,ZahnleiterD, StössH, Beinder E,Abou JamraR, Ekici AB, Schröder-Kress N, Aigner T, Kirchner T, Reis A, Brandstätter JH, Rauch A. 2011....
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References
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TL;DR: An epidemiological and genetical study of osteogenesis imperfecta in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI, and the largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae.
Abstract: An epidemiological and genetical study of osteogenesis imperfecta (OI) in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI. The largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae. A large proportion of adults had presenile deafness or a family history of presenile conductive hearing loss. A second group, who comprised the majority of newborns with neonatal fractures, all died before or soon after birth. These had characteristic broad, crumpled femora and beaded ribs in skeletal x-rays. Autosomal recessive inheritance was likely for some, if not all, of these cases. A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine. The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age. All patients in this group were sporadic cases. The mode of inheritance was not resolved by the study, but it is likely that the group is heterogeneous with both dominant and recessive genotypes responsible for the syndrome. The fourth group of patients showed dominant inheritance of osteoporosis leading to fractures, with variable deformity of long bones, but normal sclerae.
1,903 citations
TL;DR: By providing an updated overview of recognized entities with skeletal involvement and of the underlying gene defects, the new Nosology can provide practical diagnostic help, facilitate the recognition of new entities, and foster and direct research in skeletal biology and genetic disorders.
Abstract: The objective of the paper is to provide the revision of the Nosology of Constitutional Disorders of Bone that incorporates newly recognized disorders and reflects new molecular and pathogenetic concepts. Criteria for inclusion of disorders were (1) significant skeletal involvement corresponding to the definition of skeletal dysplasias, metabolic bone disorders, dysostoses, and skeletal malformation and/or reduction syndromes, (2) publication and/or MIM listing, (3) genetic basis proven or very likely, and (4) nosologic autonomy confirmed by molecular or linkage analysis and/or distinctive diagnostic features and observation in multiple individuals or families. Three hundred seventy-two different conditions were included and placed in 37 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 215 were associated with one or more of 140 different genes. Nosologic status was classified as final (mutations or locus identified), probable (pedigree evidence), or bona fide (multiple observations and clear diagnostic criteria, but no pedigree or locus evidence yet). The number of recognized genetic disorders with a significant skeletal component is growing and the distinction between dysplasias, metabolic bone disorders, dysostoses, and malformation syndromes is blurring. For classification purposes, pathogenetic and molecular criteria are integrating with morphological ones but disorders are still identified by clinical features and radiographic appearance. Molecular evidence leads to confirmation of individual entities and to the constitution of new groups, but also allows for delineation of related but distinct entities and indicates a previously unexpected heterogeneity of molecular mechanisms; thus, molecular evidence does not necessarily simplify the Nosology, and a further increase in the number of entities and growing complexity is expected. By providing an updated overview of recognized entities with skeletal involvement and of the underlying gene defects, the new Nosology can provide practical diagnostic help, facilitate the recognition of new entities, and foster and direct research in skeletal biology and genetic disorders. © 2006 Wiley-Liss, Inc.
318 citations
"Nosology and classification of gene..." refers methods in this paper
...…the increasing complexity of information, revisions of the Nosology have been delegated to an expert group nominated ad hoc within the ISDS to ensure an adequate representation of clinical, radiological and molecular expertise (2001 and 2006 revisions) [Hall, 2002; Superti-Furga and Unger, 2007]....
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Journal Article•
219 citations
TL;DR: The last International Classification of Constitutional Disorders of Bone was published in 1998 and since then rapid advances have been made in identifying the molecular changes responsible for defined conditions and new disorders are constantly being delineated.
Abstract: The last International Classification of Constitutional Disorders of Bone was published in 1998. Since then rapid advances have been made in identifying the molecular changes responsible for defined conditions and new disorders are constantly being delineated. For these reasons a further update on the classification is appropriate. It has been expended to not only the osteochondrodysplasias (33 groups) but also genetically determined dysostoses (3 groups).
194 citations
144 citations
"Nosology and classification of gene..." refers methods in this paper
...The Sillence classification, published 30 years ago, provided a first systematic clinical classification and made correlations to the inheritance pattern of individual clinical types [Sillence and Rimoin, 1978; Sillence et al., 1979a,b]....
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