INVITED COMMENT
Significant Clinical Benefits of Molecular Studies in the Skeletal Dysplasias Andrea Superti-Furga* Department of Pediatrics, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland Manuscript Received: 21 November 2014; Manuscript Accepted: 5 December 2014
In this issue of the Journal, Dr. Terhal and her associates share their experience on the clinical complications occurring in individuals who have one of the chondrodysplasias associated with dominant mutations in COL2A1, the gene coding for type 2 collagen—the prototypic cartilage collagen. As our readers are probably already aware of, the so-called type 2 collagenopathies cover a wide spectrum of severity (from achondrogenesis type 2 to Stickler syndrome and familial necrosis of the capital femoral epiphysis) and show considerable variation both in clinical features and in radiographic features (with or without metaphyseal involvement, with or without shortening of fingers and metatarsals, etc.). In spite of the wide variation, the “milestone” conditions such as spondyloepiphyseal dysplasia congenita (SEDC) described in 1966 [Spranger and Wiedemann, 1966], and Kniest dysplasia, described in 1952 [Kniest, 1952] are frequent and are part of every medical geneticist’s cultural heritage. In the skeletal dysplasias, the path to diagnosis remains difficult, and expert interpretation of the radiographic features combined with thorough clinical evaluation is the most important first step to molecular diagnosis. However, once the correct diagnosis has been suspected and molecularly confirmed, what can we offer in terms of anticipatory guidance, prevention and—if needed—intervention? Collagen 2 disorders have an impact on the skeleton but also on the mandible and palate, the eye, and the inner ear; and neurologic complications from cervical spine instability have been reported. But what can we tell parents and patients about the true incidence of these manifestations and complications, and does knowledge of the underlying mutation help us in predicting their occurrence and severity? There is also a conspicuous lack of evidence on the efficacy of orthopedic or surgical measures. As a consequence, the approaches vary widely between centers, and affected individuals may be subject to numerous surgical procedures (femoral head valgisation and or paravertebral rodding), or be placed on conservative measures only (physiotherapy, swim therapy, and bracing). The lack of evidence may be taken as an indication that no single approach is clearly superior to others. Yet, some form of evidence is badly needed to guide a transparent discussion between professionals and families. Recently, Dr. Terhal’s group had already provided us with the bonus of molecularly-based growth curves for individuals with type 2 collagenopathies [Terhal et al., 2012]. In this new study, the focus is placed on the occurrence of complications and on the relationship with the underlying mutation. This information is based on molecularly proven cases that include milder variants that would
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Superti-Furga A. 2015. Significant clinical benefits of molecular studies in the skeletal dysplasias. Am J Med Genet Part A 167A:476–477.
have been excluded from older studies because of their non-typical features. This is crucial at a time where we are learning from nextgeneration sequencing studies that clinical manifestations from mutations in known genes are highly variable, and “textbook” cases are the exception rather than the rule. Although far from providing answers to all of the above questions, and with all the limitations given by the study design—a retrospective compilation of patients’ charts—Dr. Terhal’s new report provides some insights, such as the association of ocular complications with splicing mutations and the relatively low overall risk of neurologic complications in children, and the overall picture that emerges is more detailed than it has been thus far; the ability to put a figure on those risks of complications is certainly helpful. The report by Dr. Terhal inspires additional reflections on the future of genetic diagnosis. For one, there appears to be a benefit in having a combination of molecular diagnostics and clinical expertise in the same center. While prospective clinical studies would be best, it remains difficult for a single clinical center to collect more than a handful or a dozen of cases of patients with the same disorder (except for achondroplasia, or for osteogenesis imperfecta that is intrinsically very heterogeneous). Therefore, a collection of cases initiated by an academic diagnostic laboratory, even if retrospective, may be a good option. Similar laboratory-initiated studies have proven useful in other rare skeletal conditions (e.g., progressive Grant sponsor: Leenaards Foundation in Lausanne (www.leenaards.org). Correspondence to: Prof. Andrea Superti-Furga, Leenaards Professor of Pediatrics, University of Lausanne, Head of the Department of Pediatrics, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com) DOI 10.1002/ajmg.a.36931
476
SUPERTI-FURGA pseudorheumatoid dysplasia [Garcia-Segarra et al., 2012]). Prospective clinical studies with recruitment immediately following molecular confirmation may the the logical next step. Second, having international coordination between expert centers also continues to prove beneficial. When the European Skeletal Dysplasia Network was started in 2002, agreement were taken by which individual centers would be in charge for distinct diagnostic tests, no matter which country they were in. This has allowed for the build-up of patient cohorts allowing for this type of retrospective studies [Terhal et al., 2012,2015; Garcia-Segarra et al., 2012]. Although ESDN funding has long stopped, the structural benefit has endured (and the diagnostic web site at www.esdn.org keeps running). Considering the benefit of a combination between molecular diagnostics and clinical expertise spurs some considerations on times ahead. How will exome sequencing, that has robustly entered the clinical routine and is here to stay (or to be replaced soon by genome sequencing), change the game and affect clinical research? Specifically, if diagnostic studies in the form of exome sequencing will be obtained at each and every peripheral clinic (perhaps even with miniaturized, pocketable nanopore sequencing units), and the information will not be collected in a diagnostic center, do we risk losing the information? Not every single case may be worthy of scientific publication yet every single case may be a valuable piece of the mosaic delineating the larger picture. Already, scientific journals are trying to cope with the flood of information coming from clinical exome sequencing. How not to lose the precious information coming from widespread exome sequencing, and yet to bundle it to significant quantums that would be above the noise level? Several scenarios, not mutually exclusive, may be envisaged. Locusspecific databases may be helpful, with curators surveying the literature (or the online databases) and collecting evidence pertaining to one gene and its many clinical facets. Alternatively, the process will become entirely de-centralized, with case reports published online only, and being available for automated literature search and reviews – what is the latest evidence, say, on glycine-toaspartate changes in COL2A1? As a third option, will dedicated patient registries be established that collect data contributed voluntarily from single centers and produce periodic updates? Might this be an avenue to revalue the role of patients and their associations, with registries that are co-driven by clinical researchers and patient associations? Our Journal has a long-standing tradition of publishing case reports of outstanding value and significance—treasure your exceptions“, as it is often said [Carey 2006a,b]. Yet, as a parent of a child with a “rare” mutation, it would feel better not to be a rare exception, but to have as many similar cases as possible to provide solid evidence for prognosis and treatment. The aim of not losing the value intrinsic to each and every genome-phenome observation and yet to bundle that information to a significant
477 entity that can be scientifically scrutinized, is important. Until that aim will be achieved, molecularly based, large case series such the one by Dr. Terhal, will continue to deliver valuable contributions to ameliorate counseling and treatment of affected individuals and their families.
ACKNOWLEDGMENTS My thanks to Dr. Sheila Unger for discussions and a critical revision of the manuscript. This work was supported by a grant of the Leenaards Foundation in Lausanne (www.leenaards.org).
REFERENCES Carey JC. 2006a. Significance of case reports in the advancement of medical scientific knowledge. Am J Med Genet A 140:2131–2134. Carey JC. 2006b. A species not extinct: Publication of case reports and scientific knowledge. Am J Med Genet A 140:801–803. Garcia-Segarra N, Mittaz L, Campos-Xavier AB, Bartels CF, Tuysuz B, Alanay Y, Cimaz R, Cormier-Daire V, Di Rocco M, Duba HC, Elcioglu NH, Forzano F, Hospach T, Kilic E, Kuemmerle-Deschner JB, Mortier G, Mrusek S, Nampoothiri S, Obersztyn E, Pauli RM, Selicorni A, Tenconi R, Unger S, Utine GE, Wright M, Zabel B, Warman ML, Superti-Furga A, Bonafe´ L. 2012. The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): A review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals. Am J Med Genet C Semin Med Genet 160C:217–229. Kniest W. 1952. Zur Abgrenzung des dysostosis enchondralis von der Chondrodystrophie. Zeitschr Kinderheilk 70:633–640. Spranger J, Wiedemann HR. 1966. Dysplasia spondyloepiphysaria congenita. Helv Paediatr Acta 21:598–602. Terhal PA, van Dommelen P, Le Merrer M, Zankl A, Simon ME, Smithson SF, Marcelis C, Kerr B, Kinning E, Mansour S, Hennekam RC, van der Hout AH, Cormier-Daire V, Lund AM, Goodwin L, Me´garbane´ A, Lees M, Betz RC, Tobias ES, Coucke P, Mortier GR. 2012. Mutation-based growth charts for SEDC and other COL2A1 related dysplasias. Am J Med Genet C Semin Med Genet 3:205–216. Terhal PA, Rutger Jan Nievelstein AJ, Eva Verver JJ, Topsakal V, van Dommelen P, Kristien Hoornaert K, Le Merrer M, Zankl A, Marleen Simon EH, Sarah Smithson F, Carlo M, Elmslie F, Goodwin L, van der Hout AH, Veenstra-Knol HE, Herkert JC, Lund AM, Hennekam RCM, Me´garbane´ A, Lees MM, Wilson LC, Male A, Hurst J, Alanay Y, Annere´n G, Bet3 RC, Ernie Bongers EMHF, Cormier-Daire V, Dieux A, David A, Elting MW, van den Ende J, Green A, van Hagen JM, Hertel NM, Holder-Espinasse M, den Hollander N, Homfray T, Hove HD, Price S, Raas-Rothschild A, Rohrbach M, Schroeter B, Suri M, Thompson EM, Tobias ES, Toutain A, Vreeburg M, Wakeling E, Knoers NV, Coucke P, Mortier GR. 2015. A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing Spondyloepiphyseal Dysplasia Congenita or a related phenotype. Am J Med Genet A 140:461–475.
Significant Clinical Benefits of Molecular Studies in the Skeletal Dysplasias Andrea Superti-Furga* Department of Pediatrics, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland Manuscript Received: 21 November 2014; Manuscript Accepted: 5 December 2014
In this issue of the Journal, Dr. Terhal and her associates share their experience on the clinical complications occurring in individuals who have one of the chondrodysplasias associated with dominant mutations in COL2A1, the gene coding for type 2 collagen—the prototypic cartilage collagen. As our readers are probably already aware of, the so-called type 2 collagenopathies cover a wide spectrum of severity (from achondrogenesis type 2 to Stickler syndrome and familial necrosis of the capital femoral epiphysis) and show considerable variation both in clinical features and in radiographic features (with or without metaphyseal involvement, with or without shortening of fingers and metatarsals, etc.). In spite of the wide variation, the “milestone” conditions such as spondyloepiphyseal dysplasia congenita (SEDC) described in 1966 [Spranger and Wiedemann, 1966], and Kniest dysplasia, described in 1952 [Kniest, 1952] are frequent and are part of every medical geneticist’s cultural heritage. In the skeletal dysplasias, the path to diagnosis remains difficult, and expert interpretation of the radiographic features combined with thorough clinical evaluation is the most important first step to molecular diagnosis. However, once the correct diagnosis has been suspected and molecularly confirmed, what can we offer in terms of anticipatory guidance, prevention and—if needed—intervention? Collagen 2 disorders have an impact on the skeleton but also on the mandible and palate, the eye, and the inner ear; and neurologic complications from cervical spine instability have been reported. But what can we tell parents and patients about the true incidence of these manifestations and complications, and does knowledge of the underlying mutation help us in predicting their occurrence and severity? There is also a conspicuous lack of evidence on the efficacy of orthopedic or surgical measures. As a consequence, the approaches vary widely between centers, and affected individuals may be subject to numerous surgical procedures (femoral head valgisation and or paravertebral rodding), or be placed on conservative measures only (physiotherapy, swim therapy, and bracing). The lack of evidence may be taken as an indication that no single approach is clearly superior to others. Yet, some form of evidence is badly needed to guide a transparent discussion between professionals and families. Recently, Dr. Terhal’s group had already provided us with the bonus of molecularly-based growth curves for individuals with type 2 collagenopathies [Terhal et al., 2012]. In this new study, the focus is placed on the occurrence of complications and on the relationship with the underlying mutation. This information is based on molecularly proven cases that include milder variants that would
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Superti-Furga A. 2015. Significant clinical benefits of molecular studies in the skeletal dysplasias. Am J Med Genet Part A 167A:476–477.
have been excluded from older studies because of their non-typical features. This is crucial at a time where we are learning from nextgeneration sequencing studies that clinical manifestations from mutations in known genes are highly variable, and “textbook” cases are the exception rather than the rule. Although far from providing answers to all of the above questions, and with all the limitations given by the study design—a retrospective compilation of patients’ charts—Dr. Terhal’s new report provides some insights, such as the association of ocular complications with splicing mutations and the relatively low overall risk of neurologic complications in children, and the overall picture that emerges is more detailed than it has been thus far; the ability to put a figure on those risks of complications is certainly helpful. The report by Dr. Terhal inspires additional reflections on the future of genetic diagnosis. For one, there appears to be a benefit in having a combination of molecular diagnostics and clinical expertise in the same center. While prospective clinical studies would be best, it remains difficult for a single clinical center to collect more than a handful or a dozen of cases of patients with the same disorder (except for achondroplasia, or for osteogenesis imperfecta that is intrinsically very heterogeneous). Therefore, a collection of cases initiated by an academic diagnostic laboratory, even if retrospective, may be a good option. Similar laboratory-initiated studies have proven useful in other rare skeletal conditions (e.g., progressive Grant sponsor: Leenaards Foundation in Lausanne (www.leenaards.org). Correspondence to: Prof. Andrea Superti-Furga, Leenaards Professor of Pediatrics, University of Lausanne, Head of the Department of Pediatrics, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com) DOI 10.1002/ajmg.a.36931
476
SUPERTI-FURGA pseudorheumatoid dysplasia [Garcia-Segarra et al., 2012]). Prospective clinical studies with recruitment immediately following molecular confirmation may the the logical next step. Second, having international coordination between expert centers also continues to prove beneficial. When the European Skeletal Dysplasia Network was started in 2002, agreement were taken by which individual centers would be in charge for distinct diagnostic tests, no matter which country they were in. This has allowed for the build-up of patient cohorts allowing for this type of retrospective studies [Terhal et al., 2012,2015; Garcia-Segarra et al., 2012]. Although ESDN funding has long stopped, the structural benefit has endured (and the diagnostic web site at www.esdn.org keeps running). Considering the benefit of a combination between molecular diagnostics and clinical expertise spurs some considerations on times ahead. How will exome sequencing, that has robustly entered the clinical routine and is here to stay (or to be replaced soon by genome sequencing), change the game and affect clinical research? Specifically, if diagnostic studies in the form of exome sequencing will be obtained at each and every peripheral clinic (perhaps even with miniaturized, pocketable nanopore sequencing units), and the information will not be collected in a diagnostic center, do we risk losing the information? Not every single case may be worthy of scientific publication yet every single case may be a valuable piece of the mosaic delineating the larger picture. Already, scientific journals are trying to cope with the flood of information coming from clinical exome sequencing. How not to lose the precious information coming from widespread exome sequencing, and yet to bundle it to significant quantums that would be above the noise level? Several scenarios, not mutually exclusive, may be envisaged. Locusspecific databases may be helpful, with curators surveying the literature (or the online databases) and collecting evidence pertaining to one gene and its many clinical facets. Alternatively, the process will become entirely de-centralized, with case reports published online only, and being available for automated literature search and reviews – what is the latest evidence, say, on glycine-toaspartate changes in COL2A1? As a third option, will dedicated patient registries be established that collect data contributed voluntarily from single centers and produce periodic updates? Might this be an avenue to revalue the role of patients and their associations, with registries that are co-driven by clinical researchers and patient associations? Our Journal has a long-standing tradition of publishing case reports of outstanding value and significance—treasure your exceptions“, as it is often said [Carey 2006a,b]. Yet, as a parent of a child with a “rare” mutation, it would feel better not to be a rare exception, but to have as many similar cases as possible to provide solid evidence for prognosis and treatment. The aim of not losing the value intrinsic to each and every genome-phenome observation and yet to bundle that information to a significant
477 entity that can be scientifically scrutinized, is important. Until that aim will be achieved, molecularly based, large case series such the one by Dr. Terhal, will continue to deliver valuable contributions to ameliorate counseling and treatment of affected individuals and their families.
ACKNOWLEDGMENTS My thanks to Dr. Sheila Unger for discussions and a critical revision of the manuscript. This work was supported by a grant of the Leenaards Foundation in Lausanne (www.leenaards.org).
REFERENCES Carey JC. 2006a. Significance of case reports in the advancement of medical scientific knowledge. Am J Med Genet A 140:2131–2134. Carey JC. 2006b. A species not extinct: Publication of case reports and scientific knowledge. Am J Med Genet A 140:801–803. Garcia-Segarra N, Mittaz L, Campos-Xavier AB, Bartels CF, Tuysuz B, Alanay Y, Cimaz R, Cormier-Daire V, Di Rocco M, Duba HC, Elcioglu NH, Forzano F, Hospach T, Kilic E, Kuemmerle-Deschner JB, Mortier G, Mrusek S, Nampoothiri S, Obersztyn E, Pauli RM, Selicorni A, Tenconi R, Unger S, Utine GE, Wright M, Zabel B, Warman ML, Superti-Furga A, Bonafe´ L. 2012. The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): A review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals. Am J Med Genet C Semin Med Genet 160C:217–229. Kniest W. 1952. Zur Abgrenzung des dysostosis enchondralis von der Chondrodystrophie. Zeitschr Kinderheilk 70:633–640. Spranger J, Wiedemann HR. 1966. Dysplasia spondyloepiphysaria congenita. Helv Paediatr Acta 21:598–602. Terhal PA, van Dommelen P, Le Merrer M, Zankl A, Simon ME, Smithson SF, Marcelis C, Kerr B, Kinning E, Mansour S, Hennekam RC, van der Hout AH, Cormier-Daire V, Lund AM, Goodwin L, Me´garbane´ A, Lees M, Betz RC, Tobias ES, Coucke P, Mortier GR. 2012. Mutation-based growth charts for SEDC and other COL2A1 related dysplasias. Am J Med Genet C Semin Med Genet 3:205–216. Terhal PA, Rutger Jan Nievelstein AJ, Eva Verver JJ, Topsakal V, van Dommelen P, Kristien Hoornaert K, Le Merrer M, Zankl A, Marleen Simon EH, Sarah Smithson F, Carlo M, Elmslie F, Goodwin L, van der Hout AH, Veenstra-Knol HE, Herkert JC, Lund AM, Hennekam RCM, Me´garbane´ A, Lees MM, Wilson LC, Male A, Hurst J, Alanay Y, Annere´n G, Bet3 RC, Ernie Bongers EMHF, Cormier-Daire V, Dieux A, David A, Elting MW, van den Ende J, Green A, van Hagen JM, Hertel NM, Holder-Espinasse M, den Hollander N, Homfray T, Hove HD, Price S, Raas-Rothschild A, Rohrbach M, Schroeter B, Suri M, Thompson EM, Tobias ES, Toutain A, Vreeburg M, Wakeling E, Knoers NV, Coucke P, Mortier GR. 2015. A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing Spondyloepiphyseal Dysplasia Congenita or a related phenotype. Am J Med Genet A 140:461–475.
