{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:32:34Z","timestamp":1760059954008,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University Research Institute of Maternal and Child Health and Precision Medicine"},{"name":"School of Medicine of the National Kapodistrian University of Athens"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Osteodysplastic syndromes comprise a very diverse group of clinically and genetically heterogeneous disorders characterized by defects in bone and connective tissue development, as well as in bone density. Here, we report the case of a 48-year-old female with a complex medical history characterized by bone dysplasia, hyperostosis, and partial tooth agenesis. Methods: Genetic testing was performed using WES analysis and Sanger sequencing. Molecular modeling analysis and dynamics simulation explored the impact of detected pathogenic variants. Results: The genetic analysis detected multiple pathogenic variants in genes CREB3L1, SLCO2A1, SFRP4, LRP5, and LRP6, each of which has been associated with rare osteodysplastic syndromes. The patient was homozygous for the same rare alleles associated with three of the identified autosomal recessive disorders osteogenesis imperfecta type XVI, primary hypertrophic osteoarthropathy, and metaphyseal dysplasia Pyle type. She also had a variant linked to autosomal dominant endosteal hyperostosis and a variant previously associated with increased risk of osteoporosis and bone fractures. Two of the detected variants are predicted to cause abnormal splicing, while molecular modeling and dynamics simulations analysis suggest that the other three variants probably confer altered local secondary structure and flexibility that may have functionally devastating consequences. Conclusions: Our case highlights the rare coexistence of multiple osteodysplastic syndromes in a single patient that may complicate differential diagnosis. Furthermore, this case emphasizes the necessity for early genetic investigation of such complex cases with overlying phenotypic traits, followed by genetic counseling, facilitating orchestration of clinical interventions and allowing prevention and\/or prompt management of manifestations.<\/jats:p>","DOI":"10.3390\/genes16080871","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T14:11:44Z","timestamp":1753366304000},"page":"871","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genotype\u2013Phenotype Correlation Insights in a Rare Case Presenting with Multiple Osteodysplastic Syndromes"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6695-186X","authenticated-orcid":false,"given":"Christos","family":"Yapijakis","sequence":"first","affiliation":[{"name":"Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"},{"name":"Choremion Laboratory, Research Institute of Maternal and Child Health and Precision Medicine, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2561-9595","authenticated-orcid":false,"given":"Iphigenia","family":"Gintoni","sequence":"additional","affiliation":[{"name":"Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"},{"name":"Choremion Laboratory, Research Institute of Maternal and Child Health and Precision Medicine, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0065-259X","authenticated-orcid":false,"given":"Myrsini","family":"Chamakioti","sequence":"additional","affiliation":[{"name":"Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"},{"name":"Choremion Laboratory, Research Institute of Maternal and Child Health and Precision Medicine, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleni","family":"Koniari","sequence":"additional","affiliation":[{"name":"Choremion Laboratory, Research Institute of Maternal and Child Health and Precision Medicine, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleni","family":"Papanikolaou","sequence":"additional","affiliation":[{"name":"Choremion Laboratory, Research Institute of Maternal and Child Health and Precision Medicine, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Kassi","sequence":"additional","affiliation":[{"name":"1st Department of Internal Medicine, School of Medicine, National Kapodistrian University of Athens, Laikon Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1823-6102","authenticated-orcid":false,"given":"Dimitrios","family":"Vlachakis","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3098-5264","authenticated-orcid":false,"given":"George P.","family":"Chrousos","sequence":"additional","affiliation":[{"name":"Choremion Laboratory, Research Institute of Maternal and Child Health and Precision Medicine, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1002\/ajmg.a.63132","article-title":"Nosology of genetic skeletal disorders: 2023 revision","volume":"191","author":"Unger","year":"2023","journal-title":"Am. J. Med. Genet."},{"key":"ref_2","first-page":"214","article-title":"Demystifying Skeletal Dysplasias: A Practical Approach for the Pediatric Endocrinologist","volume":"98","author":"Alves","year":"2025","journal-title":"Horm. Res. Paediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1002\/ajmg.a.33909","article-title":"Nosology and classification of genetic skeletal disorders: 2010 revision","volume":"155","author":"Warman","year":"2011","journal-title":"Am. J. Med. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev-genom-082908-150158","article-title":"Signaling pathways in human skeletal dysplasias","volume":"11","author":"Baldridge","year":"2010","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1146\/annurev.cellbio.042308.113308","article-title":"Genetic control of bone formation","volume":"25","author":"Karsenty","year":"2009","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nature01657","article-title":"Developmental regulation of the growth plate","volume":"423","author":"Kronenberg","year":"2003","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1146\/annurev-genom-090314-045904","article-title":"Advances in Skeletal Dysplasia Genetics","volume":"16","author":"Geister","year":"2015","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3095","DOI":"10.1210\/jc.2013-1505","article-title":"New genes in bone development: What\u2019s new in osteogenesis imperfecta","volume":"98","author":"Marini","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","first-page":"25","article-title":"An unusual presentation of osteogenesis imperfecta type I","volume":"4","author":"Rebelo","year":"2011","journal-title":"Int. Med. Case Rep. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nrg3031","article-title":"Exome sequencing as a tool for Mendelian disease gene discovery","volume":"12","author":"Bamshad","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"36","DOI":"10.21873\/invivo.13052","article-title":"Molecular Mechanisms Involved in Craniosynostosis","volume":"37","author":"Yapijakis","year":"2023","journal-title":"In Vivo"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-3-031-31978-5_16","article-title":"The Impact of Genetic Variability of TGF-Beta Signaling Biomarkers in Major Craniofacial Syndromes","volume":"1423","author":"Yapijakis","year":"2023","journal-title":"Adv. Exp. Med. Biol."},{"doi-asserted-by":"crossref","unstructured":"Paltoglou, G., Ziakas, N., Chrousos, G.P., and Yapijakis, C. (2024). Cephalometric Evaluation of Children with Short Stature of Genetic Etiology: A Review. Children, 11.","key":"ref_13","DOI":"10.20944\/preprints202405.1588.v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e20230040","DOI":"10.1590\/1678-7757-2023-0040","article-title":"Dental anomalies in individuals with osteogenesis imperfecta: A systematic review and meta-analysis of prevalence and comparative studies","volume":"31","author":"Prado","year":"2023","journal-title":"J. Appl. Oral Sci. Rev. FOB"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.bone.2018.06.019","article-title":"Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy","volume":"114","author":"Lindahl","year":"2018","journal-title":"Bone"},{"doi-asserted-by":"crossref","unstructured":"Cui, M., Kanemoto, S., Cui, X., Kaneko, M., Asada, R., Matsuhisa, K., Tanimoto, K., Yoshimoto, Y., Shukunami, C., and Imaizumi, K. (2015). OASIS modulates hypoxia pathway activity to regulate bone angiogenesis. Sci. Rep., 5.","key":"ref_16","DOI":"10.1038\/srep16455"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"123","DOI":"10.7150\/ijms.90189","article-title":"The Regulatory Network of CREB3L1 and Its Roles in Physiological and Pathological Conditions","volume":"21","author":"Zhao","year":"2024","journal-title":"Int. J. Med. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s40246-022-00448-2","article-title":"Regulon active landscape reveals cell development and functional state changes of human primary osteoblasts in vivo","volume":"17","author":"Wang","year":"2023","journal-title":"Hum. Genom."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1210\/endrev\/bnab017","article-title":"Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types","volume":"43","author":"Jovanovic","year":"2022","journal-title":"Endocr. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s13023-020-01361-4","article-title":"Mutations in COL1A1\/A2 and CREB3L1 are associated with oligodontia in osteogenesis imperfecta","volume":"15","author":"Andersson","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"62","DOI":"10.5009\/gnl18261","article-title":"Distinction between chronic enteropathy associated with the slco2a1 gene and crohn\u2019s disease","volume":"13","author":"Yanai","year":"2019","journal-title":"Gut Liver"},{"doi-asserted-by":"crossref","unstructured":"Lu, Q., Xu, Y., Zhang, Z., Li, S., and Zhang, Z. (2023). Primary hypertrophic osteoarthropathy: Genetics, clinical features and management. Front. Endocrinol., 14.","key":"ref_22","DOI":"10.3389\/fendo.2023.1235040"},{"key":"ref_23","first-page":"0013","article-title":"Primary hypertrophic osteoarthropathy due to a novel SLCO2A1 mutation masquerading as acromegaly","volume":"2017","author":"Mangupli","year":"2017","journal-title":"Endocrinol. Diabetes Metab. Case Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101507","DOI":"10.1016\/j.berh.2020.101507","article-title":"Hypertrophic osteoarthropathy","volume":"34","year":"2020","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1002\/jbmr.4310","article-title":"Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy","volume":"36","author":"Xu","year":"2021","journal-title":"J. Bone Min. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"104689","DOI":"10.1016\/j.ejmg.2022.104689","article-title":"Novel pathogenic variants in SLCO2A1 causing autosomal dominant primary hypertrophic osteoarthropathy","volume":"66","author":"Bloch","year":"2023","journal-title":"Eur. J. Med. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1259\/dmfr\/44987850","article-title":"Pyle\u2019s disease: An incidental finding in a routine dental patient","volume":"35","author":"Narayananan","year":"2006","journal-title":"Dentomaxillofacial Radiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"S110","DOI":"10.7196\/SAMJ.2016.v106i6.11011","article-title":"Pyle metaphyseal dysplasia in an African child: Case report and review of the literature","volume":"106","author":"Wonkam","year":"2020","journal-title":"S. Afr. Med. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1056\/NEJMoa1509342","article-title":"Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle\u2019s Disease","volume":"374","author":"Kiper","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s11914-022-00727-w","article-title":"Sfrp4 and the Biology of Cortical Bone","volume":"20","author":"Chen","year":"2022","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_31","first-page":"56","article-title":"Pyle\u2019s Disease: A human model of differentiated cortical and trabecular homeostasis","volume":"16","author":"Arboleya","year":"2020","journal-title":"Reum. Clin. (Engl. Ed.)"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14138","DOI":"10.1073\/pnas.1900881116","article-title":"Sfrp4 repression of the Ror2\/Jnk cascade in osteoclasts protects cortical bone from excessive endosteal resorption","volume":"116","author":"Chen","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.2106\/00004623-200111000-00004","article-title":"Dominant endosteal hyperostosis. Skeletal characteristics and review of literature","volume":"83","author":"Beals","year":"2001","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1128\/MCB.01343-14","article-title":"Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblast","volume":"35","author":"Frey","year":"2015","journal-title":"Mol. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.bone.2017.03.044","article-title":"LRP5: From bedside to bench to bone","volume":"102","author":"Williams","year":"2017","journal-title":"Bone"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"R37","DOI":"10.1186\/ar4466","article-title":"Low-density lipoprotein receptor-related protein 5 governs Wnt-mediated osteoarthritic cartilage destruction","volume":"16","author":"Shin","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.2147\/TCRM.S330530","article-title":"Associations of LRP5 and MTHFR Gene Variants with Osteoarthritis Prevalence in Elderly Women: A Japanese Cohort Survey Randomly Sampled from a Basic Resident Registry","volume":"17","author":"Nakano","year":"2021","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1359\/JBMR.050904","article-title":"Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men","volume":"21","author":"Rivadeneira","year":"2006","journal-title":"J. Bone Min. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5089","DOI":"10.1007\/s00784-022-04540-8","article-title":"Tooth abnormalities associated with non-syndromic cleft lip and palate: Systematic review and meta-analysis","volume":"26","author":"Wambier","year":"2022","journal-title":"Clin. Oral Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1177\/0022034517724149","article-title":"Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis","volume":"97","author":"Dinckan","year":"2018","journal-title":"J. Dent. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41439-021-00162-w","article-title":"A novel LRP6 variant in a Japanese family with oligodontia","volume":"8","author":"Goto","year":"2021","journal-title":"Hum. Genome Var."},{"doi-asserted-by":"crossref","unstructured":"Huang, Y.X., Gao, C.Y., Zheng, C.Y., Chen, X., Yan, Y.S., Sun, Y.Q., Dong, X.Y., Yang, K., and Zhang, D.L. (2021). Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis. Front. Genet., 12.","key":"ref_42","DOI":"10.3389\/fgene.2021.688241"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41525-021-00262-0","article-title":"Rare phenotype: Hand preaxial polydactyly associated with LRP6-related tooth agenesis in humans","volume":"6","author":"Zhang","year":"2021","journal-title":"NPJ Genom. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/871\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:15:32Z","timestamp":1760033732000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/871"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,24]]},"references-count":43,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["genes16080871"],"URL":"https:\/\/doi.org\/10.3390\/genes16080871","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2025,7,24]]}}}