{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T02:02:05Z","timestamp":1783389725978,"version":"3.54.6"},"reference-count":22,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,24]],"date-time":"2021-01-24T00:00:00Z","timestamp":1611446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>We report an extremely rare case of combined classical and periodontal Ehlers\u2212Danlos syndrome (EDS) with early severe periodontitis and a generalized lack of attached gingiva. A German family with classical EDS was investigated by physical and dental evaluation and exome and Sanger sequencing. Due to the specific periodontal phenotype in the affected child, an additional diagnosis of periodontal EDS was suspected. Physical and genetic examination of two affected and three unaffected family members revealed a family diagnosis of classical EDS with a heterozygous mutation in COL5A1 (c.1502del; p.Pro501Leufs*57). Additional to the major clinical criteria for classical EDS\u2014generalized joint hypermobility, hyperelastic skin, and atrophic scarring \u2014the child aged four years presented with generalized alveolar bone loss up to 80%, early loss of two lower incisors, severe gingival recession, and generalized lack of attached gingiva. Due to these clinical findings, an additional diagnosis of periodontal EDS was suspected. Further genetic analysis revealed the novel missense mutation c.658T&gt;G (p.Cys220Gly) in C1R in a heterozygous state. Early severe periodontitis in association with generalized lack of attached gingiva is pathognomonic for periodontal EDS and led to the right clinical and genetic diagnosis in the present case.<\/jats:p>","DOI":"10.3390\/biom11020149","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T02:07:00Z","timestamp":1611540420000},"page":"149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Prepubertal Periodontitis in a Patient with Combined Classical and Periodontal Ehlers\u2013Danlos Syndrome"],"prefix":"10.3390","volume":"11","author":[{"given":"Friedrich","family":"Stock","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University Hospital M\u00fcnster, Vesaliusweg 12, D-48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Hanisch","sequence":"additional","affiliation":[{"name":"Research Unit Rare Diseases with Orofacial, Manifestations (RDOM), Department of Cranio-Maxillofacial Surgery, University Hospital M\u00fcnster, Albert-Schweitzer-Campus 1, Building W 30, D-48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Lechner","sequence":"additional","affiliation":[{"name":"Praxis f\u00fcr Humangenetik T\u00fcbingen, Paul-Ehrlich-Stra\u00dfe 23, D-72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Biskup","sequence":"additional","affiliation":[{"name":"Praxis f\u00fcr Humangenetik T\u00fcbingen, Paul-Ehrlich-Stra\u00dfe 23, D-72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Bohring","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital M\u00fcnster, Vesaliusweg 12, D-48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0046-8274","authenticated-orcid":false,"given":"Johannes","family":"Zschocke","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr-Stra\u00dfe 1, A-6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6169-6812","authenticated-orcid":false,"given":"Ines","family":"Kapferer-Seebacher","sequence":"additional","affiliation":[{"name":"Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Anichstra\u00dfe 35, A-6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 international classification of the Ehlers-Danlos syndromes","volume":"175","author":"Malfait","year":"2017","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1111\/cge.13683","article-title":"COL1-related overlap disorder: A novel connective tissue disorder incorporating the osteogenesis imperfecta\/Ehlers-Danlos syndrome overlap","volume":"97","author":"Morlino","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.ajhg.2018.02.018","article-title":"Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome","volume":"102","author":"Blackburn","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/ajmg.1320290316","article-title":"International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986","volume":"29","author":"Beighton","year":"1988","journal-title":"Am. J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/(SICI)1096-8628(19980428)77:1<31::AID-AJMG8>3.0.CO;2-O","article-title":"Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK)","volume":"77","author":"Beighton","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.ajhg.2016.08.019","article-title":"Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement","volume":"99","author":"Pepin","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kapferer-Seebacher, I., Oakley-Hannibal, E., Lepperdinger, U., Johnson, D., Ghali, N., Brady, A.F., Sobey, G.J., Zschocke, J., and Van Dijk, F.S. (2020). Prospective clinical investigations of children with periodontal Ehlers\u2013Danlos syndrome identify generalized lack of attached gingiva as a pathognomonic feature. Genet. Med.","DOI":"10.1038\/s41436-020-00985-y"},{"key":"ref_8","first-page":"2537","article-title":"C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome","volume":"5","author":"Amberger","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.smim.2013.04.004","article-title":"Role of complement in host-microbe homeostasis of the periodontium","volume":"25","author":"Hajishengallis","year":"2013","journal-title":"Semin. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Isola, G., Polizzi, A., Patini, R., Ferlito, S., Alibrandi, A., and Palazzo, G. (2020). Association among serum and salivary A. actinomycetemcomitans specific immunoglobulin antibodies and periodontitis. BMC Oral Health, 20.","DOI":"10.1186\/s12903-020-01258-5"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.dci.2018.05.023","article-title":"The complement component 1 q (C1q) in Nile tilapia (Oreochromis niloticus): Functional characterization in host defense against bacterial infection and effect on cytokine response in macrophages","volume":"87","author":"Chen","year":"2018","journal-title":"Dev. Comp. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104997","DOI":"10.1016\/j.archoralbio.2020.104997","article-title":"Identification of the different salivary Interleukin-6 profiles in patients with periodontitis: A cross-sectional study","volume":"122","author":"Isola","year":"2020","journal-title":"Arch. Oral Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S171","DOI":"10.1111\/jcpe.12947","article-title":"Manifestations of systemic diseases and conditions that affect the periodontal attachment apparatus: Case definitions and diagnostic considerations","volume":"45","author":"Albandar","year":"2018","journal-title":"J. Clin. Periodontol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1111\/jcpe.12988","article-title":"A Chinese family with periodontal Ehlers-Danlos syndrome associated with missense mutation in the C1R gene","volume":"45","author":"Wu","year":"2018","journal-title":"J. Clin. Periodontol."},{"key":"ref_15","first-page":"9","article-title":"The key role of the dental practitioner in early diagnosis of periodontal Ehlers-Danlos syndromes: A rare case report of siblings","volume":"51","author":"Brinkmann","year":"2020","journal-title":"Quintessence Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10048-018-0560-x","article-title":"Periodontal Ehlers-Danlos syndrome is associated with leukoencephalopathy","volume":"20","author":"Waisfisz","year":"2019","journal-title":"Neurogenetics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1111\/jcpe.12807","article-title":"Periodontal manifestations of Ehlers-Danlos syndromes: A systematic review","volume":"44","author":"Lundberg","year":"2017","journal-title":"J. Clin. Periodontol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/j.1600-0714.1992.tb01031.x","article-title":"Ehlers Danlos syndrome type I with novel dental features","volume":"21","author":"Pope","year":"1992","journal-title":"J. Oral Pathol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1308\/135576111797512793","article-title":"Ehlers-Danlos syndrome (classic type): Report of a case presenting with an unusual dental anomaly","volume":"18","author":"Cho","year":"2011","journal-title":"Prim. Dent. Care"},{"key":"ref_20","first-page":"5","article-title":"Dental Findings and Mutational Analysis of a Case with Ehlers-Danlos Syndrome","volume":"2","author":"Hakki","year":"2017","journal-title":"J. Dent. Oral Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hanisch, M., Hoffmann, T., Bohner, L., Hanisch, L., Benz, K., Kleinheinz, J., and Jackowski, J. (2019). Rare Diseases with Periodontal Manifestations. Int. J. Environ. Res. Public Health, 16.","DOI":"10.3390\/ijerph16050867"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"39636","DOI":"10.1038\/srep39636","article-title":"Ehlers-Danlos syndrome hypermobility type is associated with rheumatic diseases","volume":"7","author":"Rodgers","year":"2017","journal-title":"Sci. Rep."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/2\/149\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:14:48Z","timestamp":1760159688000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/2\/149"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,24]]},"references-count":22,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["biom11020149"],"URL":"https:\/\/doi.org\/10.3390\/biom11020149","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,24]]}}}