{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:47:14Z","timestamp":1790286434988,"version":"4.1.0"},"reference-count":16,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T00:00:00Z","timestamp":1682640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Calvarial doughnut lesions (CDL) with bone fragility with or without spondylometaphyseal dysplasia (MIM: #126550) is a rare autosomal dominant skeletal disorder characterized by low bone mineral density, spinal and peripheral fractures, and specific sclerotic lesions of the cranial bones. In the current classification of skeletal disorders, the disease is included in the group of bone fragility disorders along with osteogenesis imperfecta. The disease is caused by pathogenic variants in the SGMS2 gene, the protein product of which is sphingomyelin synthase 2, which primarily contributes to sphingomyelin (SM) synthesis\u2014the main lipid component of the plasma membrane essential for bone mineralization. To date, 15 patients from eight families with CDL with bone fragility have been described in the literature, and a recurrent variant c.148C&gt;T (p.Arg50Ter) in the SGMS2 gene has been identified, which was found in patients from six families. We diagnosed the disease in 11 more patients from three unrelated families, caused by the same heterozygous nonsense variant c.148C&gt;T (p.Arg50Ter) in the SGMS2 gene. Our results show wide interfamilial and intrafamilial phenotypic variability in patients with a detected recurrent variant in the SGMS2 gene, the presence of which must be taken into consideration in the diagnosis of the disease. The primary analysis of this variant will contribute to optimal molecular genetic diagnostics, which can reduce diagnostic costs and time.<\/jats:p>","DOI":"10.3390\/ijms24098021","type":"journal-article","created":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T10:51:52Z","timestamp":1682679112000},"page":"8021","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Clinical and Genetic Characteristics of Calvarial Doughnut Lesions with Bone Fragility in Three Families with a Reccurent SGMS2 Gene Variant"],"prefix":"10.3390","volume":"24","author":[{"given":"Elena","family":"Merkuryeva","sequence":"first","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2672-6294","authenticated-orcid":false,"given":"Tatiana","family":"Markova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0841-3024","authenticated-orcid":false,"given":"Anton","family":"Tyurin","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Bashkir State Medical University, 450008 Ufa, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Valeeva","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Bashkir State Medical University, 450008 Ufa, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Kenis","sequence":"additional","affiliation":[{"name":"The Turner Scientific Research Institute for Children\u2019s Orthopedics, 196603 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2883-4029","authenticated-orcid":false,"given":"Maria","family":"Sumina","sequence":"additional","affiliation":[{"name":"State Healthcare Institution of Sverdlovsk Region \u201cClinical and Diagnostic Center \u201cMother\u2019s and Child Health Protection\u201d, 620067 Ekaterinburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Sorokin","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4905-1303","authenticated-orcid":false,"given":"Olga","family":"Shchagina","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7293-3438","authenticated-orcid":false,"given":"Mikhail","family":"Skoblov","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Nefedova","sequence":"additional","affiliation":[{"name":"Independent Clinical Bioinformatics Laboratory, 123181 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8643-850X","authenticated-orcid":false,"given":"Rita","family":"Khusainova","sequence":"additional","affiliation":[{"name":"Laboratory of Human Molecular Genetics, Institute of Biochemistry and Genetics, 450000 Ufa, Russia"},{"name":"Healthy Longevity Center, Ufa University of Science and Technology, 450008 Ufa, Russia"},{"name":"Medical Genetics Department, Bashkir State Medical University, 450008 Ufa, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Zakharova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Dadali","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Kutsev","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"314","DOI":"10.2214\/ajr.105.2.314","article-title":"The calvarial \u201cdoughnut lesion\u201d: A previously undescribed entity","volume":"105","author":"Keats","year":"1969","journal-title":"Am. J. Roentgenol. Radium Ther. Nucl. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1148\/119.2.385","article-title":"Familial \u201cdoughnut\u201d lesions of the skull. A benign, hereditary dysplasia","volume":"119","author":"Bartlett","year":"1976","journal-title":"Radiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/s002560050167","article-title":"Fragile bone syndrome associated with craniognathic fibro-osseous lesions and abnormal modeling of the tubular bones: Report of two cases and review of the literature","volume":"25","author":"Nishimura","year":"1996","journal-title":"Skelet. Radiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e126180","DOI":"10.1172\/jci.insight.126180","article-title":"Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2","volume":"4","author":"Pekkinen","year":"2019","journal-title":"JCI Insight"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4205","DOI":"10.1128\/MCB.05893-11","article-title":"Reducing plasma membrane sphingomyelin increases insulin sensitivity","volume":"31","author":"Li","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.bbalip.2013.12.003","article-title":"The role of sphingomyelin and sphingomyelin synthases in cell death, proliferation and migration-from cell and animal models to human disorders","volume":"1841","author":"Taniguchi","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"115261","DOI":"10.1016\/j.bone.2020.115261","article-title":"Musculoskeletal phenotype in two unrelated individuals with a recurrent nonsense variant in SGMS2","volume":"134","author":"Robinson","year":"2020","journal-title":"Bone"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e10537","DOI":"10.1002\/jbm4.10537","article-title":"Abnormal bone tissue organization and osteocyte lacunocanalicular network in early-onset osteoporosis due to SGMS2 mutations","volume":"5","author":"Blouin","year":"2021","journal-title":"JBMR Plus"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1002\/1096-8628(2001)9999:9999<::AID-AJMG1154>3.0.CO;2-0","article-title":"Calvarial \u2018doughnut lesions\u2019: Clinical spectrum of the syndrome, report on a case, and review of the literature","volume":"99","author":"Baumgartner","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3174\/ng.3130058","article-title":"Calvarial lesions and pseudolesions: Diff erential diagnosis and pictorial review of pathologic entities presenting with focal calvarial abnormalities","volume":"3","author":"Lerner","year":"2013","journal-title":"Neurographics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1007\/s13244-018-0643-0","article-title":"Radiological review of skull lesions","volume":"9","author":"Gomez","year":"2018","journal-title":"Insights Imaging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"dev192948","DOI":"10.1242\/dev.192948","article-title":"A developmental stage-specific network approach for studying dynamic co-regulation of transcription factors and MicroRNAs during craniofacial development","volume":"147","author":"Yan","year":"2020","journal-title":"Development"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"189","DOI":"10.2220\/biomedres.40.189","article-title":"Knockdown of sphingomyelin synthase 2 inhibits osteoclastogenesis by decreasing RANKL expression in mouse primary osteoblasts","volume":"40","author":"Yoshikawa","year":"2019","journal-title":"Biomed. Res."},{"key":"ref_14","first-page":"CD005088","article-title":"Bisphosphonate therapy for osteogenesis imperfecta","volume":"10","author":"Dwan","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1002\/ajmg.a.33040","article-title":"Calvarial doughnut lesions and osteoporosis: A new three-generation family and review","volume":"149","author":"Jaakkola","year":"2009","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. 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