{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T02:26:01Z","timestamp":1766975161594,"version":"3.48.0"},"reference-count":17,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,12]]},"abstract":"ABSTRACT<\/jats:title>\n \n Chondrocalcinosis (CCAL), also known as calcium pyrophosphate dihydrate deposition disease (CPPDD), is a frequent multifactorial condition in the elderly, but there are two rare autosomal dominant Mendelian forms, CCAL1 (OMIM %600668) and CCAL2. Only three families with molecularly proven CCAL1 have been reported. Here, we describe an additional family from Germany (12 individuals, nine living) with CPPDD manifesting in the third decade of life, presenting with severe spinal problems and variable levels of disability, only two of them with hip problems. The mildly impaired growth in this family (median height at age 20: 10th percentile) may represent an as yet undescribed sign of CCAL1, or alternatively familial short stature. In all documented families and in this family, the disorder resulted from the recurrent heterozygous stop\u2010loss variant NM_002546.4:c.1205A>T; p.(Ter402Leuext*19) in\n TNFRSB11B<\/jats:italic>\n on chromosome 8q24, which predicts an extended osteoprotegerin protein with 19 additional amino acid residues. The pathomechanism of CCAL1 is not known. Biallelic\n TNFRSF11B<\/jats:italic>\n loss\u2010of\u2010function variants cause autosomal recessive juvenile Paget's disease of bone (PDB5); shared features between CCAL1 and PDB5 include demineralization, osteoporosis, increased fractures, and a progressive height loss with age, but PDB5 and CCAL1 have very different phenotypes and heterozygous carriers of PDB5\u2010associated variants are asymptomatic. Summing up, NM_002546.4:c.1205A>T represents a rare type of stop\u2010lost variant, likely a gain\u2010of\u2010function variant, and to date no other variant is known to cause CCAL1. Our findings expand the phenotypic spectrum of CCAL1 and underscore that CCAL1 is a distinct rare Mendelian disorder for which the underlying molecular basis is now known.\n <\/jats:p>","DOI":"10.1002\/ajmg.a.64185","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T09:54:56Z","timestamp":1753869296000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Further Evidence That Chondrocalcinosis 1 (\n CCAL1<\/scp>\n ) is a Confirmed Mendelian Phenotype With a Known Molecular Basis"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4692-4188","authenticated-orcid":false,"given":"Anna\u2010Christina","family":"Pansa","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mareike","family":"Selig","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Wingendorf","sequence":"additional","affiliation":[{"name":"Orthopedic Medical Practice Kirchen\/Sieg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0538-8211","authenticated-orcid":false,"given":"Matthew A.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine King's College London London UK"},{"name":"Genomics England London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6329-696X","authenticated-orcid":false,"given":"Oliver","family":"Bartsch","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical Care Center University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1086\/302186"},{"key":"e_1_2_9_3_1","first-page":"692","article-title":"Linkage of Early\u2010Onset Osteoarthritis and Chondrocalcinosis to Human Chromosome 8q","volume":"56","author":"Baldwin C. T.","year":"1995","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_9_4_1","first-page":"19","article-title":"A Mutation in the Gene TNFRSF11B Encoding Osteoprotegerin Causes an Idiopathic Hyperphosphatasia Phenotype","volume":"21","author":"Cundy T.","year":"2002","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_9_5_1","first-page":"97","article-title":"Crystal Deposition Disease in the Elderly","volume":"12","author":"Doherty M.","year":"1986","journal-title":"Clinical Rheumatology"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.49.7.528"},{"volume-title":"NM_002546.4(TNFRSF11B):c.1205A>T","year":"2025","author":"GnomAD","key":"e_1_2_9_7_1"},{"key":"e_1_2_9_8_1","first-page":"263","article-title":"Synovianalysis: An Aid in Arthritis Diagnosis","volume":"12","author":"Hollander J. L.","year":"1961","journal-title":"Bulletin on the Rheumatic Diseases"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/4.7.1225"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41678"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1086\/343054"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-205149"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keac232"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1511117"},{"key":"e_1_2_9_15_1","first-page":"2103","volume-title":"Calcium Pyrophosphate Crystal Deposition Disease, Pseudogout, and Articular Chondrocalcinosis","author":"Ryan L. M.","year":"1997"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2018.03.005"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1086\/343053"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.139105"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.64185","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T02:23:08Z","timestamp":1766974988000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.64185"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":17,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/ajmg.a.64185"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.64185","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"type":"print","value":"1552-4825"},{"type":"electronic","value":"1552-4833"}],"subject":[],"published":{"date-parts":[[2025,7,30]]},"assertion":[{"value":"2025-03-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e64185"}}