{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T07:51:39Z","timestamp":1781596299353,"version":"3.54.5"},"reference-count":14,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinics and Practice"],"abstract":"<jats:p>Background: Pycnodysostosis is a rare autosomal recessive skeletal disorder caused by biallelic pathogenic variants in CTSK, which encodes cathepsin K, a lysosomal cysteine protease required for osteoclast-mediated degradation of bone matrix. Case Report: We describe a girl with short stature, skeletal deformities, osteosclerosis, craniofacial features, clavicular dysplasia, and radiological evidence of fractures. Clinical exome sequencing identified two heterozygous CTSK variants, c.85T &gt; C (p.Trp29Arg) and c.679A&gt;T (p.Ile227Phe), both currently classified as variants of uncertain significance. Segregation analysis showed that the variants were inherited in trans. Computational modeling and in silico prediction tools supported a possible deleterious effect on cathepsin K structure or function. Serum cathepsin K was higher in the patient than in two age-matched controls; this result is reported as an exploratory observation only. Increased serum cathepsin K may reflect altered expression, secretion, clearance, or accumulation of dysfunctional protein, but cannot be interpreted as proof of compensatory upregulation. Conclusions: The patient\u2019s clinical and radiographic features, the biallelic trans configuration of the CTSK variants, their rarity in population databases, and computational predictions support p.Trp29Arg and p.Ile227Phe as strong candidate disease-associated variants. Functional studies are required to confirm their effect on cathepsin K expression, maturation, and enzymatic activity.<\/jats:p>","DOI":"10.3390\/clinpract16060115","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:46:28Z","timestamp":1781588788000},"page":"115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pycnodysostosis: Report of Two Novel CTSK Variants in a Child"],"prefix":"10.3390","volume":"16","author":[{"given":"Daniela","family":"Trotta","sequence":"first","affiliation":[{"name":"Department of Pediatrics, S. Spirito Hospital, Azienda Sanitaria Pescara, 65124 Pescara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9416-2523","authenticated-orcid":false,"given":"Rossella","family":"Ferrante","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2555-3571","authenticated-orcid":false,"given":"Michele","family":"Sallese","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Viele","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0949-0280","authenticated-orcid":false,"given":"Claudia","family":"Rossi","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Science, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Scorrano","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Savelli","sequence":"additional","affiliation":[{"name":"Imaging Department, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Catenaro","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, S. Spirito Hospital, Azienda Sanitaria Pescara, 65124 Pescara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"De Laurenzi","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1908-6671","authenticated-orcid":false,"given":"Maurizio","family":"Aric\u00f2","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, S. Spirito Hospital, Azienda Sanitaria Pescara, 65124 Pescara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1126\/science.273.5279.1236","article-title":"Pycnodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature, maps to chromosome 1q21","volume":"273","author":"Gelb","year":"1996","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1006\/geno.1997.4631","article-title":"Structure and chromosomal assignment of the human cathepsin K gene","volume":"41","author":"Gelb","year":"1997","journal-title":"Genomics"},{"key":"ref_3","unstructured":"Franklin by Genoox (2026, May 21). CTSK Gene Variant Interpretation Database. 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Rare Dis."}],"container-title":["Clinics and Practice"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-7283\/16\/6\/115\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T06:53:14Z","timestamp":1781592794000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-7283\/16\/6\/115"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":14,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["clinpract16060115"],"URL":"https:\/\/doi.org\/10.3390\/clinpract16060115","relation":{},"ISSN":["2039-7283"],"issn-type":[{"value":"2039-7283","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]}}}