{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T05:39:10Z","timestamp":1773812350822,"version":"3.50.1"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Acroscyphodysplasia (ASD) is an ultra-rare skeletal dysplasia characterized by severe brachydactyly, metaphyseal scaphoid knee deformities, growth retardation, and intellectual disability. To date, only seven cases of ASD have been reported, all associated with missense variants in the <jats:italic>PDE4D<\/jats:italic> gene. We report a 7-year-old girl with ASD features, including midface hypoplasia, severe growth retardation (\u22124.81 Shwachman\u2013Diamond syndrome (SDS) height), progressive postnatal development of \u201ccup-shaped\u201d knee metaphyses, and unilateral humeral bowing, demonstrating mosaic growth plate involvement. Whole-genome sequencing revealed a novel <jats:italic>PDE4D<\/jats:italic> missense variant (c.934C&amp;gt;T, p. Leu312Phe) in the upstream conserved region 2 (UCR2) autoinhibitory domain, which is distinct from known acrodysostosis-associated variants. Expanding the clinical and radiological characteristics, as well as the mutation spectrum of <jats:italic>PDE4D<\/jats:italic>-related ASD, is crucial for understanding syndrome variability, aiding in earlier detection, and improving recurrence risk assessment.<\/jats:p>","DOI":"10.3389\/fmed.2025.1623593","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T05:27:33Z","timestamp":1755840453000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: The widening genetic and phenotypic spectrum of ultra-rare PDE4D-related acroscyphodysplasia"],"prefix":"10.3389","volume":"12","author":[{"given":"Anna","family":"Morgul","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margarita","family":"Sharova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir","family":"Kenis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Orlova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oxana","family":"Ryzhkova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Markova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2529","DOI":"10.1002\/ajmg.a.36669","article-title":"Acroscyphodysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2","volume":"164","author":"Mitsui","year":"2014","journal-title":"Am J Med Genet A"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1038\/s41431-018-0135-1","article-title":"Expanding the phenotypic spectrum of variants in PDE4D\/PRKAR1A: from acrodysostosis to acroscyphodysplasia","volume":"26","author":"Michot","year":"2018","journal-title":"Eur J Hum Genet"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1111\/j.1399-0004.1991.tb03043.x","article-title":"Metaphyseal acroscyphodysplasia","volume":"39","author":"Verloes","year":"1991","journal-title":"Clin Genet"},{"key":"ref4","first-page":"106","article-title":"Su un caso di disostosi periferica. [A case of peripheral dysostosis.]","volume":"18","author":"Bellini","year":"1966","journal-title":"Minerva Pediatr"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/BF00347374","article-title":"Metaphyseal chondrodysplasia with ectodermal dysplasia","volume":"7","author":"Jequier","year":"1981","journal-title":"Skeletal Radiol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1186\/s12881-020-01127-6","article-title":"Fourteen-year follow-up of a child with acroscyphodysplasia with emphasis on the need for multidisciplinary management: a case report","volume":"21","author":"Kartalias","year":"2020","journal-title":"BMC Med Genet"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"E2328","DOI":"10.1210\/jc.2012-2326","article-title":"PRKAR1A and PDE4D mutations cause Acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance","volume":"97","author":"Linglart","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"145","DOI":"10.3389\/fped.2020.00145","article-title":"GNAS, PDE4D, and PRKAR1A mutations and GNAS methylation changes are not a common cause of isolated early-onset severe obesity among Finnish children","volume":"8","author":"Loid","year":"2020","journal-title":"Front Pediatr"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.cellsig.2015.11.001","article-title":"PDE4D phosphorylation: a coincidence detector integrating multiple signaling pathways","volume":"28","author":"Mika","year":"2016","journal-title":"Cell Signal"},{"key":"ref10","doi-asserted-by":"publisher","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 Med"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1002\/ajmg.a.61174","article-title":"Clinical and molecular spectrum of CHOPS syndrome","volume":"179","author":"Raible","year":"2019","journal-title":"Am J Med Genet A"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/srep17154","article-title":"Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia","volume":"5","author":"Royer-Bertrand","year":"2015","journal-title":"Sci Rep"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1042\/BJ20131681","article-title":"The upstream conserved regions (UCRs) mediate homo-and hetero-oligomerization of type 4 cyclic nucleotide phosphodiesterases (PDE4s)","volume":"459","author":"Xie","year":"2014","journal-title":"Biochem J"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"3883","DOI":"10.1093\/hmg\/ddx271","article-title":"Mutations causing acrodysostosis-2 facilitate activation of phosphodiesterase 4D3","volume":"26","author":"Briet","year":"2017","journal-title":"Hum Mol Genet"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"E1414","DOI":"10.1073\/pnas.1419906112","article-title":"Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4","volume":"112","author":"Cedervall","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1111\/j.1460-9568.2008.06349.x","article-title":"Enhanced long-term potentiation and impaired learning in phosphodiesterase 4D-knockout (PDE4D\u2212\/\u2212) mice","volume":"28","author":"Rutten","year":"2008","journal-title":"Eur J Neurosci"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1055\/s-2003-43259","article-title":"Correlation of Corpus Callosal morphometry with cognitive and motor function in periventricular Leukomalacia","volume":"34","author":"Davatzikos","year":"2003","journal-title":"Neuropediatrics"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1623593\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T05:27:34Z","timestamp":1755840454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1623593\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":17,"alternative-id":["10.3389\/fmed.2025.1623593"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2025.1623593","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,22]]},"article-number":"1623593"}}