{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T14:01:47Z","timestamp":1784901707078,"version":"3.55.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Piezo2 channels are mechanosensors expressed in dorsal root ganglia and Merkel cells, and involved in proprioception and touch sensation. PIEZO2 pathogenic variants cause rare autosomal dominant and recessive disorders. Dominant forms include distal arthrogryposis type 3, 5, and Marden-Walker syndrome, whereas the recessive form corresponds to distal arthrogryposis with impaired proprioception and touch (DAIPT). Given the rarity of these conditions, additional reports are essential to refine their phenotypic characterization.<\/jats:p>\n                  <jats:p>We conducted a multicenter, retrospective study to identify patients with genetically confirmed PIEZO2-related disorders. We collected clinical data through a standardized assessment. Previously published cases were included when more detailed phenotypic information was available.<\/jats:p>\n                  <jats:p>We identified 44 individuals with a clinical diagnosis of PIEZO2-related disorders. Among them, we selected 42 patients with a confirmed molecular diagnosis. Sixteen of them (10 males and 6 females; median age at diagnosis: 8 years; range 0.9-14) carried biallelic pathogenic PIEZO2 variants. They typically presented with neonatal hypotonia and respiratory distress with feeding difficulties. Distal arthrogryposis was associated with a variable multisystemic involvement, including the musculoskeletal system with scoliosis, hip dislocation and laryngomalacia. Twenty-five patients (11 males and 14 females; median age at diagnosis: 7 years; range 0.3-39 years) carried monoallelic variants, exhibiting a broad phenotypic spectrum. An additional prenatal diagnosis (at 23 weeks of gestation) was reported among heterozygous cases. In our cohort, ten previously unpublished causative variants were identified. A systematic assessment of skeletal muscle involvement revealed a severe myofibrillar disarray in one case.<\/jats:p>\n                  <jats:p>This study provides a comprehensive and systematic phenotypic characterization of patients across the spectrum of PIEZO2-related disorders. Our findings support a clear clinical distinction between recessive and dominant forms. The clinical manifestations extend beyond the peripheral nervous system and the Merkel cells, suggesting a broader PIEZO2 tissue expression during early developmental stages. Dominant PIEZO2-related disorders are heterogeneous, ranging from mild to severe forms. Our study also suggests that many patients exhibit a respiratory involvement, emphasizing the need for regular respiratory follow-up in the long-term clinical management of both dominant and recessive forms.<\/jats:p>","DOI":"10.1093\/brain\/awag249","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T12:06:30Z","timestamp":1784721990000},"source":"Crossref","is-referenced-by-count":0,"title":["Beyond distal arthrogryposis: refining the phenotypic landscape of\n                    <i>PIEZO2<\/i>\n                    -related disorders"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0454-2464","authenticated-orcid":false,"given":"Giuliana","family":"Capece","sequence":"first","affiliation":[{"name":"PhD Program in Translation Specialistic Medicine \u201cG.B. Morgagni\u201d, Curriculum \u201cClinical and Translational Neurosciences, University of Padova , 35122 Padova ,","place":["Italy"]},{"name":"Department of Neurosciences, DNS, University of Padova , 35121 Padova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Francesca","family":"Di Feo","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center , 00290 Helsinki ,","place":["Finland"]},{"name":"Department of Medical and Clinical Genetics, Medicum, University of Helsinki , 00014 Helsinki ,","place":["Finland"]},{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (DINOGMI), University of Genova , 16126 Genova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeniya","family":"Melnik","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics , 115522 Moscow ,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Dadali","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics , 115522 Moscow ,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Markova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics , 115522 Moscow ,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Verloes","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique, H\u00f4pital Robert Debr\u00e9, AP-HP Paris Nord , 75019 Paris , , ERN ITHACA","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Ruscitti","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique, H\u00f4pital Robert Debr\u00e9, AP-HP Paris Nord , 75019 Paris , , ERN ITHACA","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"L\u00e9vy","sequence":"additional","affiliation":[{"name":"Genetics Department, Robert Debr\u00e9 University Hospital, AP-HP Paris Nord , 75019 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Natera-de Benito","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]},{"name":"Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]},{"name":"Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII , 28029 Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Ortez","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]},{"name":"Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Nascimiento","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]},{"name":"Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]},{"name":"Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII , 28029 Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1711-7489","authenticated-orcid":false,"given":"Berta","family":"Estevez-Arias","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]},{"name":"Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]},{"name":"Genomics Unit \u2013 NGS, Diagnostic Laboratory Service, Hospital Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Jou","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]},{"name":"Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de D\u00e9u , 08950 Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei","family":"Kurbatov","sequence":"additional","affiliation":[{"name":"Research Institute of Experimental Biology and Medicine, Voronezh State Medical University N.N. Burdenko , 394036 Voronezh ,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysylu","family":"Murtazina","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics , 115522 Moscow ,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artem","family":"Sharkov","sequence":"additional","affiliation":[{"name":"Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University , 125412 Moscow ,","place":["Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour","family":"Elkhateeb","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust , Cambridge CB2 3EH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walaa","family":"ElNaggar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Neurology and Metabolic Medicine Unit, Kasr Al-Ainy School of Medicine, Cairo University , 4390330 Cairo ,","place":["Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"Faletra","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC) , 33100 Udine ,","place":["Italy"]},{"name":"Department of Medicine, University of Udine , 33100 Udine ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catia","family":"Mio","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine , 33100 Udine ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Schymick","sequence":"additional","affiliation":[{"name":"Santa Clara Valley Medical Center , San Jose, CA 95128 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige","family":"Calvert","sequence":"additional","affiliation":[{"name":"Santa Clara Valley Medical Center , San Jose, CA 95128 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasemin","family":"Alanay","sequence":"additional","affiliation":[{"name":"Division of Pediatric Genetics, Department of Pediatrics, Acibadem University, School of Medicine , 34457 Istanbul ,","place":["Turkey"]},{"name":"Rare Diseases and Orphan Drugs Application and Research Center-ACURARE, Acibadem University , 34457 Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0657-2408","authenticated-orcid":false,"given":"Esra","family":"Isik","sequence":"additional","affiliation":[{"name":"Ege University Faculty of Medicine, Department of Pediatric Genetics , 35100 Izmir ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berkay","family":"Y\u0131ld\u0131z","sequence":"additional","affiliation":[{"name":"School of Medicine, Acibadem Mehmet Ali Aydinlar University , 34752 Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somayeh","family":"Bakhtiari","sequence":"additional","affiliation":[{"name":"Barrow Neurological Institute, Phoenix Children's , Phoenix, 85013 Arizona ,","place":["USA"]},{"name":"Department of Child Health, University of Arizona College of Medicine \u2013 Phoenix , Phoenix, AZ 85004 ,","place":["USA"]},{"name":"Department of Cellular & Molecular Medicine, University of Arizona College of Medicine \u2013 Phoenix , Phoenix, AZ 85004 ,","place":["USA"]},{"name":"Department of Neurology, University of Arizona College of Medicine \u2013 Phoenix , Phoenix, AZ 85004 ,","place":["USA"]},{"name":"Program in Genetics, University of Arizona College of Medicine \u2013 Phoenix , Phoenix, AZ 85004 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C","family":"Kruer","sequence":"additional","affiliation":[{"name":"Barrow Neurological Institute, Phoenix Children's , Phoenix, 85013 Arizona ,","place":["USA"]},{"name":"Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children's Hospital , Phoenix, AZ 85016 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Neurology with Heimer Institute for Muscle Research, University Hospital Bergmannsheil , 44789 Bochum ,","place":["Germany"]},{"name":"Department of Paediatric Neurology, Center for Neuromuscular Disorders in Children and Adolescents, University Clinic Medicine , 45147 Essen ,","place":["Germany"]},{"name":"Brain and Mind Research Institute, Children's Hospital of Eastern Ontario Research Institute , Ottawa, ON, K1H 8L1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9629-7053","authenticated-orcid":false,"given":"Heike","family":"K\u00f6lbel","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, Center for Neuromuscular Disorders in Children and Adolescents, University Clinic Medicine , 45147 Essen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossein","family":"Darvish","sequence":"additional","affiliation":[{"name":"Nikagene Genetic Diagnostic Laboratory , Gorgan ,","place":["Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohreh","family":"Vosoogh","sequence":"additional","affiliation":[{"name":"Clinical Research Development Unit (CRDU), Sayad Shirazi Hospital, Golestan University of Medical Sciences , Gorgan ,","place":["Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliane","family":"Chouery","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University , Byblos P.O. Box 36 ,","place":["Lebanon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cybel","family":"Mehawej","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University , Byblos P.O. Box 36 ,","place":["Lebanon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"M\u00e9garban\u00e9","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University , Byblos P.O. Box 36 ,","place":["Lebanon"]},{"name":"Institut Jerome Lejeune , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Andoni Urtizberea","sequence":"additional","affiliation":[{"name":"Institut de Myologie , 75013 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henriette V F","family":"Senghor","sequence":"additional","affiliation":[{"name":"Neurology Department, Centre Hospitalier National Universitaire de Fann , BP 5035, Dakar ,","place":["Senegal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moustapha","family":"Ndiaye","sequence":"additional","affiliation":[{"name":"Neurology Department, Centre Hospitalier National Universitaire de Fann , BP 5035, Dakar ,","place":["Senegal"]},{"name":"Universit\u00e9 Cheikh Anta Diop de Dakar , BP 5005, Dakar ,","place":["Senegal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro M","family":"Rodriguez Cruz","sequence":"additional","affiliation":[{"name":"Neurology Department, Centre Hospitalier National Universitaire de Fann , BP 5035, Dakar ,","place":["Senegal"]},{"name":"Universit\u00e9 Cheikh Anta Diop de Dakar , BP 5005, Dakar ,","place":["Senegal"]},{"name":"Centro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG) , 08028 Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3075-6525","authenticated-orcid":false,"given":"Luca","family":"Bello","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, DNS, University of Padova , 35121 Padova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7740-4156","authenticated-orcid":false,"given":"Elena","family":"Pegoraro","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, DNS, University of Padova , 35121 Padova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjarne","family":"Udd","sequence":"additional","affiliation":[{"name":"Tampere University Hospital, Tampere Neuromuscular Center , Pirkanmaa, 33101 Tampere \u00a0","place":["Finland"]},{"name":"Vaasa Central Hospital , Ostrobothnia, 65130 Vaasa ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2591-244X","authenticated-orcid":false,"given":"Marco","family":"Savarese","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center , 00290 Helsinki ,","place":["Finland"]},{"name":"Department of Medical and Clinical Genetics, Medicum, University of Helsinki , 00014 Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,24]]},"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag249\/69941633\/awag249.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag249\/69941633\/awag249.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T13:08:26Z","timestamp":1784898506000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/advance-article\/doi\/10.1093\/brain\/awag249\/8741303"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/brain\/awag249","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]},"article-number":"awag249"}}