{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:36:30Z","timestamp":1791999390167,"version":"4.4.0"},"reference-count":32,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T00:00:00Z","timestamp":1630627200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Primary lymphedema, a rare disease, has a genetic cause in ~40% of patients. Recently, loss\u2010of\u2010function mutations in <jats:italic>PIEZO1<\/jats:italic>, which encodes the mechanotransducer protein PIEZO1, were described as causing primary lymphedema, when gain\u2010of\u2010function <jats:italic>PIEZO1<\/jats:italic> mutations were attributed to dehydrated hereditary stomatocytosis type\u20101 (DHS), a dominant red cell hemolytic disorder, with ~20% of patients having perinatal edema. Lymphedema was diagnosed in a 36\u2010year\u2010old man from a three\u2010generation DHS family, with a <jats:italic>PIEZO1\u2010<\/jats:italic>allele harboring 3 missense mutations in <jats:italic>cis<\/jats:italic>. Four affected family members had severe fetal and neonatal edema, most severe in the proband, whose generalized edema with prevailing ascites resolved after 8\u2009months. Our patient's intermittent lower limb\u2010lymphedema episodes during hot periods appeared at puberty; they became persistent and bilateral at age 32. Clinical Stemmer's sign confirmed lymphedema. Lower leg lymphoscintigraphy showed substantial dermal backflow in both calves, predominantly on the right. Noncontrast magnetic resonance lymphography showed bilateral lower limb lymphedema, dilated dysplastic lymphatic iliac, and inguinal trunks. Exome\u2010sequencing analysis identified no additional pathogenic variation in primary lymphedema\u2010associated genes. This is the first description of well\u2010documented lymphedema in an adult with PIEZO1\u2013DHS. The pathophysiology of <jats:italic>PIEZO1<\/jats:italic>\u2010associated primary lymphedema is poorly understood. Whether it infers overlapping phenotypes or different mechanisms of gain\u2010 and loss\u2010of\u2010function <jats:italic>PIEZO1<\/jats:italic> mutations deserves further investigation.<\/jats:p>","DOI":"10.1002\/ajmg.a.62476","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T09:57:46Z","timestamp":1630663066000},"page":"243-248","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<scp><i>PIEZO1<\/i><\/scp>\u2010gene gain\u2010of\u2010function mutations with lower limb lymphedema onset in an adult: Clinical, scintigraphic, and noncontrast magnetic resonance lymphography findings"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6745-1469","authenticated-orcid":false,"given":"St\u00e9phane","family":"Vignes","sequence":"first","affiliation":[{"name":"Unit\u00e9 de Lymphologie, Centre de R\u00e9f\u00e9rence des Maladies Vasculaires Rares 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