{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:38:04Z","timestamp":1787614684632,"version":"build-2736575974"},"reference-count":27,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Dermatol"],"published-print":{"date-parts":[[2026,3,1]]},"abstract":"\n Importance<\/jats:title>\n \n Acanthosis nigricans (AN) is commonly associated with impaired glucose tolerance, but early, severe presentation in individuals with normoglycemia may identify individuals at risk for systemic disease. While gain of function epidermal growth factor receptor (\n EGFR<\/jats:italic>\n ) pathogenic variants are associated with pulmonary cancers, their role in syndromic skin disease has not been clearly defined. This study identified activating\n EGFR<\/jats:italic>\n variants that were associated with a syndrome characterized by generalized acquired keratoderma accentuated at flexural sites, woolly hair, palmoplantar keratoderma, and pulmonary disease with lung nodules, and the results suggest\n EGFR<\/jats:italic>\n inhibitor therapeutic efficacy.\n <\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n To determine the genetic basis of early-onset, syndromic AN and assess response to pathogenesis-directed therapy.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n Patients included 2 individuals with normoglycemia with early-onset periorificial hyperpigmentation and flexural skin thickening that subsequently generalized and 1 individual with an original diagnosis of widespread epidermal nevus. Participants underwent whole-exome sequencing and studies of affected skin and keratinocytes.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n EGFR<\/jats:italic>\n variant identification and assessment of pathway activation in lesional skin and keratinocytes, pulmonary function testing, lung imaging, and clinical response to\n EGFR<\/jats:italic>\n inhibition.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n All 3 participants (aged 8, 18, and 17 years; 2 male individuals and 1 female individual) had an\n EGFR L858R<\/jats:italic>\n variant, which arose as either de novo in generalized cases or a somatic variant in mosaic disease. Lesional skin and cultured keratinocytes demonstrated increased\n EGFR<\/jats:italic>\n pathway activity, which was suppressed by pharmacologic inhibition in vitro. Systemic treatment with\n EGFR<\/jats:italic>\n inhibitors was associated with skin disease regression, improvement in pulmonary disease, and resolution or reduction of the number of pulmonary nodules.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n The findings of this case series study define a syndromic disorder with increased risk of pulmonary disease and lung nodules in patients with acquired, generalized AN that is associated with activating\n EGFR<\/jats:italic>\n variants. Pulmonary nodules are precursor lesions for lung cancer, and treatment with EGFR inhibitions is associated with near-complete resolution of skin and pulmonary disease. Early recognition of syndromic\n EGFR<\/jats:italic>\n AN will permit identification of individuals at risk for systemic disease who are candidates for\n EGFR<\/jats:italic>\n -targeted therapy.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamadermatol.2025.5414","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T16:00:48Z","timestamp":1768406448000},"page":"236","source":"Crossref","is-referenced-by-count":2,"title":["De Novo Germline\n L858R EGFR<\/i>\n Variants and Generalized Acanthosis Nigricans"],"prefix":"10.1001","volume":"162","author":[{"given":"Xingyuan","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark Y.","family":"Jeng","sequence":"additional","affiliation":[{"name":"Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Beijing Children\u2019s Hospital, Capital Medical University (National Center for Children\u2019s Health, China), Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson","family":"Ugwu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Peking University First Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Echeandia-Francis","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryland D.","family":"Mortlock","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut"},{"name":"Department of Genetics, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitra V.","family":"Mani","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Rekhtman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna J.","family":"Podolanczuk","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Fiorino","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonology, Weill Cornell Medicine, New York-Presbyterian Phyllis and David Komansky Children\u2019s Hospital, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Plodkowski","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramrada","family":"Lekwuttikarn","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Stanford University School of Medicine, Palo Alto, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Stanford University School of Medicine, Palo Alto, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"Walsh","sequence":"additional","affiliation":[{"name":"Regeneron, Tarrytown, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena A.","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimiao","family":"Lin","sequence":"additional","affiliation":[{"name":"Dermatology Hospital, Southern Medical University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith A.","family":"Choate","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut"},{"name":"Department of Genetics, Yale University School of 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