A recent Doximity poll conducted in collaboration with Every Cure surveyed 40 practicing dermatologists on their familiarity with Olmsted syndrome, a rare genetic skin disorder, and erlotinib, an EGFR inhibitor with emerging case-based evidence as a targeted treatment. The poll identified important knowledge gaps in both recognition of Olmsted syndrome and awareness of erlotinib as a potential treatment.
Looking at the Literature
Every Cure, a nonprofit that aims to repurpose drugs, leveraged an AI-powered platform and scientific, clinical, and regulatory expertise to identify erlotinib and prioritize it for further evaluation as a potential treatment for Olmsted syndrome.
Olmsted syndrome is an ultra-rare genodermatosis, with fewer than 100 cases reported in the medical literature. It causes painful, mutilating palmoplantar keratoderma and keratotic plaques around the eyes, mouth, and nose. The disease is progressive and there are currently no FDA-approved treatments. The most common genetic cause is a gain-of-function mutation in TRPV3, resulting in excessive calcium influx in keratinocytes and aberrant activation of the EGFR signaling pathway, which is associated with many of the disease manifestations. Erlotinib, an EGFR inhibitor approved for the treatment of certain cancers, directly blocks this receptor, supporting a strong mechanistic rationale for treating most cases of Olmsted syndrome.
To date, 15 published reports describing at least 29 patients with Olmsted syndrome treated with erlotinib have consistently demonstrated improvements in skin disease, pain, and functional outcomes, including restoration of ambulation in some previously wheelchair-dependent patients. Although these data remain limited to uncontrolled clinical observations and there are currently no prospective clinical trials or guideline recommendations, the consistency of reported responses prompted us to ask whether this emerging evidence had translated into awareness among practicing dermatologists.
We asked dermatologists the following question: Which statement best describes your current knowledge of Olmsted syndrome and its management? The results yielded two knowledge gaps.
Understanding Olmsted Syndrome and Erlotinib
The first and largest gap was disease recognition. More than half — 57% — of community dermatologists reported being unfamiliar with Olmsted syndrome. Because community dermatologists may be the first physicians to evaluate patients with unexplained palmoplantar keratoderma, limited recognition may delay genetic testing, referral to centers with expertise in rare genodermatoses, and consideration of targeted therapies.
Olmsted syndrome should be considered in patients with bilateral transgradient palmoplantar keratoderma accompanied by painful periorificial hyperkeratotic plaques. Supporting findings include nail dystrophy, alopecia, oral leukokeratosis, corneal abnormalities, and pain or pruritus that appears disproportionate to the degree of hyperkeratosis. Although inherited palmoplantar keratodermas can be difficult to distinguish clinically, recognizing these features can prompt confirmatory genetic testing and referral to centers with expertise in rare genodermatoses. As targeted therapies emerge, establishing a molecular diagnosis has direct therapeutic implications.
The second gap was awareness of erlotinib as a potential targeted therapy. While erlotinib remains an off-label treatment, the published literature has steadily expanded over the past decade. Our poll suggests that awareness of this emerging evidence remains limited among practicing dermatologists. As molecular diagnosis increasingly informs treatment decisions, familiarity with the evolving literature may help clinicians counsel patients, facilitate referral to centers with expertise in rare genodermatoses, and identify individuals who may benefit from individualized treatment decisions.
From Olmsted Syndrome to Broader Keratinopathies
Interest in EGFR inhibition now extends beyond Olmsted syndrome. Investigators are launching the first Phase 1/2 clinical trial of low-dose oral erlotinib in genetically confirmed keratinopathies. The trial will enroll adults with epidermolytic ichthyosis, pachyonychia congenita, and epidermolytic palmoplantar keratoderma to evaluate the safety and efficacy of EGFR inhibition across a broader spectrum of genetic skin disorders.
The rationale for this clinical study stems from the clinical experience in Olmsted syndrome. Investigators proposed that aberrant EGFR signaling is a shared downstream pathway across multiple inherited disorders of keratinization and note that erlotinib, first reported as an effective treatment for Olmsted syndrome, has since become the treatment of choice for adults and children with the condition at their institution.
Why This Matters
The results of this poll suggest there is an opportunity to improve awareness of both Olmsted syndrome and the growing body of evidence supporting Erlotinib as a potential treatment. Although Olmsted syndrome is rare, increasing recognition of its characteristic clinical features may facilitate earlier diagnosis, appropriate genetic testing, and referral to centers with expertise in rare genodermatoses. Broader awareness of emerging targeted therapies and the evidence supporting their use may help ensure that patients with rare genetic skin disorders are identified sooner and considered for appropriate treatment options.
Every Cure is a nonprofit biotech organization dedicated to saving and improving lives by repurposing drugs. Founded on pioneering drug repurposing research conducted at the University of Pennsylvania, Every Cure uses advanced data science and AI-driven approaches to systematically evaluate all approved drugs against all diseases. This comprehensive strategy helps uncover the most promising and efficient opportunities for helping people — particularly those with rare, neglected, and underserved conditions. By accelerating drug repurposing, Every Cure aims to deliver safer, faster, and more affordable treatments to patients who currently have limited or no options. For more information, visit everycure.org.
