Does inhibiting the epidermal growth factor receptor and mammalian target of rapamycin signaling pathways have therapeutic utility in Olmsted syndrome?
In this case series of 4 children with Olmsted syndrome, skin biopsies performed in 2 patients revealed increased activation of mammalian target of rapamycin signaling and epidermal growth factor receptor signaling. After treatment with oral sirolimus and/or erlotinib, all 4 patients showed substantial clinical and symptomatic improvement.
Findings from this study suggest that oral sirolimus and erlotinib may represent a novel, promising, and well-tolerated therapy for Olmsted syndrome.
Olmsted syndrome is a rare and disabling genodermatosis for which no successful treatment is currently available.
To evaluate the clinical response to the mammalian target of rapamycin (mTOR) inhibitor sirolimus and/or the epidermal growth factor receptor (EGFR) inhibitor erlotinib among patients with Olmsted syndrome.
Design, Setting, and Participants
This case series focused on 4 children with treatment-refractory Olmsted syndrome. These children received treatments (initiated in 2017 and 2018) at the outpatient dermatology clinic at the Children’s Hospital of Wisconsin in Milwaukee, Wisconsin; Children’s National Hospital in Washington, DC; and Hospital Infantil Pequeno Príncipe, Curitiba in Paraná, Brazil.
Immunohistochemical analyses for mTOR and EGFR activation were performed on skin biopsy specimens from 2 patients. Oral sirolimus was administered to these 2 patients at a dosage of 0.8 mg/m2 twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL. Erlotinib was administered to all 4 patients at a dosage of 2 mg/kg/d.
Main Outcomes and Measures
Clinical responses were assessed with visual analog scales for pruritus and pain and/or the Children’s Dermatology Life Quality Index. Adverse effects were monitored throughout treatment.
Four patients (mean [SD] age, 7  years; 2 boys and 2 girls) were analyzed. Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation. Patients 1 and 2 were initially treated with sirolimus, displaying substantial clinical improvement in erythema and periorificial hyperkeratosis afterward. When switched to erlotinib, these patients showed substantial palmoplantar keratoderma (PPK) improvement. Patients 3 and 4 were treated with erlotinib only and later showed rapid and near complete resolution of PPK and substantial improvement in Children’s Dermatology Life Quality Index scores. All 4 patients had sustained improvements in pruritus and pain. No severe adverse effects were reported.
Conclusions and Relevance
This study’s findings suggest that the EGFR-mTOR cascade may play a substantial role in the pathophysiological process of Olmsted syndrome and may serve as a major therapeutic target. Oral sirolimus and erlotinib may be a promising, life-altering treatment for pediatric patients with Olmsted syndrome.
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Zhang A, Duchatelet S, Lakdawala N, et al. Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome. JAMA Dermatol. 2020;156(2):196–200. doi:10.1001/jamadermatol.2019.4141
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