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Brief Report
January 2, 2020

Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome

Author Affiliations
  • 1Department of Dermatology, Medical College of Wisconsin, Milwaukee
  • 2Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France
  • 3Paris University, Paris, France
  • 4Ronald O. Perelman Department of Dermatology, New York University, New York
  • 5Department of Pediatrics (Hematology/Oncology), Medical College of Wisconsin, Milwaukee
  • 6The George Washington University School of Medicine and Health Sciences, Division of Hematology/Oncology, Children's National Hospital, Washington, DC
  • 7The George Washington University School of Medicine and Health Sciences, Department of Dermatology, Children's National Hospital, Washington, DC
  • 8Department of Dermatology, University of Alabama at Birmingham, Birmingham
  • 9GeneDx, Gaithersburg, Maryland
  • 10Pediatric Oncology, Hospital Infantil Pequeno Príncipe, Curitiba, Paraná, Brazil
  • 11Department of Dermatology and Pediatrics (Pediatric Dermatology), Medical College of Wisconsin, Milwaukee
  • 12Department of Genetics, Necker Hospital, Paris, France
JAMA Dermatol. Published online January 2, 2020. doi:10.1001/jamadermatol.2019.4141
Key Points

Question  Does inhibiting the epidermal growth factor receptor and mammalian target of rapamycin signaling pathways have therapeutic utility in Olmsted syndrome?

Findings  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.

Meaning  Findings from this study suggest that oral sirolimus and erlotinib may represent a novel, promising, and well-tolerated therapy for Olmsted syndrome.

Abstract

Importance  Olmsted syndrome is a rare and disabling genodermatosis for which no successful treatment is currently available.

Objective  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.

Exposures  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.

Results  Four patients (mean [SD] age, 7 [6] 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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