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

• Authors: April Zhang, Sabine Duchatelet, Nikita Lakdawala, Richard L Tower, Carrie Diamond, Kalyani Marathe, India Hill, Gabriele Richard, Yaser Diab, Anna Yasmine Kirkorian, Flora Watanabe, Dawn H Siegel, Alain Hovnanian
• Journal: JAMA dermatology (JAMA Dermatol) Vol. 156 Issue 2 Pg. 196-200 (02 01 2020) ISSN: 2168-6084 [Electronic] United States
• PMID: 31895414 (Publication Type: Case Reports, Journal Article)

Chemical References

• Immunosuppressive Agents
• Protein Kinase Inhibitors
• Erlotinib Hydrochloride
• MTOR protein, human
• EGFR protein, human
• ErbB Receptors
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adolescent
• Brazil
• Child
• Child, Preschool
• ErbB Receptors (antagonists & inhibitors)
• Erlotinib Hydrochloride (administration & dosage)
• Female
• Humans
• Immunosuppressive Agents (administration & dosage)
• Infant
• Keratoderma, Palmoplantar (drug therapy, genetics)
• Male
• Protein Kinase Inhibitors (administration & dosage)
• Signal Transduction (drug effects)
• Sirolimus (administration & dosage)
• Syndrome
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Treatment Outcome