PMID- 31895414 OWN - NLM STAT- MEDLINE DCOM- 20201103 LR - 20211204 IS - 2168-6084 (Electronic) IS - 2168-6068 (Print) IS - 2168-6068 (Linking) VI - 156 IP - 2 DP - 2020 Feb 1 TI - Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome. PG - 196-200 LID - 10.1001/jamadermatol.2019.4141 [doi] AB - 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 Principe, Curitiba in Parana, 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. FAU - Zhang, April AU - Zhang A AD - Department of Dermatology, Medical College of Wisconsin, Milwaukee. FAU - Duchatelet, Sabine AU - Duchatelet S AD - Institut National de la Sante et de la Recherche Medicale, Unite Mixte de Recherche 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France. AD - Paris University, Paris, France. FAU - Lakdawala, Nikita AU - Lakdawala N AD - Ronald O. Perelman Department of Dermatology, New York University, New York. FAU - Tower, Richard L AU - Tower RL AD - Department of Pediatrics (Hematology/Oncology), Medical College of Wisconsin, Milwaukee. FAU - Diamond, Carrie AU - Diamond C AD - The George Washington University School of Medicine and Health Sciences, Division of Hematology/Oncology, Children's National Hospital, Washington, DC. FAU - Marathe, Kalyani AU - Marathe K AD - The George Washington University School of Medicine and Health Sciences, Department of Dermatology, Children's National Hospital, Washington, DC. FAU - Hill, India AU - Hill I AD - Department of Dermatology, University of Alabama at Birmingham, Birmingham. FAU - Richard, Gabriele AU - Richard G AD - GeneDx, Gaithersburg, Maryland. FAU - Diab, Yaser AU - Diab Y AD - The George Washington University School of Medicine and Health Sciences, Division of Hematology/Oncology, Children's National Hospital, Washington, DC. FAU - Kirkorian, Anna Yasmine AU - Kirkorian AY AD - The George Washington University School of Medicine and Health Sciences, Department of Dermatology, Children's National Hospital, Washington, DC. FAU - Watanabe, Flora AU - Watanabe F AD - Pediatric Oncology, Hospital Infantil Pequeno Principe, Curitiba, Parana, Brazil. FAU - Siegel, Dawn H AU - Siegel DH AD - Department of Dermatology and Pediatrics (Pediatric Dermatology), Medical College of Wisconsin, Milwaukee. FAU - Hovnanian, Alain AU - Hovnanian A AD - Institut National de la Sante et de la Recherche Medicale, Unite Mixte de Recherche 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France. AD - Paris University, Paris, France. AD - Department of Genetics, Necker Hospital, Paris, France. LA - eng PT - Case Reports PT - Journal Article PL - United States TA - JAMA Dermatol JT - JAMA dermatology JID - 101589530 RN - 0 (Immunosuppressive Agents) RN - 0 (Protein Kinase Inhibitors) RN - DA87705X9K (Erlotinib Hydrochloride) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM CIN - doi: 10.1001/jamadermatol.2019.4126 MH - Adolescent MH - Brazil MH - Child MH - Child, Preschool MH - ErbB Receptors/antagonists & inhibitors MH - Erlotinib Hydrochloride/*administration & dosage MH - Female MH - Humans MH - Immunosuppressive Agents/administration & dosage MH - Infant MH - Keratoderma, Palmoplantar/*drug therapy/genetics MH - Male MH - Protein Kinase Inhibitors/*administration & dosage MH - Signal Transduction/drug effects MH - Sirolimus/*administration & dosage MH - Syndrome MH - TOR Serine-Threonine Kinases/antagonists & inhibitors MH - Treatment Outcome PMC - PMC6990762 COIS- Conflict of Interest Disclosures: Dr Richard reported receiving payment for genetic testing from GeneDx outside the submitted work. No other disclosures were reported. EDAT- 2020/01/03 06:00 MHDA- 2020/11/04 06:00 PMCR- 2021/01/02 CRDT- 2020/01/03 06:00 PHST- 2020/01/03 06:00 [pubmed] PHST- 2020/11/04 06:00 [medline] PHST- 2020/01/03 06:00 [entrez] PHST- 2021/01/02 00:00 [pmc-release] AID - 2758216 [pii] AID - dbr190008 [pii] AID - 10.1001/jamadermatol.2019.4141 [doi] PST - ppublish SO - JAMA Dermatol. 2020 Feb 1;156(2):196-200. doi: 10.1001/jamadermatol.2019.4141.