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A repurposed cancer drug shows promise for the treatment of a rare but disabling non-malignant disease in children that is characterized by palmoplantar keratoderma (PPK) and periorificial hyperkeratotic plaques, two case series indicated.

In the first, two boys and two girls with the disease, known as and caused by transient receptor potential vanilloid 3 (TRPV3) mutations, demonstrated that treatment with the oral mammalian target of rapamycin (mTOR) inhibitor sirolimus (Rapamune) and/or the epidermal growth factor receptor (EGFR) inhibitor erlotinib (Tarceva) quickly produced substantial clinical improvement in all four children.

Alain Hovnanian, MD, PhD, of Institut National de la Santé et de la Recherche Médicale in Paris, and colleagues reported that two patients initially treated with sirolimus had significant resolution of erythema and periorificial hyperkeratosis. However, resolution of PPK was observed only after the children were switched to erlotinib, the team noted in the study online in .

In the other two patients who were treated with erlotinib alone, there was rapid and near complete resolution of PPK and substantial improvement in Children's Dermatology Life Quality Index .

All four patients (median age of 7) had sustained improvements in pruritus and pain with transient hair loss and acneiform eruptions that responded well to topical medications, and no other adverse events were reported, the researchers said.

"We identified the EGFR-mTOR cascade as a therapeutic target for Olmsted syndrome," they wrote. "Oral sirolimus and erlotinib may be a promising, life-altering treatment for pediatric patients with Olmsted syndrome."

Currently, there is no satisfactory treatment for Olmsted syndrome, the investigators noted, adding that although erlotinib has been used to treat , it has not been used in pediatric patients.

Most cases of Olmsted syndrome result from pathogenic mutations in the TRPV3 gene -- as was the case for all four children in the series. (In the animal model, signaling leads to EGFR transactivation.) Less frequently, Olmsted syndrome can be caused by the MBTPS2 gene.

In the multicenter study, treatments initiated in 2017 and 2018 were received at the Children's Hospital of Wisconsin in Milwaukee, the Children's National Hospital in Washington, D.C., and the Hospital Infantil Pequeno Príncipe, Curitiba in Paraná in Brazil.

In the first two patients -- twin girls -- both had hyperkeratotic plaques on the scalp, which progressed to the periorbital and perioral skin, ears, neck, axillae, and genital area. The girls also had severe erythema on the head and neck and diffuse alopecia. At 6 months of age, both patients developed painful PPK and were treated with oral acitretin (Soriatane), which was then discontinued after 6 months due to lack of improvement.

Immunohistochemical analyses for mTOR and EGFR activation were performed on skin biopsy specimens, the researchers said. Initial treatment with oral sirolimus at a dose of 0.8 mg/m² twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL, resulted in rapid and substantial clinical improvement in erythema and periorificial hyperkeratotic plaques as well as in pruritus and pain scores in both girls. PPK, however, showed no improvement.

The researchers reported that after 9 months, both patients were then switched to erlotinib at 2 mg/kg/d, which resulted in significant improvement in PPK, with the second patient able to start walking within 2 weeks of initiation of erlotinib therapy.

In the third and fourth patients, who were treated with erlotinib alone (administered to all four patients at a dose of 2 mg/kg/d), there was fast, dramatic, and near-complete resolution of skin inflammation and PPK, the study authors said.

Patient 3, a 10-year-old boy, presented with painful PPK on his feet, which had started at 2 years of age. He also had hyperkeratosis of the external auditory canals. Treatment with acitretin 10 to 15 mg daily since the age of 5 had resulted in only limited improvement.

Patient 4, a teenage boy with painful diffuse PPK starting at 2 years of age, had no periorificial hyperkeratosis. He had been treated with acitretin 10 mg daily from the age of 4 with little benefit.

The study authors noted that the study was limited by the absence of a control group and the small number of cases. Also, there were no standardized rating scales for Olmsted syndrome.

"Although the preliminary observations were promising, larger studies with longer follow-up periods can further assess clinical advantages, long-term safety, clinical course after drug discontinuation, and responses in patients with Olmsted syndrome with different mutations," the team wrote.

Second Series

Results from a second case series in three teenagers treated with erlotinib from May 2018 to May 2019 would appear to support the findings. Christine Bodemer, MD, PhD, and Céline Greco, MD, PhD, of Hôpital Necker in Paris, and colleagues, also reporting in , found that erlotinib in doses lower than those used to treat malignant disease could rapidly resolve the clinical manifestations of Olmsted syndrome caused by TRPV3 mutations.

The study included two brothers ages 15 and 17 and an unrelated 13-year-old girl. All presented with debilitating PPK that had progressed since infancy, along with intolerable pain with erythromelalgia, anorexia, insomnia, and severe growth delay. Two patients used a wheelchair and the third used crutches. All were socially isolated and severely depressed, the researchers reported.

After 3 months of therapy with erlotinib, all three patients had resolution of hyperkeratosis and pain, allowing them to wear shoes and walk, the researchers said. Anorexia and insomnia also resolved, and growth improved.

These benefits persisted during 12 months of treatment and follow-up without any major adverse effects, the investigators wrote.

"Targeting EGFR transactivation with erlotinib therapy may result in clinical remission in an orphan disease that lacks an effective intervention. This therapy could be extended to other keratinization disorders with similar pathological mechanisms," the team noted.

Study limitations, the researchers said, included the small number of patients and that the results need to be confirmed by more studies with more patients and other Olmsted syndrome mutations.

"We anticipate that these patients will need to be maintained on erlotinib treatment at the lowest dose that keeps them in remission, as long as no considerable adverse effects are observed," Bodemer, Greco, and co-authors stated.

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