In a small case series, investigators used molecular diagnostic techniques to help identify an activating EGFR variant in patients with a novel acanthosis nigricans (AN) syndrome that responded to EGFR-targeting therapies. Resolution of these patients’ skin manifestations and accompanying lung nodule reductions suggested that early identification and treatment of such patients is critical to prevent malignant transformation, according to the authors.

Researchers including co-senior author Keith A. Choate, MD, PhD, enrolled two unrelated patients who presented with severe syndromic AN marked by early-onset generalized keratoderma accentuated at flexural sites, woolly hair, palmoplantar keratoderma, and lung nodules, all in the context of normoglycemia. Choate is Aaron B. and Marguerite Lerner Professor and Chair of Dermatology and professor of genetics and pathology at Yale University in New Haven, Connecticut. The paper was recently published in JAMA Dermatology.

“In this study,” Choate told Medscape Medical News, “we observed patients who had a much more generalized, widespread form of keratoderma that was similar to, but much more dramatic than, classical [AN].” Along with global skin thickening, he explained, these patients — both boys, ages 16 and 8 (patients 1 and 2) — had facial skin laxity, changes in hair texture and morphology, and pulmonary nodules.

Whole-exome sequencing of genomic DNA extracted from these patients’ saliva and blood samples vs those of their unaffected parents revealed that the boys possessed heterozygous de novo gain-of-function mutations in EGFR; specifically, the same L858R mutation that has been observed in lung cancer. Investigators also found the same mutation in a 17-year-old girl (patient 3) with hyperpigmented linear verrucous plaques on the forehead and left leg who had been diagnosed with widespread epidermal nevus. In her case, the variation appeared only in lesional keratinocytes.

Pulmonary Problems

Low-dose chest CT scans of the male patients revealed that both had numerous bilateral ground-glass and solid pulmonary nodules. In patient 1, lung nodule biopsy showed multifocal atypical pneumocyte proliferation consistent with atypical adenomatous hyperplasia. Additionally, next-generation sequencing of tumor tissue detected somatic gene variants including EGFR p.V834L, a second-site mutation which investigators interpreted as a possible precancerous state.

Regarding EGFR activation, immunofluorescence staining of patient 2’s affected skin revealed elevated levels of the downstream EGFR pathway effector phosphorylated RPS6 vs control. Similarly, immunoblotting analyses of lysates from in vitro-differentiated primary keratinocytes from patients 1 and 3 reflected elevated phosphorylation of EGFR, Akt, and ERK1/2.

Muting the Mutation

Turning off the EGFR mutation with targeted therapy using EGFR inhibitors provided substantial improvement for both the male patients. Investigators gave patient 1 osimertinib (Tagrisso), 40 mg daily, after 2 weeks at 20 mg daily. Patient 2 received erlotinib, 3 mg/kg daily. Within 1 month, both patients experienced remission of hypohidrosis, normalization of hyperkeratotic skin, and substantial reduction in hyperpigmentation and palmoplantar keratoderma. Moreover, these patients’ hair became straighter, although not denser. By week 16, patients 1 and 2 achieved complete skin disease remission, persistent through 12 and 6 months, respectively.

As for pulmonary manifestations, serial chest CT scans revealed reductions in the nodule size and number for both patients. At 5 months, for example, patient 1 experienced 72.9% shrinkage in a left lower lobe nodule, with no further changes thereafter.

For patient 3, investigators chose topical trametinib because their previous research showed that most epidermal nevi stemmed from activating RAS mutations, which activate the MEK pathway. However, this treatment only slightly flattened the patient’s facial lesions. Ultimately, Choate reported, topical erlotinib gave the patient much better results.

Going Beyond Skin Deep

The study’s most important lesson, Choate told Medscape Medical News, is that clinicians who see a generalized AN-like phenotype presenting at an early age without classical AN drivers such as metabolic disease should consider that syndromic AN carries potentially significant comorbidity up to and including cancer.

“There are likely patients like this out there in the population who are being seen in routine dermatology practice,” he said. “So it’s very important to consider the possibility that patients who present with this constellation of findings — generalized early skin thickening and changes in hair texture and facial features — as potentially having a syndromic disorder that could be very effectively treated by using targeted therapy,” or potentially lethal if untreated.

The case series, moreover, emphasizes that when dermatologists see a patient with signs of a genetic disorder such as the present one, he said, “it’s important to get all the way to certainty about what’s driving it. This is why we need to be more broadly employing genetic testing in routine dermatology practice.”

For internists, he added, the publication provides an opportunity to recognize the contributions dermatologists can make to diagnosis and therapy. Because patient 1 also presented with impaired exercise tolerance, Choate explained, “it was the combined efforts of a team that included pulmonology, oncology, and dermatology that ultimately decided to initiate therapy. It takes care coordination across specialties to manage and treat syndromic disorders.”

The study was supported by grants from the National Institutes of Health and the National Natural Science Foundation of China. Choate reported being an investigator for AbbVie, Janssen, BioCryst, and Regeneron and a scientific advisor for ResVita Bio.