Research

JAMA Dermatology | Brief Report

Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib

to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome
Caused by TRPV3 Mutations
Céline Greco, MD, PhD; Stéphanie Leclerc-Mercier, MD; Sarah Chaumon, NP; François Doz, MD, PhD;
Smail Hadj-Rabia, MD, PhD; Thierry Molina, MD, PhD; Claude Boucheix, MD; Christine Bodemer, MD, PhD

Related article
IMPORTANCE Olmsted syndrome is a genodermatosis characterized by painful and mutilating Supplemental content
palmoplantar keratoderma (PPK) that progresses from infancy onward and lacks an effective
treatment. It is most often caused by mutations in the transient receptor potential vanilloid 3
(TRPV3) gene. In animal models and keratinocyte cell lines, TRPV3 signaling leads to
epidermal growth factor receptor (EGFR) transactivation.

OBJECTIVE To examine the possibility of blocking EGFR transactivation with the inhibitor
erlotinib hydrochloride to treat PPK in patients with Olmsted syndrome due to TRPV3
mutations.

DESIGN, SETTING, AND PARTICIPANTS In this case series, 3 patients from 2 unrelated families
who had TRPV3-mutation–associated PPK were treated with erlotinib from May 5, 2018,
through May 13, 2019.

MAIN OUTCOMES AND MEASURES Clinical follow-up included evaluation of PPK progression,
pain and interventions for pain, as well as erlotinib dose adjustment based on treatment
effect, plasma levels, and tolerance.

RESULTS The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe
palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay,
anorexia, and insomnia, which had been progressing since infancy despite numerous
therapies. Two patients were confined to wheelchairs owing to intense pain and joint
restrictions because of hyperkeratosis. All patients experienced depression and did not
engage in social activities. Within 3 months of initiating therapy with erlotinib, hyperkeratosis
and pain disappeared. All patients were able to touch the ground with their feet, wear shoes,
and walk. Anorexia and insomnia remitted and paralleled improved growth. In addition, the
patients resumed social activities. These improvements were sustained across 12 months of
treatment and follow-up. The doses of erlotinib used were lower than those used in oncology,
and only mild to moderate adverse effects were noted.

CONCLUSIONS AND RELEVANCE The findings of this study report improvement of PPK in
patients with Olmsted syndrome caused by TRPV3 mutations when treated with erlotinib.
Targeting EGFR transactivation with erlotinib therapy may result in clinical remission in an
orphan disease that lacks an effective intervention.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Christine
Bodemer, MD, PhD, Department of
Dermatology (christine.bodemer@
aphp.fr), and Céline Greco, MD, PhD
(celine.greco@inserm.fr),
Department of Pain and Palliative
Medicine, Hôpital Necker,
JAMA Dermatol. doi:10.1001/jamadermatol.2019.4126 149 Rue de Sèvres, Paris FR-75015,
Published online January 2, 2020. France.

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 Research Brief Report Erlotinib for Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations
O
lmsted syndrome (OS) is a heterogeneous genoder-
matosis characterized by painful and debilitating,
inflammatory palmoplantar keratoderma (PPK), pseu-
doainhum, curved thickened nails, and periorificial hyperker-
atosis. No effective treatment is available, and patients’ qual-
ity of life is considerably altered. Two genes are implicated in
OS: TRPV3 (OMIM 614594), which encodes transient receptor
potential vanilloid 3 (TRPV3),1-3 a temperature-sensitive tran-
sient receptor potential cation channel that is highly ex-
pressed in keratinocytes4-6; and less frequently, MBTPS2
(OMIM 300294), which encodes membrane-bound transcrip-
tion factor protease, site 2.2 The mechanism linking these mu-
tated genes to the disease phenotype has not been fully
elucidated.6
Cheng et al7 showed that TRPV3 activation is associated
with epidermal growth factor receptor (EGFR) signaling
through a process of transactivation,8,9 involving activation
of the membrane protease ADAM17, which cleaves the
membrane precursor of transforming growth factor α
(TGFA), an EGFR ligand. Cheng et al observed that TRPV3
knockout mice had curled whiskers and a perm hair pheno-
type reminiscent of TGFA and EGFR hypomorphic waved-1
and waved-2 mutants.10 These authors also showed that
EGFR activation lowers the TRPV3 activation threshold.
Complementary to these data, genetic studies on mice indi-
cated that EGFR plays an essential role in keratinocyte pro-
liferation and differentiation as well as, more generally, skin
homeostasis.3,10
Because functional studies of several dominant TRPV3 mu-
tations have demonstrated a gain of function,1,3,11 we hypoth-
esized that the signs and symptoms of OS could result from
TRPV3-induced EGFR transactivation. We proposed admin-
istering erlotinib hydrochloride, an EGFR inhibitor, to treat 3
patients12,13 who were debilitated by progressive OS due to
TRPV3 mutations.
Methods
In this case series of a prospective intervention that was not
registered as a clinical trial, erlotinib therapy was started at an
initial dosage of 70 mg/m2/d according to its use in treating
other diseases. The dosage was adjusted based on tolerability
and weight gain. Clinical outcomes were evaluated, includ-
ing blood concentrations of erlotinib at the following times:
monthly during the first 6 months and every 2 months there-
after. The institutional review board of the reference center for
genodermatoses, the MAGEC-Necker Hospital, Paris, ap-
proved the study. Written informed consent was obtained from
the patients’ parents prior to starting therapy.
Results
In this case series, 3 patients (2 brothers aged 15 and 17 years
and a 13-year-old girl from 2 unrelated families) with TRPV3-
mutation–associated PPK, were treated with erlotinib from
May 5, 2018, through May 13, 2019.
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Key Points
Question Can epidermal growth factor receptor transactivation
be targeted with erlotinib, an epidermal growth factor receptor
inhibitor, to treat palmoplantar keratoderma in patients with
Olmsted syndrome caused by transient receptor potential vanilloid
3 (TRPV3) mutations?
Findings In this case report, 3 patients with severe and disabling
Olmsted syndrome caused by TRPV3 mutations experienced
remission of their palmoplantar keratoderma within less than 3
months of initiating therapy with erlotinib hydrochloride.
Hyperkeratosis and pain disappeared, and remission was
sustained with ongoing treatment without major adverse effects.
Meaning This study’s findings suggest that erlotinib targets the
molecular pathogenesis of Olmsted syndrome caused by TRPV3
mutations and may be an effective treatment for painful
hyperkeratosis of this genetic disorder.
Patients 1 and 2 were brothers (Figure 1) and had compound
heterozygous mutations p.Gly568Cys and p.Gln216_Gly262del
in TRPV3.12 Patient 1 (Figure 1A), aged 17 years and profoundly
depressed, had significant focal PPK with erythromelalgia symp-
toms and progressive right ankle deformity. He was confined to
a wheelchair and placed his feet continuously on an ice pack. His
growth and puberty were hindered because of this condition:
weight, 48 kg (z score, −2.3); height, 1.54 m (z score, −2.9); and
Tanner stage 3. Treatments with topical keratolytics, oral reti-
noids, and rapamycin were not effective. Administration of pred-
nisone, 2 mg/kg/d, improved the patient’s pain and keratoderma,
although these conditions relapsed at 1 mg/kg/d. His pain was
constantly rated 7 to 10 on a 10-point visual analog scale, and it
was resistant to opioids. He also had insomnia, loss of autonomy,
and profound depression. A plantar skin biopsy showed strong
phospho–extracellular signal-regulated kinase (ERK) expression
by epidermal cells (Figure 2A and eMethods in the Supplement),
which was not seen in control skin (eFigure in the Supplement),
indicating activation of the ERK/mitogen-activated protein ki-
nase (MAPK) pathway. Erlotinib therapy was initiated at 100 mg/d
and increased to 125 mg/d on day 30. Pain reduced within days,
with near-complete remission of the patient’s keratoderma by
day 90 (Figure 1B). At 12 months, he was no longer depressed,
he had no pain (0 on a 10-point visual analog scale), and pain
treatment was discontinued. The patient was able to walk, wear
shoes, and return to school. His weight was 53 kg (z score, −1.8),
and height, 1.60 m (z score, −2.2). Tanner stage progressed to
stage 5. Adverse effects included a mild acneiform eruption and
moderate diffuse hair loss. Erlotinib blood concentrations var-
ied between 558 ng/mL and 842 ng/mL.
Patient 2 (Figure 1C), aged 15 years, had less painful PPK,
although his symptoms increased progressively until crutches
were needed at age 14 years. Erlotinib therapy was started at 100
mg/d (height, 1.60 m [z score, −1.2]; weight, 39 kg [z score, −2.3])
and was reduced within 7 days to 50 mg/d because of abdomi-
nal pain and nausea that resolved completely. Pain medication
was rapidly discontinued, and hyperkeratosis disappeared within
1 month (Figure 1D). Crutches were no longer necessary. Erlotinib
doses were progressively adapted to the patient’s growth.
His blood concentrations remained under 500 ng/mL. Twelve
jamadermatology.com
 Erlotinib for Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations Brief Report Research

Figure 1. Evolution of Plantar Keratoderma in Patients 1 and 2

A Skin lesions in patient 1 at day 0 B Near complete remission in patient C Skin lesions in patient D Complete
1 at day 90 2 at day 0 remission in
patient 2 at day 90

Figure 2. Phospho–Extracellular Signal-Regulated Kinase (ERK) Labeling Before Erlotinib Treatment in Patients 1 and 3

A Phospho-ERK labeling before erlotinib treatment in patient 1 B Phospho-ERK labeling before erlotinib treatment in patient 3

A, Strong nuclear staining (arrowheads) of numerous keratinocytes in the upper part of the hyperplastic epidermis below a thick parakeratosis area (original
magnification ×100). B, Strong nuclear staining (arrowheads) of numerous keratinocytes in the hyperplastic epidermis (original magnification ×100).

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 Research Brief Report Erlotinib for Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations

Figure 3. Evolution of Palmoplantar Keratoderma (PPK) in Patient 3

A Plantar skin lesions at day 0 B Near complete remission at day 90

C Palmar skin lesions at day 0 D Complete remission at day 90

months later, his height was 1.65 m (z score, −1.1), and weight, 50
kg (z score, −1.2). Adverse effects included localized hair loss and
superficial desquamation of pulp of the fingers and toes that dis-
appeared with dose adjustment.
Patient 3 was a girl, aged 13 years, with a dominant hetero-
zygous missense TRPV3 mutation p.Leu673Phe.13 She was deeply
depressed, had manifestations of erythromelalgia and a consid-
erably large plantar keratoderma (Figure 3A), predominantly on
the right side, and had focal palmar keratoderma (Figure 3C). Her
right leg was a little shorter than the left, with pseudoainhum of
the right toes. Pain and joint restriction confined her to a wheel-
chair. Anorexia and insomnia severely hindered her growth and
puberty as follows: weight, 22 kg (z score, −5.3); height, 1.28 m
(z score, −4.1); and Tanner stage 1. Treatment with topical kera-
tolytics, oral retinoids, topical and oral sirolimus (through 18
months), and oral corticosteroids was ineffective. Pain (5-10 on
a 10-point visual analog scale) was only moderately improved
by the use of high-dose opioids. A skin biopsy specimen showed
strong phospho-ERK expression by epidermal cells (Figure 2B).
Erlotinib therapy was started at 50 mg/d and then increased to
75 mg/d after 1 month. Pain significantly improved within 30
days. Hyperkeratosis disappeared within 90 days (Figure 3B
and D). Pain medications were reduced and discontinued at 2
months. Depression, anorexia, and insomnia disappeared, and
her puberty began at month 4. Within less than 6 months, the
patient was running and wearing shoes. At 12 months, her weight
was 33 kg (z score, −2.7) and height, 1.39 m (z score, −3.27) with
a Tanner stage 4. The pseudoainhum had disappeared and the
toes were distinct, with nails observed. Blood erlotinib concen-
tration remained below 500 ng/mL. The only adverse effect was
a mild diffuse alopecia. For all 3 patients, therapy was continued
through 12 months of follow-up, and clinical remission of symp-
toms persisted.
Discussion
This study’s findings report the disappearance of PPK and pain
in 3 patients diagnosed with OS due to TRPV3 mutations within
less than 3 months of starting erlotinib therapy. In addition, their
anorexia and insomnia resolved, and their growth improved. Only
mild adverse effects were observed, and the benefits persisted
through 12 months of treatment and follow-up. To support these
findings, a 31-year-old woman with disabling OS was treated with

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 Erlotinib for Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations Brief Report Research

erlotinib, starting in 2009 and continuing for 2 years, in addition
to administering oral retinoids and surgical parings to decrease
keratinocyte proliferation. A partial but clear improvement in her
painful PPK was observed.14 However, this patient was not ge-
netically characterized.
This study’s therapeutic approach focused on the gene in-
volved in the patients’ disease. The purpose of using an EGFR
inhibitor was to break the vicious cycle of reciprocal TRPV3/
EGFR activation initiated by constitutive activation of mu-
tated TRPV3. The erlotinib-induced complete remission in the
patients confirmed EGFR’s role as an important mediator of
TRPV3 activity. This finding was in agreement with in vivo/in
vitro experimental observations7 and in situ activation of the
ERK/MAPK pathway observed in these patients. The rapid pain
relief suggested that unidentified mediators secreted by ab-
normal keratinocytes triggered cutaneous nociceptive neuro-
nal receptors.5 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. Treatment resistance, as observed in on-
cology, is not expected because the biological properties of ab-
normal keratinocytes differ from those of malignant cells, usu-
ally resulting from an accumulation of mutations that endow
the cells with invasive growth properties as well as DNA re-
pair and apoptosis defects.15
Limitations
This study has limitations. Additional studies with more pa-
tients and other OS mutations are needed to confirm these
results.
Conclusions
Erlotinib therapy, in lower doses than those used in oncol-
ogy, may be an effective treatment for PPK in patients with OS
caused by TRPV3 mutations. Targeting EGFR transactivation
by drug repurposing leads to considerable remission in pa-
tients with a nonmalignant disease displaying abnormal ke-
ratinocytes proliferation. This therapy could be extended
to other keratinization disorders with similar pathological
mechanisms.

ARTICLE INFORMATION
Accepted for Publication: August 17, 2019.
Published Online: January 2, 2020.
doi:10.1001/jamadermatol.2019.4126
Author Affiliations: Department of Pain and
Palliative Care Unit, Hôpital Necker-Enfants Malades,
Assistance Publique Hôpitaux de Paris (APHP), Paris,
France (Greco, Chaumon); Université Paris Sud,
Université Paris-Saclay, Inserm, UMR-S935, Villejuif,
France (Greco, Boucheix); Department of
Pathology, Hôpital Necker-Enfants Malades, APHP,
Paris, France (Leclerc-Mercier, Molina); Department
of Dermatology, Reference Center for Genoderma-
toses (MAGEC), Hôpital Necker-Enfants Malades,
APHP, Paris, France (Leclerc-Mercier, Hadj-Rabia,
Bodemer); Curie Institute, Oncology Center SIREDO
(Care Innovation Research for Children,
Adolescents, and Young Adults With Cancer), Paris,
France (Doz); The Imagine Institute, U1163, Inserm,
Université Paris Descartes-Sorbonne Paris Cité,
Paris, France (Hadj-Rabia, Bodemer); Université
Paris Descartes-Sorbonne Paris Cité, EA7324, Paris,
France (Molina).
Author Contributions: Drs Greco and Bodemer
had full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Greco, Doz, Boucheix,
Bodemer.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Greco, Boucheix,
Bodemer.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Greco, Boucheix.
Administrative, technical, or material support:
Greco, Leclerc-Mercier, Chaumon, Molina,
Bodemer.
Supervision: Greco, Bodemer.
Conflict of Interest Disclosures: Dr Molina
reported receiving personal fees from Merck outside
the submitted work. No other disclosures were
reported.
Funding/Support: Dr Greco was partially
supported by Ecole de l’Inserm Liliane-Bettencourt
and Fondation Bettencourt-Schueller during this
study. No financial support was used for this study.
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study; collec-
tion, management, analysis, and interpretation of the
data; preparation, review, or approval of the
manuscript; and decision to submit the manuscript
for publication.
Additional Contributions: We sincerely thank the
patients and their families for granting permission to
publish this information. Benoit Blanchet, PharmD,
and Nihel Khoudour, PharmD (Assistance Publique–
Hôpitaux de Paris, Hôpital Cochin, Plateforme
Biologie du Médicament), provided measurements
of erlotinib concentrations; Carole Leclerc, NP
(Department of Pathology), helped in immunohisto-
chemistry; and Nathalia Bellon, MD, Lilia Bekel, MD,
and Isabelle Corset, NP (Departments of Pathology
and Dermatology) helped in patient care. These
contributors were not financially compensated for
their contributions.
Additional Contributions: We thank the patients
for granting permission to publish this information.
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