Olmsted syndrome patients can finally put their foot down

By Warren R. Heymann, MD
January 20, 2021
Vol. 3, No. 3

Reading Olmsted’s seminal paper entitled “Keratodermia Palmaris et Plantaris Congenitalis” is captivating reading on multiple levels. In that era of descriptive dermatology, there is an allure in how he differentiates his patient from keratodermas described by the giants of dermatology — Unna, Vörner, Neumann, and others. He recognized that his patient, a 5-year-old Italian boy, had something distinct — a palmoplantar keratoderma associated with hyperkeratotic lesions of the circumoral and circumanal region. He stated: “authors are practically unanimous in maintaining that the hereditary congenital from is incurable.” (1) Dr. Olmsted, it may have taken 93 years, but if you were alive today, you would revel in what has now been accomplished.

(I understand that many DWI&I readers may be asking why they should read about a rare syndrome with an incidence that is literally one-in-a-million. There is a good reason — read on!)

Olmsted syndrome (OS) classically characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and periorificial keratotic plaques; there is also marked clinical heterogeneity. OS usually becomes apparent at birth or in early childhood. The disorder is observed in both sexes, although male cases are more frequent. The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques. According to Duchatelet and Hovnanian: “The diagnosis relies mainly on clinical features associating severe PPK and periorificial keratotic plaques, but can be challenging in patients with incomplete phenotype or atypical features.” Oft associated features include hair and nail abnormalities, leukokeratosis, corneal dystrophy and recurrent infections. Pain and itching are variable but can be severe. Most cases are sporadic, although familial cases with different modes of inheritance were also described. Mutations in the TRPV3 (Transient receptor potential vanilloid-3) gene have been identified as a cause of autosomal dominant (gain-of-function mutations) or recessive OS. Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene were identified in a recessive X-linked form. (2) Interestingly, this latter mutation would explain overlapping features with IFAP (Ichthyosis Follicularis, Atrichia, and Photosensitivity) and Keratosis Follicularis Spinulosa Decalvans. (3) Recently, mutations in PERP have been defined in patients with OS. PERP encodes a p53/p63 tetraspan membrane protein functioning as a desmosome component and an apoptosis mediator. These patients have hair phenotypes ranging from curly blonde hair to alopecia universalis. (4, 5)

Current treatments of OS consist of emollients, keratolytics, retinoids, or corticosteroids offering only minimal benefit. Specific management of pain and itching is important to reduce the morbidity of the disease. Complications of OS result from a progressive keratoderma and auto-amputation of digits, preventing patients from grasping and walking, thereby confining them to a wheelchair.

I encourage you to look at images of the dramatic results utilizing targeted therapy for OS described in the following two articles.

Greco et al explored the possibility of blocking EGFR transactivation with the inhibitor erlotinib hydrochloride to treat PPK in patients with OS due to TRPV3 mutations. This hypothesis is based on the finding that TRPV3 activation is associated with epidermal growth factor receptor (EGFR) signaling through a process of transactivation. 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 because of intense pain and joint restrictions due to hyperkeratosis. All patients were depressed 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. Importantly, the patients resumed social activities. These improvements were sustained over a year 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. (6)

Zhang et al analyzed 4 children (2 boys and 2 girls) with OS. Skin immunostaining indicated 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 only treated with erlotinib and demonstrated rapid and near complete resolution of PPK. All 4 patients had sustained improvements in pruritus and pain. No severe adverse effects were reported. (7)

Aside from the spectacular, life-altering effect on OS patients, the effectiveness of erlotinib on pruritus may have broader implications. Zhao et al demonstrated that TRPV3 and PAR2 were upregulated in skin biopsies from patients and mice with atopic dermatitis (AD), whereas their inhibition attenuated scratching and inflammatory responses in mouse AD models. The authors concluded that these results reveal a previously unrecognized link between TRPV3 and PAR2 in keratinocytes to convey itch information, suggesting that a blockade of PAR2 or TRPV3 individually or both may be potential antipruritic therapy in AD. (8)

Point to Remember: Targeted therapy with the epidermal growth factor inhibitor erlotinib may profoundly improve the lives of patients with Olmsted syndrome. The offshoot of this discovery is that it may open a new therapeutic pathway for atopic dermatitis patients with intractable pruritus.

Our Expert’s Viewpoint

Yuval Ramot, MD, MSc
Associate Professor of Dermatology
Hadassah Medical Center, Hebrew University of Jerusalem, The Faculty of Medicine
Jerusalem, Israel

The huge progress that has been made in the genetic field in recent years, and the possibility to identify the causative gene for many monogenic hereditary conditions using new and relatively accessible genetic tools, have not skipped dermatology. We now know the genes responsible for many monogenic dermatology conditions (9). This information has allowed us to diagnose our patients more accurately and to provide genetic counseling for affected families. The next question that arose is whether we can take advantage of this newly acquired knowledge to treat these hereditary conditions, that for many years were considered incurable. The first option that comes to mind is to try and use gene therapy. The skin is an excellent candidate to try such modalities, being very accessible and therefore simpler for genetic manipulation, and since changes are easily observed in the skin. Gene therapies using gene editing or vector-assisted treatments have indeed been tried, some of them with success, in several hereditary skin conditions (e.g. epidermolysis bullosa, pachyonychia congenita) (10, 11). However, many of these treatments are still experimental, and the development of such treatments encounter many hurdles in their path for clinical implementation.

Maybe a more practical way to circumvent these obstacles is to decipher the underlying mechanisms that stand at the basis of these conditions. This becomes a more feasible approach when the culprit gene is known, and therefore a better understanding of the activated pathway is achievable. It is also possible to use in such cases medications and treatments that are already available on the market. A prominent example is the use of mTOR inhibitors for several genodermatoses, such as tuberous sclerosis complex and the different RASopathies, which were utilized in these conditions based on the proposed activated pathways due to the mutated genes (12). Other examples include the use of JAK inhibitors in CANDLE and SAVI syndromes based on the understanding that these are conditions where interferon is stimulated (therefore also called interferonopathies) (13-15). The finding that TRPV3 mutations can lead to transactivation of EGFR led to the assumption that blocking this receptor can result in symptom amelioration in Olmsted syndrome patients. This has recently been proven in several prominent examples (16, 17), which brings hope to patients worldwide. Unfortunately, this class of medications is still rather expensive, and not easily available for many patients. Hopefully, such treatment approaches will become available for other genetic skin and hair disorders, such as the genetic skin and hair diseases caused by mutations in keratin (18, 19).

1. Olmsted HC. Keratodermia palmaris et plantaris congenitalis: Repot of a case showing associated lesions of unusual location. Am J Dis Child 1927; 33: 757-764.

2. Duchatelet S, Hovnanian A. Olmsted syndrome: Clinical, molecular, and therapeutic aspects. Orphanet J Rare Dis 2015;10:33. doi: 10.1186/s13023-015-0246-5.

3. Nemer G Safi R, Kreidieh F, Usta J, et al. Understanding the phenotypic similarities between IFAP and Olmsted syndrome from a molecular perspective: The interaction of MBTPS2 and TRPV3. Arch Dermatol Res 2017; 309: 637-643.

4. Duchatelet S, Boyden LM, Ishida-Yamamoto A, Zhou J, et al. Mutations in PERP cause dominant and recessive keratoderma. J Invest Dermatol 2019; 139: 380-390.

5. Dai S, Sun Z, Lee M, Wang H, et al. Olmsted syndrome with alopecia universalis caused by heterogeneous mutation in PERP. Br J Dermatol 2020; 182: 242-244.

6. Greco C, Leclerc-Mercier S, Chaumon S, Doz F, et al. Use of epidermal growth factor receptor inhibitor erlotinib to treat palmoplantar keratoderma in patients with Olmsted syndrome caused by TRPV3 mutations. JAMA Dermatol 2020; 156: 191-195.

7. Zhang A, Duchatelet S, Lakdawala N, Tower RL, et al. Targeted inhibition of the epidermal growth factor receptor and mammalian target of rapamycin signaling pathways in Olmsted syndrome. JAMA Dermatol 2020; 156: 196-200.

8. Zhao J, Munanairi A, Liu XY, Zhang J, et al. PAR2 mediates itch via TRPV3 signaling in keratinocytes. J Invest Dermatol 2020; Jan 28 doi: 10.1016/j.jid.2020.01.012. [Epub ahead of print].

9. Ramot Y, Zlotogorski A. Molecular genetics of alopecias. Curr Probl Dermatol. 2015;47:87-96.

10. Bruckner-Tuderman L. Newer Treatment Modalities in Epidermolysis Bullosa. Indian Dermatol Online J. 2019;10(3):244-50.

11. Leachman SA, Hickerson RP, Schwartz ME, Bullough EE, Hutcherson SL, Boucher KM, et al. First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol Ther. 2010;18(2):442-6.

12. Salido-Vallejo R, Garnacho-Saucedo G, Velez A. Elucidation of the mTOR Pathway and Therapeutic Applications in Dermatology. Actas Dermosifiliogr. 2016;107(5):379-90.

13. Jabbari A, Dai Z, Xing L, Cerise JE, Ramot Y, Berkun Y, et al. Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib. EBioMedicine. 2015;2(4):351-5.

14. Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, et al. Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 2012;64(3):895-907.

15. Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128(7):3041-52.

16. Greco C, Leclerc-Mercier S, Chaumon S, Doz F, Hadj-Rabia S, Molina T, et al. Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations. JAMA Dermatol. 2020;156(2):191-5.

17. Zhang A, Duchatelet S, Lakdawala N, Tower RL, Diamond C, Marathe K, et al. Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome. JAMA Dermatol. 2020;156(2):196-200.

18. Ramot Y, Olah A, Paus R. Cover Image: Neuroendocrine treatment of inherited keratin disorders by cannabinoids? Br J Dermatol. 2018;178(6):1469.

19. Ramot Y, Paus R. Harnessing neuroendocrine controls of keratin expression: a new therapeutic strategy for skin diseases? Bioessays. 2014;36(7):672-86.

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