PERP-pEDD (palmoplantar Epidermal Differentiation Disorder)

Also known as Olmsted syndrome

PERP-pEDD is a rare genetic skin condition that causes extremely painful, thickened skin on the palms and soles, along with scaly patches around the mouth, nose, and eyes and in skin folds such as the armpits, breast, and groin.¹ It is caused by variants in the PERP gene (p53 apoptosis effector related to PMP-22), and is a known genetic cause of Olmsted syndrome (OS). Other genetic causes of Olmsted syndrome include variants in MBTPS2 and TRPV3. PERP variants can also cause erythrokeratoderma (EK), a related condition marked by patches of reddened, thick, scaly skin.^2,3 

Biology 

PERP is a protein that helps hold skin cells together at structures called desmosomes.⁴ Desmosomes are the “glue” that keeps the outer layer of skin (the epidermis) intact and able to act as a barrier (Figure 1). 

  

Figure 1. Desmosome in epidermis. Adapted from (Ihrie & Attardi, 2005.⁵ PERP proteins help glue skin cells (indicated in the blue horizonal lines) together and are integral for the scaffolding of skin cells and tissue structure.  

When PERP doesn’t work properly, desmosomes can’t form correctly, and the skin becomes fragile and easily damaged by everyday friction and pressure. In response, the epidermis produces excess skin cells (hyperproliferation), which builds into the thick, painful, yellowish plaques of skin seen on the palms and soles.⁶ Over time, this thickening may spread to the tops of the hands, wrists, and ankles. Other common features include thickened patches around the mouth, nose, and eyes (periorificial plaques), yellow and woolly hair, dental cavities, and abnormal nail growth. Symptoms typically begin in infancy and progress gradually. 

Disclaimer: Signs and symptoms can look different from person to person. The images on this page may not reflect every patient’s experience.

Prevalence 

PERP-pEDD is extremely rare. As of 2026, 2 patients with genetically confirmed PERP-pEDD diagnoses are fully enrolled in our patient registry, though many cases likely go undiagnosed or unreported. In the published medical literature, approximately 85 cases of Olmsted syndrome, including TRPV3, MBTPS2, and PERP, have been described since the condition was first reported in 1927.^7,8 The number of these specifically attributable to PERP variants is much smaller and still being characterized. 

The Recurrence Risk 

Because PERP-pEDD can be inherited in different ways, the chance that a child will also carry a PERP variant depends on the specific genetic variant a patient carries.⁹ Some PERP variants are autosomal dominant (AD), meaning a single altered gene copy is enough to cause the condition; others are autosomal recessive (AR), meaning two altered copies (one inherited from each parent) are needed (Figure 2). 

  

Figure 2. Autosomal dominant (A) and autosomal recessive (B) inheritance patterns. Adapted from (ScienceDirect, n.d.).¹⁰ (A) There is a 50% chance of recurrence. (B) There is a 25% chance of recurrence and a 50% chance of a child being a carrier of the pathogenic variant. 

If you or a family member are considering having children, a genetic counselor can help estimate your specific recurrence risk based on your variant and discuss testing options. 

Treatments 

There is currently no cure for PERP-pEDD. Treatment should always be guided by a physician experienced with the condition. Several options below, particularly oral medications, carry side effects that require medical supervision. Modern treatment focuses on symptom management and skin health, and commonly includes: 

• NSAIDs (nonsteroidal anti-inflammatory drugs), topical lidocaine, and cold-water soaks to help manage pain and discomfort 

• Urea, salicylic acid, and ammonium lactate to help break down plaques on the soles and palms 

• Over-the-counter moisturizers and petrolatum to soften and smooth cracked, rough skin 

• Corticosteroids, which may help reduce local skin inflammation 

• Topical retinoids, which may help slow down hyper-proliferation of skin 

• Oral retinoids and steroids, which may be considered for very severe cases 

• Surgical removal of thickened skin layers in very rare cases, although plaques often return 

Each patient’s experience of PERP-pEDD is unique. A care team spanning multiple specialties, including dermatology, genetics, and pain management, among others, can work together to tailor a treatment plan to each patient’s needs. 

Ongoing Research 

Researchers are exploring new treatment targets for PERP-pEDD. Erlotinib, a targeted cancer medication that inhibits epidermal growth factor receptor (EGFR), has shown promising results in reducing pain and callus buildup in patients with related conditions, including Olmsted syndrome caused by TRPV3 variants and pachyonychia congenita caused by keratin gene (KRT16, KRT6A) variants.^11–13 

A small case series presented in 2023 reported that two patients with PERP-related Olmsted syndrome were treated with erlotinib and experienced reductions in pain and skin thickness.¹⁴ While these early findings are promising, they come from a very small number of patients. Larger, longer-term studies are needed to confirm erlotinib’s safety and effectiveness specifically in the PERP-pEDD population. 

Support Group 

Connecting with other patients and families who experience similar features can be an important source of support, even if they don’t share the same affected gene. Through the PC Project community, patients and loved ones can learn from and support one another and they navigate a challenging skin condition together. Newsletters, virtual and in person patient support meetings, and a private Facebook group offers individuals and families an understanding and compassionate community.  

From a 49-year-old registry patient with PERP-pEDD: 

“I want everyone, in the PC Project group to know I’m very grateful for everything. Seeing and hearing everyone else has already helped me realize I’m not crazy about my pain. Others are describing their pain, and I’m literally crying because they sound just like my issues. Knowing I’m not alone is very big to me.” 

References 

1. Sprecher E, Ishida-Yamamoto A, Schwartz J, et al. Palmoplantar epidermal differentiation disorders: a new classification toward pathogenesis-based therapy. Br J Dermatol. 2025;193(3):364-380. doi:10.1093/bjd/ljaf054 

2. Eytan O, Fuchs-Telem D, Mevorach B, et al. Olmsted Syndrome Caused by a Homozygous Recessive Mutation in TRPV3. J Invest Dermatol. 2014;134(6):1752-1754. doi:10.1038/jid.2014.37 

3. Caengprasath N, Theerapanon T, Porntaveetus T, Shotelersuk V. MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders. J Transl Med. 2021;19(1):114. doi:10.1186/s12967-021-02779-5 

4. Kowalczyk AP, Green KJ. Structure, function, and regulation of desmosomes. Prog Mol Biol Transl Sci. 2013;116:95-118. doi:10.1016/B978-0-12-394311-8.00005-4 

5. Ihrie RA, Attardi LD. A New Perp in the Lineup: Linking p63 and Desmosomal Adhesion. Cell Cycle. 2005;4(7):873-876. doi:10.4161/cc.4.7.1836 

6. Ihrie RA, Marques MR, Nguyen BT, et al. Perp Is a p63-Regulated Gene Essential for Epithelial Integrity. Cell. 2005;120(6):843-856. doi:10.1016/j.cell.2005.01.008 

7. Olmsted HC. KERATODERMIA PALMARIS ET PLANTARIS CONGENITALIS: REPORT OF A CASE SHOWING ASSOCIATED LESIONS OF UNUSUAL LOCATION. Am J Dis Child. 1927;33(5):757. doi:10.1001/archpedi.1927.04130170055008 

8. Frantz T, Kirwin D, Crotty A, Lyford W. Novel TRPV3 loss-of-function mutation in Olmsted syndrome with attenuated phenotype. JAAD Case Rep. 2024;50:4-5. doi:10.1016/j.jdcr.2024.05.013 

9. Duchatelet S, Boyden LM, Ishida-Yamamoto A, et al. Mutations in PERP Cause Dominant and Recessive Keratoderma. J Invest Dermatol. 2019;139(2):380-390. doi:10.1016/j.jid.2018.08.026 

10. Woodis KM, Garlisi Torales LD, Wolf A, Britt A, Sheppard SE. Updates in Genetic Testing for Head and Neck Vascular Anomalies. Oral Maxillofac Surg Clin N Am. 2024;36(1):1-17. doi:10.1016/j.coms.2023.09.001 

11. Basset J, Marchal L, Hovnanian A. EGFR Signaling Is Overactive in Pachyonychia Congenita: Effective Treatment with Oral Erlotinib. J Invest Dermatol. 2023;143(2):294-304.e8. doi:10.1016/j.jid.2022.08.045 

12. Zhang J, Guo M, Yuan D, Wei J, Cui H. Erlotinib therapy for Olmsted syndrome with p.L655P missense mutation in the TRPV3 gene: a case report. Front Med. 2025;12:1512673. doi:10.3389/fmed.2025.1512673 

13. Greco C, Leclerc-Mercier S, Chaumon S, 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. doi:10.1001/jamadermatol.2019.4126 

14. Basset J, Marchal L, Dekeuleneer V, et al. 852 Olmsted syndrome due to PERP mutations shows activation of the EGFR pathway and is improved by oral erlotinib. J Invest Dermatol. 2023;143(5):S146. doi:10.1016/j.jid.2023.03.862