Also known as Mal de Meleda
SLURP1-pEDD is a rare genetic skin condition that causes palmoplantar keratoderma (PPK) and, in some patients, progressive symmetric erythrokeratoderma (PSEK). Affected skin can appear whitish and diffusely thickened on the palms and soles, sometimes extending to openings on the body such as the mouth. Nail dystrophy and spreading keratoderma are also common. The condition is extremely painful, and patients are at high risk for secondary bacterial and fungal infections. It is caused by variants in the SLURP1 gene (secreted LY6/PLAUR domain containing 1), and is a known genetic cause of an epidermal differentiation disorder formerly known as Mal de Meleda1–3.
Biology
SLURP1 is a protein important for cell-to-cell communication in the skin. It is secreted and can interact with the alpha-7 nicotinic acetylcholine receptor (α7-nAChR), which helps support normal cell growth and apoptosis (cell death)4,5. Loss-of-function variants in SLURP1 can disrupt this regulation, resulting in unchecked epidermal proliferation and hyperkeratosis.
SLURP1 is also found at the endoplasmic reticulum (ER) membrane in palmoplantar epidermal cells, where it interacts with the calcium pump SERCA2b. This interaction helps keep cytosolic calcium levels low, which prevents pressure-driven activation of signaling pathways (such as pPERK-NRF2) that would otherwise trigger hyperproliferation of skin cells6 (Figure 1) . When SLURP1 function is disrupted, it can cause extreme thickening of the skin and dysregulated inflammation.
Figure 1. Murine mouse model of SLURP1 adapted from Di et al. (2025)6. SLURP1 is localized to the endoplasmic reticulum (ER) membrane in the granular layer of the epidermis. In Wildtype (WT) mice, SLURP1 and calcium pump SERCA2b interact to regulate cytosolic calcium levels. Without normal SLUPR1 function, mechanical stress can cause calcium to accumulate in cytosol and promote unregulated epidermal proliferation and inflammation.
Patients with autosomal recessive (AR) SLURP1-pEDD often present with uniformly thickened, yellowish skin covering the entire palms and soles. Palmoplantar skin may break easily and take on a soggy, whitish appearance from prolonged exposure to trapped moisture in fissures. Keratoderma commonly spreads beyond the ankles and wrists. Symptoms typically appear in infancy and progress over time7. Autosomal dominant (AD) SLURP1-pEDD appears to develop distinct palmoplantar plaques without nail dystrophy or extracutaneous symptoms, along with progressive hyperkeratosis in early childhood8.
Disclaimer: Signs and symptoms can look different from person to person. The images on this page may not reflect every patient’s experience.
The Prevalence
SLURP1-pEDD is extremely rare. As of 2026, tw0 patients with genetically confirmed SLURP1-pEDD diagnoses are fully enrolled in our patient registry, though many cases likely go undiagnosed or unreported. In the published medical literature, the condition’s prevalence is most often estimated at approximately 1 in 100,0009, though estimates vary by source and region.
The Recurrence Risk
Because SLURP1-pEDD can be inherited in different ways, the chance that a child will also carry a SLURP1 variant depends on the specific genetic variant a patient carries10,11. The majority of SLURP1 variants are autosomal recessive (AR), meaning two altered copies — one inherited from each parent — are needed to cause the condition. Recently, rare autosomal dominant (AD) variants have also been identified, meaning a single altered copy is enough (Figure 2).
Figure 2. Autosomal dominant (A) and autosomal recessive (B) inheritance patterns. Adapted from Woodis et al. 202412. (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 SLURP1-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:
- Creams with salicylic acid or high urea concentrations to help peel and soften hardened skin on the palms and soles
- Moisturizers and thick emollients to prevent painful drying and splitting
- Aluminum acetate soaks or aluminum chloride to help treat excessive sweating (hyperhidrosis) and reduce moisture and odor
- Oral retinoids, under a doctor’s care, to reduce severe skin thickening
- Antiseptic or antifungal creams to manage secondary microbial overgrowth in skin folds and fissures
- Mechanical debridement or surgical care for severe digital constrictions if movement is impaired
Each patient’s experience of SLURP1-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 SLURP1-pEDD and investigating the differences between AR and AD SLURP1 pathology. Recent work has found that SLURP1 variants associated with AD disease are linked to increased NF-κB signaling in skin cells11, suggesting that pathways which regulate NF-κB activity may be worth exploring as treatment targets. Some researchers have proposed JAK inhibition as one such candidate approach13, though further investigation of the signaling pathways involved in SLURP1-related disease is still needed to confirm this and identify the most promising therapeutic strategies.
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 as they navigate a challenging skin condition together. Newsletters, virtual and in-person patient support meetings, and a private Facebook group offer individuals and families an understanding and compassionate community.
References
1. Arredondo J, Chernyavsky AI, Webber RJ, Grando SA. Biological Effects of SLURP-1 on Human Keratinocytes. J Invest Dermatol. 2005;125(6):1236-1241. doi:10.1111/j.0022-202X.2005.23973.x
2. Fischer J, Bouadjar B, Heilig R, et al. Mutations in the gene encoding SLURP-1 in Mal de Meleda. Hum Mol Genet. 2001;10(8):875-880. doi:10.1093/hmg/10.8.875
3. Favre B, Plantard L, Aeschbach L, et al. SLURP1 is a late marker of epidermal differentiation and is absent in Mal de Meleda. J Invest Dermatol. 2007;127(2):301-308. doi:10.1038/sj.jid.5700551
4. Shulepko MA, Bychkov ML, Shenkarev ZO, et al. Biochemical Basis of Skin Disease Mal de Meleda: SLURP-1 Mutants Differently Affect Keratinocyte Proliferation and Apoptosis. J Invest Dermatol. 2021;141(9):2229-2237. doi:10.1016/j.jid.2021.01.035
5. Chimienti F. Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda. Hum Mol Genet. 2003;12(22):3017-3024. doi:10.1093/hmg/ddg320
6. Di R, Du Q, Xie Y, et al. A mechano-resistance mechanism in skin adapts to terrestrial locomotion. Cell. 2025;188(21):5797-5808.e16. doi:10.1016/j.cell.2025.07.012
7. 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
8. Takeichi T, Hsu CK. Expanding the SLURP1 disease spectrum: from Mal de Meleda to palmoplantar keratoderma/progressive symmetric erythrokeratoderma. Br J Dermatol. 2025;192(5):793-793. doi:10.1093/bjd/ljaf059
9. Perez C, Khachemoune A. Mal de Meleda: A Focused Review. Am J Clin Dermatol. 2016;17(1):63-70. doi:10.1007/s40257-015-0157-1
10. Wang T, Tang Z, Xiao T, et al. Identification of a novel compound heterozygous mutation and a homozygous mutation of SLURP1 in Chinese families with Mal de Meleda. BMC Med Genomics. 2023;16(1):152. doi:10.1186/s12920-023-01580-1
11. Jiang X, Mortlock RD, Lomakin IB, et al. Autosomal dominant SLURP1 variants cause palmoplantar keratoderma and progressive symmetric erythrokeratoderma. Br J Dermatol. 2025;192(5):896-906. doi:10.1093/bjd/ljaf049
12. 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
13. Chernyavsky AI, Arredondo J, Galitovskiy V, Qian J, Grando SA. Upregulation of nuclear factor-kappaB expression by SLURP-1 is mediated by alpha7-nicotinic acetylcholine receptor and involves both ionic events and activation of protein kinases. Am J Physiol Cell Physiol. 2010;299(5):C903-911. doi:10.1152/ajpcell.00216.2010
