Skip to content
How It Works
Explore
Resources Ask a Question
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Ask a Question
PubMed This is a summary of 17 peer-reviewed journal articles Updated
Dermatology

The Science of EPPK: Genetics and Diagnosis

At a Glance

Epidermolytic palmoplantar keratoderma (EPPK) is caused by mutations in the KRT9 or KRT1 genes, which destabilize the skin's structural proteins. Genetic testing is the gold standard for diagnosis, as it confirms the mutation and rules out conditions with serious heart or hearing risks.

Understanding the biology of Epidermolytic palmoplantar keratoderma (EPPK) helps explain why the skin behaves the way it does. While the outward symptoms are visible on the skin, the cause is found deep within the structural “scaffolding” of the skin cells [1][2].

The Blueprint: Genes and Keratin

Your skin relies on proteins called keratins to stay strong and flexible. In EPPK, there is a mutation (a typo in the genetic code) in either the KRT9 or KRT1 genes [1][3].

  • The Scaffolding: Think of keratins as the steel beams in a skyscraper. They form a network of “intermediate filaments” that hold skin cells together [2].
  • The “Dominant-Negative” Effect: Most EPPK cases are autosomal dominant. In this context, a dominant-negative effect means that the faulty keratin protein doesn’t just “not work”—it actually actively interferes with the healthy keratin protein produced by your other, normal gene [4][5]. It’s like one bent steel beam making the entire structural frame of the building unstable.
  • Differences in Location: While KRT9 mutations usually restrict symptoms exclusively to the hands and feet, KRT1 mutations can occasionally cause mild symptoms, like general skin fragility, on other parts of the body [1][6].

What the Pathologist Sees

When a doctor performs a biopsy (taking a small sample of skin), a pathologist looks at it under a microscope. In EPPK, they look for a specific pattern called epidermolytic hyperkeratosis [7][8]:

  1. Vacuolar Degeneration: The cells in the middle and upper layers of the skin appear to have “holes” or bubbles in them (vacuoles) because the internal scaffolding has collapsed [7][6].
  2. Granular Changes: The skin’s “granular layer” becomes abnormally thick, with large, irregular clumps of protein [7].
  3. Hyperkeratosis: To compensate for the internal fragility, the body over-produces the outermost layer of skin, leading to the thick, yellowed appearance you see on the palms and soles [1][9].

The Reassurance of Genetic Testing

Because many different skin conditions can cause thickened palms and soles, Whole Exome Sequencing (WES) or targeted genetic panels are now considered the gold standard for diagnosis [10][11]. Genetic testing is empowering because it provides certainty.

Certain very rare conditions can mimic the thick skin of EPPK on the surface but carry serious systemic risks, such as cardiomyopathy (a heart condition caused by DSP gene mutations) or hearing loss (from GJB2 gene mutations) [12][13]. Importantly, once genetic testing confirms that your symptoms are caused by a KRT9 or KRT1 mutation, these serious heart and hearing risks are ruled out. Testing is done precisely to eliminate these worries and provide peace of mind.

Recent Scientific Insights

Scientists have recently discovered that variations in the DSP C-terminal domain can mimic EPPK symptoms [12][14]. This area of the protein is responsible for anchoring the “scaffolding” to the cell’s “glue” (desmosomes) [15]. If this anchor is weak, the skin reacts similarly to a KRT9 mutation, but the heart might also be at risk [16][17]. This discovery highlights why a “genotype-first” approach—starting with a genetic test—is so important for modern medical care to rule out these rare outliers [16].

Back to Starting Your Journey with EPPK

Common questions in this guide

What genes cause Epidermolytic palmoplantar keratoderma (EPPK)?
EPPK is typically caused by a mutation in either the KRT9 or KRT1 genes. These genes provide the instructions for creating keratin proteins, which act as the essential structural scaffolding for your skin cells.
What does a dominant-negative mutation mean in EPPK?
A dominant-negative effect means that the faulty keratin protein actively interferes with the healthy protein produced by your normal gene. This causes the structural frame of the skin cells to become unstable, leading to fragility and thickening.
What does a pathologist look for on an EPPK skin biopsy?
Under a microscope, a pathologist looks for a specific pattern called epidermolytic hyperkeratosis. This includes vacuolar degeneration (which looks like holes or bubbles in the cells), abnormal clumping in the granular layer, and a severely thickened outer layer of skin.
Why is genetic testing recommended for thickened skin on the hands and feet?
Genetic testing provides a definitive diagnosis and, most importantly, rules out other rare genetic conditions that mimic EPPK. Some mimicking conditions carry serious systemic risks, like heart muscle disease or hearing loss, which genetic testing can definitively eliminate as concerns.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Does my child's mutation specifically affect the KRT9 or KRT1 gene?
  2. 2.Given the results of the genetic test, have we completely ruled out risks to the heart or hearing?
  3. 3.What does the 'dominant-negative' nature of this mutation mean for future children in our family?
  4. 4.On the biopsy report, did the pathologist see 'vacuolar degeneration' or 'granular layer' changes?
  5. 5.Are there any newer research findings regarding DSP gene variations that we should be aware of?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (17)
  1. 1

    Keratin 9 L164P mutation in a Chinese pedigree with epidermolytic palmoplantar keratoderma, cytokeratin analysis, and literature review.

    Liu X, Qiu C, He R, et al.

    Molecular genetics & genomic medicine 2019; (7(11)):e977 doi:10.1002/mgg3.977.

    PMID: 31525823
  2. 2

    Genetic lessons learned from pathogenic variants in KRT1.

    Betz RC

    Journal of the European Academy of Dermatology and Venereology : JEADV 2022; (36(10)):1683-1684 doi:10.1111/jdv.18510.

    PMID: 36106438
  3. 3

    A novel mutation of KRT9 gene in a Chinese Han pedigree with epidermolytic palmoplantar keratoderma.

    Chen N, Sun J, Song Y, et al.

    Journal of cosmetic dermatology 2017; (16(3)):402-406 doi:10.1111/jocd.12263.

    PMID: 27726289
  4. 4

    Interleukin-18 as a severity marker and novel potential therapeutic target for epidermolytic ichthyosis.

    Ansai O, Miyauchi T, Hayashi R, et al.

    Clinical and experimental dermatology 2023; (48(3)):199-210 doi:10.1093/ced/llac069.

    PMID: 36656063
  5. 5

    A Small Indel Mutant Mouse Model of Epidermolytic Palmoplantar Keratoderma and Its Application to Mutant-specific shRNA Therapy.

    Lyu YS, Shi PL, Chen XL, et al.

    Molecular therapy. Nucleic acids 2016; (5()):e299 doi:10.1038/mtna.2016.17.

    PMID: 27003758
  6. 6

    Nonsense mutations in KRT1 caused recessive epidermolytic palmoplantar keratoderma with knuckle pads.

    Mo R, Lin M, Lee M, et al.

    Journal of the European Academy of Dermatology and Venereology : JEADV 2022; (36(10)):1857-1862 doi:10.1111/jdv.18189.

    PMID: 35490383
  7. 7

    Epidermolytic Hyperkeratosis in an Epidermoid (Infundibular) Cyst.

    Prestwood CA, Vandergriff T

    The American Journal of dermatopathology 2022; (44(3)):215-217 doi:10.1097/DAD.0000000000002098.

    PMID: 34966043
  8. 8

    A p.478I>T KRT1 mutation in a case of annular epidermolytic ichthyosis.

    Zaki TD, Yoo KY, Kassardjian M, Choate KA

    Pediatric dermatology 2018; (35(6)):e414-e415 doi:10.1111/pde.13643.

    PMID: 30152556
  9. 9

    Exome sequencing identifies a KRT9 pathogenic variant in a Chinese pedigree with epidermolytic palmoplantar keratoderma.

    Li C, Chen P, Sun S, et al.

    Molecular genetics & genomic medicine 2019; (7(7)):e00703 doi:10.1002/mgg3.703.

    PMID: 31074163
  10. 10

    De Novo Mutation in KRT1 Leads to Epidermolytic Palmoplantar Keratoderma: from Chinese Traditional Treatment to Prenatal Diagnosis Using Whole-Exome Sequencing-Plus.

    Ge M, Ji C, Li H, Huang H

    DNA and cell biology 2023; (42(10)):645-652 doi:10.1089/dna.2023.0154.

    PMID: 37566479
  11. 11

    Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders.

    Kim MJ, Yum MS, Seo GH, et al.

    Journal of clinical medicine 2020; (9(11)) doi:10.3390/jcm9113724.

    PMID: 33233562
  12. 12

    A frameshift variation in the DSP gene causes a novel subtype of atypical epidermolytic palmoplantar keratoderma: Case report.

    Lin C, Chen H, Lai S, et al.

    Frontiers in medicine 2025; (12()):1728762 doi:10.3389/fmed.2025.1728762.

    PMID: 41601798
  13. 13

    Clinical and Genetic Findings in Patients With Palmoplantar Keratoderma.

    Gram SB, Brusgaard K, Lei U, et al.

    JAMA dermatology 2025; (161(2)):157-166 doi:10.1001/jamadermatol.2024.4824.

    PMID: 39630431
  14. 14

    A novel heterozygous missense mutation of DSP in a Chinese Han pedigree with palmoplantar keratoderma.

    Xue K, Zheng Y, Cui Y

    Journal of cosmetic dermatology 2019; (18(1)):371-376 doi:10.1111/jocd.12533.

    PMID: 29607617
  15. 15

    How ARVC-Related Mutations Destabilize Desmoplakin: An MD Study.

    Daday C, Mateyka LM, Gräter F

    Biophysical journal 2019; (116(5)):831-835 doi:10.1016/j.bpj.2019.01.023.

    PMID: 30773294
  16. 16

    Desmoplakin-associated palmoplantar epidermal differentiation disorder: a distinct phenotype and red flag for cardiomyopathy.

    Brandt E, Heliö K, Harjama L, et al.

    Clinical and experimental dermatology 2025; doi:10.1093/ced/llaf443.

    PMID: 41108751
  17. 17

    Desmoplakin Cardiomyopathy: Role of Inflammation and Potential Role of Disease-Modifying Therapies.

    Gasperetti A, Carrick RT, Muller S, et al.

    Current cardiology reports 2025; (27(1)):12.

    PMID: 39786454

This page is for educational purposes only and does not replace professional medical advice. Always consult your dermatologist or genetic counselor for interpreting your specific genetic test or biopsy results.

Get notified when new evidence is published on Epidermolytic palmoplantar keratoderma.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.