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PubMed This is a summary of 14 peer-reviewed journal articles Updated
Dermatology

Diagnosis and Genetic Testing

At a Glance

Bothnian type palmoplantar keratoderma (PPKB) is diagnosed through genetic testing of the AQP5 gene. Testing is crucial because it confirms the exact cause of your skin thickening and rules out potentially dangerous syndromic conditions that could affect your heart.

Getting a definitive diagnosis for Bothnian type palmoplantar keratoderma (PPKB) is a process that often begins with your clinical symptoms but must be confirmed through genetic testing. Because many types of skin thickening look similar, knowing your specific genetic “blueprint” is the only way to ensure you are receiving the correct care and monitoring [1][2].

The Role of the AQP5 Gene

The primary cause of PPKB is a mutation in the AQP5 gene [3]. This gene provides instructions for making aquaporin-5, a protein that acts like a “water gate” in the cells of your sweat glands and skin [4][5].

In PPKB, this is a gain-of-function mutation [5]. This means the water channels don’t just work; they work too well or are too plentiful. This leads to:

  • Too Many Water Channels: The mutation causes too many water channels to be placed or remain on the surface of your skin cells, allowing water to flood into the skin cells much faster than normal when you are in a bath or pool [5].
  • Calcium Signaling: The mutation is also linked to increased levels of calcium inside the cells, which triggers the excessive sweating (hyperhidrosis) common in this condition [6][7].

Why Genetic Testing is Critical

Genetic testing is the “gold standard” for diagnosis [2]. It is used to distinguish PPKB from other conditions that may look the same but have very different risks.

  1. Ruling out Syndromic PPKs: Some forms of palmoplantar keratoderma are “syndromic,” meaning they affect more than just the skin. For example, conditions like Naxos disease or Carvajal syndrome cause skin thickening but are also linked to life-threatening heart issues (cardiomyopathy) and distinct “woolly” hair [8][9]. Finding an AQP5 mutation confirms that your condition is limited to your skin and sweat glands, providing peace of mind regarding your heart health [10][1].
  2. Differentiating from Nagashima-type: Nagashima-type PPK is another common form of skin thickening, but it is caused by a different gene (SERPINB7) and is autosomal recessive, meaning a person must inherit a mutated gene from both parents [11][12]. It also tends to be “transgradient,” spreading past the palms and soles to the wrists and ankles, which PPKB typically does not do [11].

How Testing is Performed

Doctors typically use a blood or saliva sample to perform Next-Generation Sequencing (NGS) [13]. This technology can scan many different skin-related genes at once to find the exact mutation. If a mutation is found, doctors may use Sanger sequencing—a highly accurate “double-check” method—to confirm the result [13][14].

Understanding Inheritance

PPKB is an autosomal dominant condition [10]. This means:

  • You only need one copy of the mutated gene (from one parent) to have the condition [3].
  • There is a 50% chance of passing the gene to each child you have.
  • The condition usually appears in every generation of a family, although the severity of the skin thickening can vary between family members [10].

Return to Overview

Common questions in this guide

What gene causes Bothnian type palmoplantar keratoderma?
PPKB is primarily caused by a mutation in the AQP5 gene. This gene provides instructions for making aquaporin-5, a protein that acts like a water channel in the cells of your skin and sweat glands.
Why is genetic testing necessary if I already have thickened skin on my hands and feet?
Genetic testing confirms your specific diagnosis and rules out more dangerous conditions. For example, it ensures your skin thickening isn't part of a syndrome that also affects the heart, such as Naxos disease or Carvajal syndrome.
What does it mean that the AQP5 mutation is a 'gain-of-function'?
A gain-of-function mutation means the water channels in your skin are overactive or too numerous. This allows water to flood into the skin cells too quickly when you bathe or swim, and it contributes to excessive sweating.
What are the chances of passing PPKB to my children?
PPKB is an autosomal dominant condition, which means you only need one copy of the mutated gene to have it. Because of this, there is a 50% chance of passing the condition to each of your children.
How is the genetic test for PPKB performed?
Doctors usually collect a simple blood or saliva sample and use a technique called Next-Generation Sequencing (NGS) to scan skin-related genes. If a mutation is found, it is often double-checked with another highly accurate method called Sanger sequencing.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which specific genetic testing method (e.g., NGS or a targeted panel) was used to confirm my AQP5 mutation?
  2. 2.Does my genetic test result definitively rule out syndromic forms of PPK that could affect my heart or hair?
  3. 3.Since PPKB is autosomal dominant, should my parents and siblings also be tested, even if their symptoms are very mild?
  4. 4.How does knowing my 'gain-of-function' mutation status change the way we manage my symptoms compared to other types of skin thickening?
  5. 5.Can you explain the difference between my 'non-transgradient' symptoms and the 'transgradient' pattern seen in conditions like Nagashima-type?

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 (14)
  1. 1

    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
  2. 2

    [Nagashima-type palmoplantar keratoderma: A little-known palmoplantar keratoderma in Europe].

    Chassain K, Croué A, Blanchard E, et al.

    Annales de dermatologie et de venereologie 2019; (146(2)):125-130 doi:10.1016/j.annder.2018.11.005.

    PMID: 30581033
  3. 3

    AQP5 pathogenic variants induce palmoplantar keratoderma Bothnia type in two Chinese families.

    Wang Y, Wang J, Li Y, et al.

    The Journal of dermatology 2022; (49(4)):463-468 doi:10.1111/1346-8138.16281.

    PMID: 35014096
  4. 4

    Hereditary palmoplantar keratoderma - phenotypes and mutations in 64 patients.

    Harjama L, Karvonen V, Kettunen K, et al.

    Journal of the European Academy of Dermatology and Venereology : JEADV 2021; (35(9)):1874-1880 doi:10.1111/jdv.17314.

    PMID: 33914963
  5. 5

    Bothnian Palmoplantar Keratoderma: Further Delineation of the Associated Phenotype.

    Fertitta L, Charbit-Henrion F, Leclerc-Mercier S, et al.

    Genes 2022; (13(12)) doi:10.3390/genes13122360.

    PMID: 36553627
  6. 6

    Effect of PACAP on sweat secretion by immortalized human sweat gland cells.

    Yamashita M, Takenoya F, Hirabayashi T, et al.

    Peptides 2021; (146()):170647 doi:10.1016/j.peptides.2021.170647.

    PMID: 34562532
  7. 7

    Involvement of aquaporin 5 and Na-K-2Cl cotransporter 1 in the pathogenesis of primary focal hyperhidrosis: evidence from the primary sweat gland cell culture.

    Lin J, Lin M, Du Q, et al.

    American journal of physiology. Cell physiology 2024; (326(1)):C206-C213 doi:10.1152/ajpcell.00274.2023.

    PMID: 38047298
  8. 8

    Cardiac magnetic resonance imaging findings in primary arrhythmogenic left ventricular cardiomyopathy with cardiocutaneous phenotype-Carvajal syndrome.

    Akintoye E, Ashwath ML

    HeartRhythm case reports 2021; (7(5)):312-315 doi:10.1016/j.hrcr.2021.01.024.

    PMID: 34026522
  9. 9

    A Novel Variant in the Desmoplakin Gene in One Case of the Rare Carvajal Syndrome with Dilated Cardiomyopathy: A Case Report and Literature Review.

    Zhao XJ, Bai CY, Li XY, et al.

    Clinical, cosmetic and investigational dermatology 2023; (16()):2737-2748 doi:10.2147/CCID.S429030.

    PMID: 37799505
  10. 10

    The first Danish family reported with an AQP5 mutation presenting diffuse non-epidermolytic palmoplantar keratoderma of Bothnian type, hyperhidrosis and frequent Corynebacterium infections: a case report.

    Krøigård AB, Hetland LE, Clemmensen O, et al.

    BMC dermatology 2016; (16(1)):7 doi:10.1186/s12895-016-0044-3.

    PMID: 27255181
  11. 11

    Nagashima-type palmoplantar keratoderma and malignant melanoma in Japanese patients.

    Korekawa A, Akasaka E, Rokunohe D, et al.

    The British journal of dermatology 2019; (180(2)):415-416 doi:10.1111/bjd.17251.

    PMID: 30256384
  12. 12

    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
  13. 13

    Evaluation of an amplicon-based custom gene panel for the diagnosis of hereditary tumors.

    Shinriki S, Maeshiro M, Shimamura K, et al.

    Neoplasma 2020; (67(4)):898-908.

    PMID: 32241160
  14. 14

    A Novel Mutation in the Myosin Binding Protein C Gene in a Prader-Willi Syndrome Pedigree.

    Liu XQ, Luo M, Liu Q, Yang GC

    Reproductive sciences (Thousand Oaks, Calif.) 2021; (28(9)):2718-2722 doi:10.1007/s43032-021-00620-4.

    PMID: 34076875

This page explains the genetics and diagnostic testing for Bothnian type palmoplantar keratoderma for educational purposes. Always consult a genetic counselor or dermatologist to interpret your specific genetic test results.

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