Improving care for patients with palmoplantar keratoderma

Introduction

As podiatrists in practice, most of us may have one or two patients in our caseload with excessive thickening of the soles of the feet which returns relentlessly even without excessive activity.  Its quite possible that the patient has a form of palmoplantar keratoderma (PPK). By its simple definition it’s a condition which there is excessive thickening (hyperkeratosis) of the soles and the palms of the feet. Mostly inherited, this condition represents a spectrum of disease which for most is a long list of conditions with just as long names. However, understanding this heterogenous group of disease can be complicated so in this blog I will try and demystify PPK.

Palmoplantar Keratoderma

What is PPK?

PPK is a wide group of disorders with varying features and symptoms or as part of a broader syndrome [1] but central to all is the clinical presentation of hyperkeratosis affecting the soles and palms to varying degrees. PPK can be hereditary, acquired and may accompany other genetic diseases such as ichthyosis or epidermolysis bullosa. Occasionally acquired form can be associated with paraneoplastic disorders (like Basex disease) or linked to internal disorders.

Various forms of the condition have been reported in history based purely on their clinical appearances. Consequently, a bewildering array of names have evolved in the medial literature often named after clinicians or locations such as Greithers disease, Vohwinkel syndrome, Olmsted syndrome (Read my paper here), Unna-Thost, Wachters PPK or Nagishima PPK, for example.  Over 50 types have been reported.

Quality of Life for patients with PPK

The effects on patients living with PPK have not been investigated widely. Everyday life can be difficult, particularly where there is both foot and hand involvement which can affect ambulation and day-to-day tasks. Pain is reported by a proportion of patient with the disease [2], often as result of fissures, blister and corns but due to the variability of the disease the root causes are difficult to elucidate.

One study assessed the impact of PPK using the Dermatology Life Quality Index (DLQI) and children’s DLQI (see may earlier blog on the DLQI here). In total 208 patients with PPK. The average DLQI score was 7.5 suggesting a moderate effect on the patient’s quality of life regardless of whether it was just on the soles or involved the palms as well  [3].

What causes PPK?

Despite the constant feature of palmoplantar hyperkeratosis, the causes are diverse. Essentially  as an epidermal disorder it can result from defects in any part of the epidermis.

Very much like building a house you need many components which make it structurally sound and effective - from bricks and mortar, wall ties to water pipes, electrical wiring, wood, nails and tiles for example. The epidermis is much the same - made up various materials, which it naturally manufactures including:

• Structural proteins (many keratin types, filaggrin, Loricrin, involucrins)

• Adhesion proteins (i.e. desmoplakin, desmoglein, plakophilins, kindlins and associated structures)

• Signalling proteins and chemicals (i.e. plakoglobin, spondins)

• Enzymes (i.e. proteases / protease inhibitors, kallikreins, cathepsin)

• Inter-cellular channels (i.e. connexins, aquaporins)

• Transcription factors (proteins that regulate gene expression)

Disruption of these molecules come about from genetic mutations – some are inherited (dominant and recessively) other are spontaneous mutations. The clinical manifestation of many of these is PPK. With improved genetic testing techniques, many have been identified with more being discovered every year.

Classification of Palmoplantar Keratoderma

Clinically, it can be difficult to distinguish one type from another so various classification systems have been proposed [4]. Most simply this has been based on the lesion’s appearance:

• Diffuse

• Striate (linear)

• Circumscribed

• Focal

• Punctate

• Spiny (Read the blog here)

In addition, a good history including the patient’s medical details, medications, occupation and family history etc., can help differentiate acquired forms of PPK. Clinically PPK can extend beyond the palms and soles (Transgrediens forms) or progress with age (Progrediens forms).

Syndromic forms of PPK may include other features such as sensorineural defects, cardiomyopathy, deafness, disorders of dentition, hair and nails and sweating abnormalities. Although helpful, this clinical classification does not further the diagnosis as many different types present in similar ways.  

A new classification system

Most recently, in a forthcoming publication a joint US/European [5] group of dermatologists has proposed a new classification system acknowledging the confusion and little therapeutic value of current nomenclature.

Firstly, they propose that PPK is defined as an “Epidermal differentiation disorder [EDD]” (like many other skin diseases affecting the epidermis) but restricted to the palms and plantar areas suggesting they be listed as “palmoplantar epidermal differentiation disorders” (or pEDDs for short).

Secondly, they categorise each condition by the name of the identified defective gene. Identifying the defective gene can give a clear diagnosis and help the clinician and patient better understand the condition and prognosis.

Thirdly, with research accelerating in disease management, when the gene at fault and affected process can be identified it means that there is greater potential to find a suitable treatment. Increasingly, we are seeing more modern drug in the biological and small molecule classifications which can target specific defects. In addition, gene therapy is showing promise. One paper has demonstrated how short interfering RNA (siRNA) was injected in the plantar callus of a patient with Pachyonychia Congenita. The siRNA effective reduced the effect of the mutant allele, allowing the healthy allele to express normal protein, ultimately reducing the callus [6].

As part of the new system the authors have classified over 50 types of pEDDs. For each of these conditions they have highlighted the previous name, the new name identifying the gene responsible, protein affected, heritability (dominant/recessive), typical age of onset, typical clinical and histological features to assist diagnosis and most importantly perhaps information on experimental (pre-clinical) and clinical evidence for treatment of each sub-type.

An example for a single condition is given the table below:

Table 1: Example of a single condition under the new classification system

*The previous term Pachyonychia Congenita encompasses four different types, each one specifically affecting a particular protein. This new nomenclature reflects a specific type affecting keratin 16.

Implications for practice

Traditionally, PPK has been a broad term for a clinical presentation of a condition which causes hyperkeratosis of the palms and soles. In truth, it covers a vast array of diagnoses which traditionally has been complex with mixed and often confusing and overlapping terminology. This new classification reflects on the recent advances in this field and seeks to organise individual conditions into an understandable form, allowing for easier recognition, diagnosis and highlighting the potential treatments.

In the past, management of most PPK did not specifically seek a cause or diagnosis merely a name based on the clinical appearance. Consequently, treatment was broad. It focussed on control of symptoms often with  topical treatments (such as salicylic acid, urea and lactic acid for example). Additionally, with the use of retinoids which reduce the skins production of hyperkeratosis. For many patients this approach was not suitable as retinoids have contra-indications, pre-cautions and side effects meaning many patients could not take them.

If the new classification is widely adopted, it will make the diagnosis easier, help patients to understand the cause of their condition. Also, as new treatments are introduced, they can be added into the therapeutic options targeting the root cause and ultimately offering better outcomes for the patients.

References

1.            Metze, D. and V. Oji, Disorders of keratinization, in McKee's Pathology of the Skin, E. Calonje, Editor. 2020, Elsevier. p. 69–151.

2.            Weinberg, R.L., et al., Pain mechanisms in hereditary palmoplantar keratodermas. British Journal of Dermatology, 2020. 182(3): p. 543–551.

3.            Singhal, R., N.G. Diwan, and P.A. Nair, Impact of Palmoplantar Dermatoses on Quality of Life. Indian Dermatol Online J, 2018. 9(5): p. 309–313.

4.            Stevens, H.P., et al., Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and proposed updated classification of the keratodermas. Archives of Dermatology, 1996. 132(6): p. 640–51.

5.            Sprecher, E., et al., Palmoplantar epidermal differentiation disorders: a new classification towards pathogenesis-based therapy. British Journal of Dermatology, 2025. (In press).

6.            Leachman, S.A., et al., First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol Ther, 2010. 18(2): p. 442–6.