Palmoplantar keratoderma (PPK): acquired and genetic causes of a not so rare

disease
Stina Schiller1*, Christina Seebode1*, Hans Christian Hennies2, Kathrin Giehl3, Steffen
Emmert1

Summary

Palmoplantar keratodermas (PPK) comprise a heterogeneous group of keratinization

disorders with hyperkeratotic thickening of palms and soles. Sporadic or acquired forms of

PPKs and genetic or hereditary forms exist. Differentiation between acquired and hereditary

forms is essential for adequate treatment and patient counseling. Acquired forms of PPK have

many causes. A plethora of mutations in many genes can cause hereditary PPK. In recent

years several new causative genes have been identi-fied. Individual PPK may be quite

heterogeneous with respect to presentation and associated symptoms. Since the various

hereditary PPK like many other monogenic diseases exhibit a very low prevalence, making of

the correct diagnosis is challen-ging and often requires a molecular genetic analysis.

Knowledge about the large but quite heterogeneous group of hereditary PPK is also important

to dissect the molecular mechanisms of epidermal differentiation on palms and soles,

ultimately leading to targeted corrective therapies in the future.

Clinical problem

Palmoplantar keratodermas (PPK) comprise a very heterogenous group of diseases. This

applies to their symptoms, as well as in genetic palmoplantar keratoderma the type of

mutation and affected genes. Due to the heterogenicity of PPK and the rarity of individual

variants, especially certain genetic ones, the course of disease, from the onset of symp-toms

to a precise diagnosis (and thus promising therapy) can be long and burdensome for the

patient. In spite of growing use of molecular testing methods, the clinical appearance of PPK

is at the forefront when diagnosing patients in everyday practice.

Clinical appearance of palmoplantar keratoderma

PPK may be divided into acquired and genetic types ; other classifications are also possible.

Based on the clinical morphology, a distinction is made between diffuse/plane, focal (patchy,

striate, filiform, or discoid) or punctate with small, round hyperkeratotic lesions (Figure 2). In

addition, the severity of disease, involvement of areas other than the palms or soles

(transgredient PPK), and the onset of other symptoms, as part of a syndrome, are used to

classify or diagnosis the disorder. In genetic PPK, molecular genetic methods are used to

identify the mutated gene, allowing for precise genetic classification. Autosomal dominant,

recessive, and X-chromosomal patterns of heredity are all possible.

Especially in patients with hyperhidrosis, there is mace-ration of the keratoses, accompanied

by a typical fetor. Mild Bacterial and mycotic superinfections are also often associated with

the disease. These require adequate therapy, including oral treatment as needed. Diagnosis of

acquired palmoplantar keratoses Acquired PPK lesions have a wide range of clinical

appearances: diffuse, focal, and punctate. The most notable histological feature of acquired

palmoplantar keratosis is hyperkeratosis, which may occur with acanthosis and/or varying

degrees of parakeratosis, hyperplasia of the stratum spinosum and granulosum, and

perivascular infiltration of inflammatory cells. The clinical appearance is usually unspecific;

hyperkeratosis of the stratum corneum is the most certain clinical feature. The onset of

acquired PPK is typically later in life, and it may affect patients who do not have a family

history of disease, despite having a corresponding etiology. Questions concerning the

patient’s occupation can aid diagnosis, as can asking whether the symptoms im-prove during

vacation. Other clues are the presence of allergies or infections. Another possible sign of

acquired PPK is symptoms that are limited to the palms and soles, and/ or are restricted to

specific areas on the palms or soles. The causes of acquired PPK vary, and include exposure
to certain chemicals (e.g., arsenic, chlorinated hydrocarbon fluids) ; side effects of certain

drugs (e.g., betaglucan, lithium, chemotherapy agents) and metabolic disorders (gravidity,

menopause, hypothyroidism, myxedema) are other possible causes . Common types are

acquired PPK due to contact allergy or toxic irritants as well as PPK in the framework of

atopic dermatitis or psoriasis.

Diagnosis of paraneoplastic palmoplantar keratoses (acquired and/or genetic)

In patients with PPK where the etiology is not clear, the physician should consider the

possibility of underlying malignant disease. Since PPK may be the first visible symptom of a

malignancy, the physician’s awareness of this manifestation may be crucial. Examples of

paraneoplastic palmoplantar keratoderma include Sézary syndrome, Bazex syndrome, and

hereditary Howel-Evans syndrome . In patients with Bazex or Sézary syndrome, treatment of

the underlying malignancy leads to improvement of cutaneous symptoms. Esophageal cancer

is common in patients with Howel-Evans syndrome, and if the doctor is aware of the

association, the tumor can be diagnosed more quickly.

Diagnosis of genetic palmoplantar keratoderma

In regard to successful corrective therapy (treatment/elimination of the cause of acquired

PPK), as well as for genetic counseling for pregnant women and patients wishing to conceive,

it is important to distinguish hereditary PPK from acquired disease. Various features should

raise suspicion of hereditary PPK: initial manifestation of disease in childhood, a positive

family history, persistent clinical appearance with little variation in the type and severity of

symptoms, and relative treatment resistance. A negative family history, or initial

manifestation during adulthood, does not exclude the possibility of hereditary PPK. Other

signs of hereditary PPK include symptoms in the framework of other syndromes (such as
deafness or premature tooth loss). In patients with hereditary PPK, there is no obvious cause;

tests for allergies and infections yield negative results. If there is suspicion of hereditary PPK,

the patient should be referred to a specialized unit for treatment and also for genetic testing.

Clinical diagnosis of hereditary palmoplantar keratoderma

In addition to the above mentioned features, in hereditary PPK, the morphology of the lesions

may aid clinical diagnosis:

 If PPK occurs in isolation, as the cardinal or accompanying symptom (in a syndrome):

are other organs or organ systems (CNS, ears, eyes, immune system, nails, hair, teeth)

affected?

 Are the keratoses diffuse/plane or focal/patchy (punctate, striate, filiform)?

 Are the keratoses only located on pressure points?

 Are other areas involved, aside from the palms and soles (transgredient)?

 Is there no scale, scale without redness (no epidermolysis) or additional redness,

inflammatory components or blistering (epidermolysis)?

Histological diagnosis

Along with the usually unspecific main histological characteristic of palmoplantar keratosis

hyperkeratosis other histological features, such as epidermolysis, may be helpful in

distinguishing epidermolytic from non-epidermolytic PPK. They may also be helpful in

distinguishing between individual entities.

Genetic diagnosis

Newer molecular genetic testing methods allow for the classification of hereditary PPK based

on the causal gene defects. These types of PPK are heterogenous in terms of genetics, but
generally the affected genes either code for epidermal structure proteins or for proteins which

regulate or influence various processes during epidermal differentiation. In recent years, a

number of various genetic mutations have been identified which may trigger PPK. For

instance, in 2013 auto-somal dominant mutations in the AQP5 gene (chromosome 12q13),

which codes for aquaporin 5, was found to trigger aquagenic, non-epidermolytic PPK

(Bothnia type). The identification of loss of function mutations in SERPINB7, whose genetic

product belongs to the family of Serineprotease inhibitors, has made it possible to distinguish

PPK (Nagashima type), based on the underlying mutations, from Mal de Meleda . An

association between PPK and hearing loss in the inner ear has also been associated with the

identification of triggering mutations in GJB2, which codes for connexin 26. These examples

show that the identification of underlying mutations is enormously important for the correct

diagnosis. Table 1 provides a summary of hereditary PPK, its clinical appearance, related

genetic defects, and altered genetic products.

Treatment of acquired and hereditary palmoplantar keratoses

There is as yet no cure for hereditary palmoplantar keratoses. In patients with acquired PPK,

the cause should be treated (toxins, infection, other factors.) or eliminated, if possible. In both

instances, optimized treatment can lead to a significant improvement in symptoms. A wide

range of treatments are available which aim to fortify the skin barrier and remove

hornification. Treatment may be local and/or systemic .

Regular baths cleanse and hydrate areas of keratinization. Routine use of hand and foot baths

lead to keratolysis and facilitates the mechanical removal of hyperkeratotic areas (e.g., during

medical foot care procedures). Mechanical keratolysis should be performed as needed. After

balneotherapy, a moisturizer should be applied in order to ensure optimal hydration of the

skin. Topical therapy with ureabased ointments improves the skin’s absorption of moisture
and has keratolytic effects; urea can be readily combined with other agents such as lactic

acid, sodium chloride, and vitamin A acid. Topical vitamin D therapy is another option. The

choice of treatment is made on an individual basis and should be accompanied by topical

antibacterial and antifungal prophylaxis. Primary therapy may continue to be supported by a

basic therapy for rehydration and skin care. In patients with severe hereditary disease,

medical foot care is indicated.

Systemic therapy with retinoids (generally acitretin), taking into account the side effects, may

lead to marked improvement of palmoplantar hyperkeratosis. In patients with blistering or

epidermolytic PPK, however, an expectant approach should be taken, given that retinoid

therapy can cause detachment of large areas of the skin and erosions. Retinoids can also

cause birth defects, and the drug is stored in adipose tissue for up to 24 months after

discontinuing its use. Regardless of whether systemic therapy is given, aggressive topical

therapy is advisable .

Promising curative therapies are available for keratinopathies due to dominant mutations.

This involves using RNA interference to switch off dominant negative alleles. Mutation

specific siRNA are introduced into the cell using various methods; the expression of the wild

type allele is not affected and is sufficient for the formation of intact keratin intermediate

filaments. Advanced forms of such corrective measures are available for pachyonychia

congenita, as well as other keratin diseases. Yet, questions on long term transport of

interfering RNA molecules in the epidermal keratinocytes and duration of molecule activity

have not yet been fully answered.

Conclusions for practice

When diagnosing and treating PPK, it is important to distinguish between acquired and

hereditary types. In acquired and paraneoplastic PPK, treatment of the underlying disease or
its trigger leads to improvement of symptoms. Hereditary forms of PPK, which are not all

that rare, may be identified and diagnosed genetically, but treatment is only symptomatic. An

exact diagnosis is essential for providing genetic counseling to the patient and their family, in

order to predict the course of disease and the risk of passing it on (Küster 2006). The

identification of new mutations that trigger PPK illustrates the complexity of disease and

incomplete picture of palmoplantar epidermal differentiation.