ddg12418.pdf

781 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209 781

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Submitted: 5.5.2014Accepted: 12.6.2014

Conflict of interestNone.

DOI: 10.1111/ddg.12418

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

SummaryPalmoplantar 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 acqui-red 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 molecu-lar mechanisms of epidermal differentiation on palms and soles, ultimately leading to targeted corrective therapies in the future.

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

(1) Department of Dermatology, Venereology, and Allergology, University Medical Center Gttingen, Germany(2) Center for Dermatogenetics, Division of Human Genetics and Department of Dermatology, Inns-bruck Medical University, and the Cologne Center for Genomics, University of Cologne, Germany(3) Department of Dermatology and Allergology at the Medical Center of the University of Munich, Germany

*Both authors contributed equally to this work.

Clinical problemPalmoplantar keratodermas (PPK) comprise a very hetero-genous 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 [1]. An overview of diagnosis and therapy of PPK is shown in Figure 1.

Clinical appearance of palmoplantar keratoderma

PPK may be divided into acquired [2] and genetic types [3]; 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, e.g., 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

Minireview Palmoplantar keratoderma

782 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209

Figure 1 History, diagnosis and therapy of palmoplantar keratodermas.

Figure 2 Different manifestations of palmoplantar keratodermas (PPK). Focal/filiform PPK: spiny keratosis (unclear origin, an underlying malignant disease is possible) (a). Focal/discoid PPK: hyperkeratotic papules, coalescing in mechanically stressed areas (punctate PPK Type 1/Buschke-Fischer-Brauer type) (b). Focal PPK, distinct in mechanically stressed areas, dystrophic nails (pachyonychia congenita) (c). Diffuse PPK: plane white to yellowish keratosis (palmoplantar keratoderma Vrner-Unna-Thost) (d). Diffuse PPK (Papillon-Lefvre syndrome) (e).

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precise genetic classification. Autosomal dominant, recessive, and X-chromosomal patterns of heredity are all possible [3].

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 appe-arances: 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 stra-tum spinosum and granulosum, and perivascular infiltrati-on of inflammatory cells. The clinical appearance is usual-ly 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 correspon-ding etiology. Questions concerning the patients occupation can aid diagnosis, as can asking whether the symptoms im-prove during vacation. Other clues are the presence of all-ergies 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) [4, 5]; side effects of certain drugs (e.g., beta-glucan, lithium, chemotherapy agents) and metabolic disorders (gravidity, menopause, hypothyroidism, myxedema) are other possible causes [2]. Common types are acquired PPK due to contact allergy or toxic irritants as well as PPK in the framework of atopic dermatitis or psoriasis [6].

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

In patients with PPK where the etiology is not clear, the phy-sician should consider the possibility of underlying malignant disease. Since PPK may be the first visible symptom of a ma-lignancy, the physicians awareness of this manifestation may be crucial. Examples of paraneoplastic palmoplantar kerato-derma include Szary syndrome, Bazex syndrome, and here-ditary Howel-Evans syndrome [79]. In patients with Bazex or Szary 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 suspi-cion of hereditary PPK: initial manifestation of disease in childhood, a positive family history, persistent clinical appe-arance with little variation in the type and severity of sym-ptoms, and relative treatment resistance. A negative family history, or initial manifestation during adulthood, does not exclude the possibility of hereditary PPK. Other signs of he-reditary PPK include symptoms in the framework of other syndromes (such as deafness or premature tooth loss). In pa-tients 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 diag-nosis: If PPK occurs in isolation, as the cardinal or accompa-

nying 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 epidermoly-

sis) or additional redness, inflammatory components or blistering (epidermolysis)?

Histological diagnosis

Along with the usually unspecific main histological charac-teristic 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 indivi-dual entities.



Genetic diagnosis

Newer molecular genetic testing methods allow for the clas-sification 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 iden-tified 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) [10]. The identification of loss-of-function mutations in SERPINB7, whose genetic product belongs to the family of serine-pro-tease inhibitors, has made it possible to distinguish PPK (Nagashima type), based on the underlying mutations, from Mal de Meleda [11]. An association between PPK and hea-ring 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 identificati-on 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 alte-red 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 [6].

Regular baths cleanse and hydrate areas of keratiniza-tion. Routine use of hand and foot baths lead to keratoly-sis and facilitates the mechanical removal of hyperkeratotic areas (e.g., during medical foot care procedures). Mechanical keratolysis should be performed as needed. After balneothe-rapy, a moisturizer should be applied in order to ensure op-timal hydration of the skin. Topical therapy with urea-based ointments improves the skins 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 ac-companied by topical antibacterial and antifungal prophyla-xis. 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 (AWMF guideline no. 013/043, http://www.ichthyose.de).

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, aggres-sive topical therapy is advisable [12].

Promising curative therapies are available for keratino-pathies due to dominant mutations. This involves using RNA interference to switch off dominant negative alleles. Mutati-on-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 interme-diate filaments [13, 14]. 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 keratinocy-tes and duration of molecule activity have not yet been fully answered.

Conclusions for practice

When diagnosing and treating PPK, it is important to dis-tinguish 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 sympto-matic. 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 (Kster 2006). The identification of new mutations that trigger PPK illustrates the complexity of disease and incomplete picture of palmoplantar epidermal differentiation.

About the authors

Christina Seebode is a doctoral student, and Stina Schiller a post-doctoral student, in Steffen Emmerts working group. They are currently investigating the role of SNAP29 in epi-dermal differentiation and have established suitable mouse models. An SNAP29 deficiency triggers the rare CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoder-ma) syndrome. Steffen Emmert is a professor in the Depart-ment of Dermatology at University Medical Center Gttin-gen with a focus on dermato-oncology. Kathrin Giehl is a lecturer at the Department of Dermatology and Allergology



Table 1 List of hereditary palmoplantar keratodermas, affected genes, relevant gene products and inheritances [3, 15].

Disease Pattern of heredity

Gene (protein) Signs Associated symptoms

Diffuse PPK

Vrner-Unna-Thost disease

AD KRT9(Keratin 9)(KRT1)(Keratin 1)

Isolated diffuse, non- transgredient PPK, histologi-cally acanthokeratolytic

Greither disease AD KRT1 (Keratin 1) Isolated diffuse, partly transgredient PPK

Manifestation of hyperkeratosis during infancy, hyperhidrosis, possible regression during 4th or 5th decade of life

Mal de Meleda AR SLURP1 (SLURP1 (Ly6/uPAR family)

Diffuse, massively transgre-dient PPK, mutilating, rarely constrictions

Nail changes, hyperhidrosis, mace-ration of keratosis/unpleasant fetor, tendency toward bacterial superin-fections

Huriez syndrome AD Unknown Diffuse, transgredient PPK Scleroatrophy of the distal extre-mities, nail changes, growth delays affecting the hand, increased risk of squamous cell carcinoma

KID syndrome AD GJB2 (GJB6)(Connexin 26(Connexin 30)

Diffuse PPK Ichthyosiform erythroderma in infants,Progressive verruciform hyperkera-toses (including scalp, face, backs of hands and dorsal aspect of the feet, buttocks)Nail dystrophies, alopeciaichthyosis, corneal clouding, hearing affecting inner ear, tenden-cy toward bacterial superinfections, risk of squamous cell carcinoma

Bart-Pumphrey syndrome

AD GJB2(Connexin 26)

diffuse PPK Loss of hearing affecting inner ear, knuckle pads, leukonychia

PPK (Bothnia type) AD AQP5(Aquaporin)

Diffuse PPK Swelling of areas after contact with water

PPK (Nagashima type)

AR SERPINB7(serine protease inhibitor)

Mild diffuse PPK (circumscri-bed hyperkeratosis with red-ness), not progressive

Diffuse mutilating PPK

Vohwinkel syndrome

AD GJB2(Connexin 26)

Diffuse, severe, yellowish PPK, mutilating

Loss of hearing affecting inner ear, hyperhidrosis, alopecia, nail dystrophy, (myopathy, possible spastic paraplegia)

Vohwinkel syndro-me, ichthyosiform variant (Camisa syndrome)

AD LOR,(Loricrin)

PPK resembling classic Vohwinkel syndrome

Mild ichthyosis





Olmsted syndrome ADX-ch.

TRPV3(MBTPS2)(TRPV3(MBTPS2)

Diffuse, mutilating PPK Perioral hyperkeratotic plaques, diffuse alopecia, onychodystrophy, oral leukokeratosis, corneal lesions, pseudoainhum

Klick syndrome AR POMP(POMP)

Diffuse, mutilating PPK Hyperkeratotic plaques, ichthyosis and papules distributed in a linear fas-hion on the arm flexures and wrists

Focal / punctate PPK

Buschke- Fischer-Brauer disease

AD AAGAB(alpha-and gamma-adaptin binding protein)

Punctate PPK

Howel-Evans- syndrome

AD RHBDF2(RHBDF2 (rhomboid protease family)

Diffuse weal-like PPK Oral leukoplakia, keratosis pilaris, esophageal carcinoma

Striated PPK

Keratosis palmo-plantaris striata (Brnauer-Fuhs- Siemens syndrome)

AD DSG1(Desmoglein)

Striate PPK

Keratosis palmo-plantaris striata

AD DSP(Desmoplakin)

Striate PPK

Keratosis palmo-plantaris striata

AD KRT1(Keratin 1)

Striate PPK on the palms, diffuse on the soles

Ectodermal dysplasia

Pachyonychia congenita

AD KRT6A / 6B / 16 / 17 (Keratin 6a / 6b / 16 / 17)

Diffuse PPK Pachyonychia/nail changes, hyperhidrosis, oral leukokeratosis, steatocystoma

Naegeli-France-schetti-Jadassohn syndrome

AD KRT14(Keratin 14)

Diffuse PPK Absence of papillary relief, nail dystrophies, anhidrosis, dental defects, hyperpigmentation and loss of pigmentation

Papillon-Lefvre syndrome

AR CTSC(Cathepsin C)

Diffuse PPK Periodontitis, tooth lost

Haim-Munk syndrome

AR CTSC(Cathepsin C)

Diffuse PPK Corresponding to Papillon-Lefvre disease, additional arachnodactyly, acroosteolysis, pes planus, finger deformities

Schpf-Schulz- Passarge syndrome

AR WNT10A Diffuse PPK Symptoms correspond to OODD + cysts affecting the eyelids, increased risk of skin tumors

Odonto- onycho-dermal dysplasia

AR WNT10A(Wnt-10a)

Diffuse PPK Hyperhidrosis, hypodontia, hypotri-chosis, dystrophic nails

Table 1 Continued.





Ectodermal dysplasia with skin fragility

AR PKP1(Plakophilin 1)

Woolly hair

Other types of syndromal PPK

Carvajal syndrome AR DSP(Desmoplakin)

Striate PPK Cardiomyopathy, woolly hair

Naxos syndrome AR JUP(Plakoglobin)

Diffuse PPK Cardiomyopathy, woolly hair

PPK as an accompanying symptom

Cowden syndrome AD PTEN(Phosphatase PTEN)

Hamartoma development, malignant transformation

Darier disease AD ATP2A2(sarco/endoplasmic calcium-ATPase isoform SERCA2)

Palmoplantar disrupted ridge pattern in the papillary relief, crusty papules in seborrheic skin areas, nail changes

Other

Filiform hyperkeratosis

AD Unknown Spiky hyperkeratosis

Table 1 Continued.

at the Medical Center of the University of Munich, where her focus is on rare and hereditary skin diseases. Hans Christi-an Hennies heads the Center for Dermatogenetics, which is part of the Division Human Genetics and the Department of Dermatology at Innsbruck Medical University and at the Cologne Center for Genomics at the University of Cologne.

Correspondence to

Univ.-Prof. Dr. med. Steffen Emmert Klinik fr Dermatologie, Venerologie und Allergologie Universittsmedizin Gttingen

Robert-Koch-Strae 40 37075 Gttingen

E-mail: [email protected]

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