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Submitted: 5.5.2014 DOI: 10.1111/ddg.12418

Accepted: 12.6.2014
Conflict of interest
None.

Palmoplantar keratoderma (PPK):

acquired and genetic causes of a
not so rare disease

Stina Schiller1*, Christina Summary

Seebode1*, Hans Christian Palmoplantar keratodermas (PPK) comprise a heterogeneous group of keratinization
Hennies2, Kathrin Giehl3, disorders with hyperkeratotic thickening of palms and soles. Sporadic or acquired
Steffen Emmert1 forms of PPKs and genetic or hereditary forms exist. Differentiation between acqui-
red and hereditary forms is essential for adequate treatment and patient counseling.
(1)Department of Dermatology, Acquired forms of PPK have many causes. A plethora of mutations in many genes
Venereology, and Allergology, can cause hereditary PPK. In recent years several new causative genes have been
University- Medical Center identi-fied. Individual PPK may be quite heterogeneous with respect to presentation
Göttingen, Germany and associated symptoms. Since the various hereditary PPK – like many other
(2) Center for Dermatogenetics, monogenic diseases – exhibit a very low prevalence, making of the correct diagnosis
Division- of Human Genetics and is challen-ging and often requires a molecular genetic analysis. Knowledge about the
Department- of Dermatology, Inns- large but quite heterogeneous group of hereditary PPK is also important to dissect
bruck Medical University, and the the molecu-lar mechanisms of epidermal differentiation on palms and soles,
Cologne- Center for Genomics, ultimately leading to targeted corrective therapies in the future.
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 problem Clinical appearance of palmoplantar

Palmoplantar 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.
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

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 Minireview Palmoplantar keratoderma

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 Vörner-Unna-
Thost) (d). Diffuse PPK (Papillon-Lefèvre syndrome) (e).

782 © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
Minireview Sclerotherapy of varicose veins
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 patient’s 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 physician’s awareness of this manifestation may be
crucial. Examples of paraneoplastic palmoplantar kerato-derma
include Sézary syndrome, Bazex syndrome, and here-ditary
Howel-Evans syndrome [7–9]. 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,
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
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.
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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 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 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
784 © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
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 (Küster 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 Emmert’s 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 Göttin-gen with a
focus on dermato-oncology. Kathrin Giehl is a lecturer at the
Department of Dermatology and Allergology
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Table 1 List of hereditary palmoplantar keratodermas, affected genes, relevant gene products and inheritances [3, 15].

Disease Pattern of Gene (protein) Signs Associated symptoms

heredity
Diffuse PPK
Vörner-Unna-Thost AD KRT9 Isolated diffuse, non--
disease (Keratin 9) transgredient PPK, histologi-
(KRT1) cally acanthokeratolytic
(Keratin 1)
Greither disease AD KRT1 (Keratin 1) Isolated diffuse, partly Manifestation of hyperkeratosis
transgredient PPK -during infancy, hyperhidrosis,
possible regression during 4th or 5th
decade of life
Mal de Meleda AR SLURP1 (SLURP1 Diffuse, massively transgre- Nail changes, hyperhidrosis, mace-
(Ly6/uPAR family) dient PPK, mutilating, rarely ration of keratosis/unpleasant fetor,
constrictions 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 Diffuse PPK Ichthyosiform erythroderma in
(GJB6) infants,
(Connexin 26 Progressive verruciform hyperkera-
(Connexin 30) toses (including scalp, face, backs of
hands and dorsal aspect of the feet,
buttocks)
Nail dystrophies, alopecia
ichthyosis, corneal clouding,
hearing- affecting inner ear, tenden-
cy toward bacterial superinfections,
risk of squamous cell carcinoma
Bart-Pumphrey AD GJB2 diffuse PPK Loss of hearing affecting inner ear,
syndrome (Connexin 26) knuckle pads, leukonychia
PPK (Bothnia type) AD AQP5 Diffuse PPK Swelling of areas after contact with
(Aquaporin) water
PPK (Nagashima AR SERPINB7 Mild diffuse PPK (circumscri-
type) (serine protease bed hyperkeratosis with red-
inhibitor) ness), not progressive
Diffuse mutilating PPK
Vohwinkel AD GJB2 Diffuse, severe, yellowish Loss of hearing affecting inner
syndrome (Connexin 26) PPK, mutilating ear, hyperhidrosis, alopecia, nail
dystrophy,- (myopathy, possible
spastic paraplegia)
Vohwinkel syndro- AD LOR, PPK resembling classic Mild ichthyosis
me, ichthyosiform (Loricrin) Vohwinkel syndrome
variant (Camisa
syndrome)

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 Minireview Palmoplantar keratoderma

Table 1 Continued.

Disease Pattern of Gene (protein) Signs Associated symptoms

heredity
Olmsted syndrome AD TRPV3 Diffuse, mutilating PPK Perioral hyperkeratotic plaques,
X-ch. (MBTPS2) diffuse alopecia, onychodystrophy,
(TRPV3 oral leukokeratosis, corneal lesions,
(MBTPS2) pseudoainhum
Klick syndrome AR POMP Diffuse, mutilating PPK Hyperkeratotic plaques, ichthyosis
(POMP) and papules distributed in a linear fas-
hion on the arm flexures and wrists
Focal / punctate PPK
Buschke-Fischer- AD AAGAB Punctate PPK
Brauer disease (alpha-and
gamma-adaptin
binding protein)
Howel-Evans-- AD RHBDF2 Diffuse weal-like PPK Oral leukoplakia, keratosis pilaris,
syndrome (RHBDF2 esophageal carcinoma
(rhomboid
protease family)
Striated PPK
Keratosis palmo- AD DSG1 Striate PPK
plantaris striata (Desmoglein)
(Brünauer-Fuhs-
Siemens syndrome)
Keratosis palmo- AD DSP Striate PPK
plantaris striata (Desmoplakin)
Keratosis palmo- AD KRT1 Striate PPK on the palms, diffuse on
plantaris striata (Keratin 1) the soles
Ectodermal dysplasia
Pachyonychia AD KRT6A / 6B / 16 / 17 Diffuse PPK Pachyonychia/nail changes,
congenita (Keratin 6a / 6b / hyperhidrosis,- oral leukokeratosis,
16 / 17) steatocystoma
Naegeli-France- AD KRT14 Diffuse PPK Absence of papillary relief, nail
schetti-Jadassohn (Keratin 14) dystrophies,- anhidrosis, dental
syndrome defects,- hyperpigmentation and
loss of pigmentation
Papillon-Lefèvre AR CTSC Diffuse PPK Periodontitis, tooth lost
syndrome (Cathepsin C)
Haim-Munk AR CTSC Diffuse PPK Corresponding to Papillon-Lefèvre
syndrome (Cathepsin C) disease, additional arachnodactyly,
acroosteolysis, pes planus, finger
deformities
Schöpf-Schulz-- AR WNT10A Diffuse PPK Symptoms correspond to OODD +
Passarge syndrome cysts affecting the eyelids, increased
risk of skin tumors
Odonto-onycho- AR WNT10A Diffuse PPK Hyperhidrosis, hypodontia, hypotri-
dermal dysplasia (Wnt-10a) chosis, dystrophic nails

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Table 1 Continued.

Disease Pattern of Gene (protein) Signs Associated symptoms

heredity
Ectodermal AR PKP1 Woolly hair
-dysplasia with skin (Plakophilin 1)
fragility
Other types of syndromal PPK
Carvajal syndrome AR DSP Striate PPK Cardiomyopathy, woolly hair
(Desmoplakin)
Naxos syndrome AR JUP Diffuse PPK Cardiomyopathy, woolly hair
(Plakoglobin)
PPK as an accompanying symptom
Cowden syndrome AD PTEN Hamartoma development,
(Phosphatase malignant transformation
PTEN)
Darier disease AD ATP2A2 Palmoplantar disrupted ridge
(sarco/endoplasmic pattern- in the papillary relief, crusty
calcium-ATPase papules in seborrheic skin areas,
isoform SERCA2) nail changes
Other
Filiform AD Unknown Spiky hyperkeratosis
hyperkeratosis

3 Braun-Falco M. Hereditary palmoplantar keratodermas. J

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 für Dermatologie, Venerologie und Allergologie
Universitätsmedizin Göttingen
Robert-Koch-Straße 40
37075 Göttingen
E-mail: semmert@gwdg.de
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788 © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209