-
781 2014 Deutsche Dermatologische Gesellschaft (DDG). Published
by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209 781
Minireview
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).
-
Minireview Sclerotherapy of varicose veins
783 2014 Deutsche Dermatologische Gesellschaft (DDG). Published
by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
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.
-
Minireview Palmoplantar keratoderma
784 2014 Deutsche Dermatologische Gesellschaft (DDG). Published
by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
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
-
Minireview Sclerotherapy of varicose veins
785 2014 Deutsche Dermatologische Gesellschaft (DDG). Published
by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
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
-
Minireview Palmoplantar keratoderma
786 2014 Deutsche Dermatologische Gesellschaft (DDG). Published
by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
Disease Pattern of heredity
Gene (protein) Signs Associated symptoms
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.
-
Minireview Sclerotherapy of varicose veins
787 2014 Deutsche Dermatologische Gesellschaft (DDG). Published
by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
Disease Pattern of heredity
Gene (protein) Signs Associated symptoms
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]
References1 Emmert S, Kuster W, Hennies HC et al. 47 patients in
14 families
with the rare genodermatosis keratosis punctata palmoplan-taris
Buschke-Fischer-Brauer. Eur J Dermatol 2003; 13: 1620.
2 Patel S, Zirwas M, English JC 3rd. Acquired palmoplantar
keratoderma. Am J Clin Dermatol 2007; 8: 111.
3 Braun-Falco M. Hereditary palmoplantar keratodermas. J Dtsch
Dermatol Ges 2009; 7: 97184; quiz 845.
4 Hsu LI, Chen GS, Lee CH et al. Use of arsenic-induced
palmoplantar hyperkeratosis and skin cancers to predict risk of
subsequent internal malignancy. Am J Epidemiol 2013; 177:
20212.
5 Passarini B, Infusino SD, Kasapi E. Chloracne: still cause for
concern. Dermatology 2010; 221: 6370.
6 Emmert B, Hallier E, Schon MP et al. Disease management
guidelines in dermatology: implementation, potentials and
limitations exemplified by the guidelines for the management of
hand eczema. Hautarzt 2011; 62: 30814.
7 Blaydon DC, Etheridge SL, Risk JM et al. RHBDF2 mutations are
associated with tylosis, a familial esophageal cancer syndrome. Am
J Hum Genet 2012; 90: 3406.
8 Delavari D, Zywica M, Hartmann M. Sudden onset of acral
erythema with hyperkeratosis and pityriasiform scales on soles,
fingertips, nose and ear helices. J Dtsch Dermatol Ges 2013; 11:
3602.
9 Jawed SI, Myskowski PL, Horwitz S et al. Primary cutaneous
T-cell lymphoma (mycosis fungoides and Sezary syndrome): part I.
Diagnosis: clinical and histopathologic features and new molecular
and biologic markers. J Am Acad Dermatol 2014; 70: 205 e116; quiz
212.
10 Blaydon DC, Lind LK, Plagnol V et al. Mutations in AQP5,
encoding a water-channel protein, cause autosomal-dominant
-
Minireview Palmoplantar keratoderma
788 2014 Deutsche Dermatologische Gesellschaft (DDG). Published
by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1209
diffuse nonepidermolytic palmoplantar keratoderma. Am J Hum
Genet 2013; 93: 3305.
11 Kubo A, Shiohama A, Sasaki T et al. Mutations in SERPINB7,
encoding a member of the serine protease inhibitor superfamily,
cause Nagashima-type palmoplantar keratosis. Am J Hum Genet 2013;
93: 94556.
12 Vahlquist A, Ganemo A, Virtanen M. Congenital ichthyosis: an
overview of current and emerging therapies. Acta Derm Venereol
2008; 88: 414.
13 Hickerson RP, Flores MA, Leake D et al. Use of self-delivery
siRNAs to inhibit gene expression in an organotypic pachyo-nychia
congenita model. J Invest Dermatol 2011; 131: 103744.
14 Leachman SA, Hickerson RP, Schwartz ME et al. First-in-human
mutation-targeted siRNA phase Ib trial of an inherited skin
disorder. Mol Ther 2010; 18: 4426.
15 Seebode C, Schiller S, Emmert S, Giehl K. Hautvernderungen an
Hnden und Fen: Wann muss man an die Gene denken? Hautarzt 2014; in
press.