Article type : Review Article

Accepted Article
Hereditary palmoplantar keratodermas. Part I. Non-syndromic

palmoplantar keratodermas: classification, clinical and genetic features

Running title: Hereditary palmoplantar keratodermas. Part I.

a b c a d
L. Guerra , M. Castori , B. Didona , D. Castiglia , G. Zambruno .

a c
Laboratory of Molecular and Cell Biology and Rare Skin Disease Center, Istituto

Dermopatico dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy;
b
Division of Medical Genetics, Casa Sollievo della Sofferenza-IRCCS, Viale dei Cappuccini

d
snc, 71013, San Giovanni Rotondo (Foggia), Italy; Genetic and Rare Diseases Research

Area and Dermatology Unit, Bambino Gesù Children’s Hospital-IRCCS, piazza Sant’Onofrio

4, 00165 Rome, Italy.

Funding sources: Italian Ministry of Health, Ricerca Corrente

Conflict of interest: none

Corresponding author:
Liliana Guerra, MD
Laboratory of Molecular and Cell Biology
Istituto Dermopatico dell’Immacolata (IDI)-IRCCS-FLMM
via dei Monti di Creta 104, 00167 Rome, Italy
Phone: +39 06 66464734
Fax: +39 06 66464456
E-mail: l.guerra@idi.it
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been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/jdv.14902

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 ABSTRACT

The term palmoplantar keratoderma (PPK) indicates any form of persistent thickening of the
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epidermis of palms and soles, and includes genetic as well as acquired conditions. We review

the nosology of hereditary PPKs that comprise an increasing number of entities with different

prognoses, and a multitude of associated cutaneous and extracutaneous features. On the basis

of the phenotypic consequences of the underlying genetic defect, hereditary PPKs may be

divided into: i. non-syndromic, isolated PPKs, which are characterized by a unique or

predominant palmoplantar involvement; ii. non-syndromic PPKs with additional distinctive

cutaneous and adnexal manifestations, here named complex PPKs; iii. syndromic PPKs, in

which PPK is associated with specific extracutaneous manifestations. To date, the diagnosis

of the different hereditary PPKs is based mainly on clinical history and features combined

with histopathological findings. In recent years, the exponentially increasing use of next

generation sequencing technologies has led to the identification of several novel disease

genes, and thus substantially contributed to elucidate the molecular basis of such a

heterogeneous group of disorders. Here, we focus on hereditary non-syndromic isolated and

complex PPKs. Syndromic PPKs are reviewed in the second part of this 2-part article, where

other well-defined genetic diseases, which may present PPK among their phenotypic

manifestations, are also listed and diagnostic and therapeutic approaches for PPKs are

summarized.

Key words:

Hereditary palmoplantar keratoderma, palmoplantar hyperkeratosis, non-syndromic,

classification

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 INTRODUCTION

Palmoplantar keratoderma (PPK) is an umbrella term for any form of persistent thickening of
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the epidermis at palmar and/or plantar surfaces, and include genetic as well as acquired

conditions. Acquired PPKs are commonly caused by inflammatory dermatoses, such as

psoriasis, eczema and chronic hand dermatitis, but can also be associated with systemic or

infectious diseases, induced by chemicals or drugs, or be a sign of internal malignancy.1

Hereditary PPKs comprise an increasing number of entities with different prognoses, and a

multitude of associated cutaneous and extracutaneous features.2 To date, the diagnosis of the

different hereditary PPKs is based mainly on inheritance pattern, age at onset, morphology,

distribution and severity of hyperkeratosis, pattern of additional dermatologic and systemic

manifestations, and histopathological findings. However, a recognized nosology of hereditary

PPKs is not yet available.

In recent years, the exponentially increasing use of next generation sequencing

methodologies has led to the identification of mutations in many genes, and thus substantially

contributed to elucidate the molecular basis of such a heterogeneous group of disorders for

better genetic counseling and personalization of care. Nevertheless, the role of the clinician in

planning molecular investigations and translating genetic results into practice remains crucial.

To date, hereditary PPKs may be classified following different approaches. In a broad sense,

hereditary PPKs may be divided, on the basis of the phenotypic consequences of the

underlying genetic defect, into:

1. non-syndromic, isolated PPKs, which are characterized by the unique or

predominant palmoplantar involvement, and represent the most common form of

hereditary PPKs;

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 2. non-syndromic PPKs with additional distinctive cutaneous and/or adnexal

manifestations, but without major extracutaneous features. We propose to name these

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forms “complex PPKs”;

3. syndromic PPKs, in which PPK is associated with a recognized set of

extracutaneous, pleiotropic manifestations linked to mutations in specific gene(s).

On the basis of distinct patterns of palmoplantar involvement, PPKs may be further classified

into:

1. diffuse PPKs, that is the most common pattern and refers to a generalized epidermal

thickening involving the entire palmoplantar surface or most of it, with or without a

sharp demarcation at the lateral aspects of palms and soles; the degree of epidermal

thickening ranges from very mild with only a fine scaling to extreme with impressive

manifestations;

2. focal PPKs, that defines the formation of multiple and potentially painful callosities,

especially at soles;

3. striate PPKs, consisting of linear lesions mostly appreciable at the volar aspect of the

fingers and palms in correspondence of the underlying tendons;

4. punctate PPKs, characterized by multiple papular lesions with epidermal thickening,

which may present a central pit or project as spiny keratosis.

Further discriminating manifestations of PPKs are constriction rings (i.e pseudoaihnum),

which feature mutilating PPKs. Sclerotizing PPKs are forms of palmoplantar involvement

with progressive scleroatrophic changes of the skin starting at the fingertips with a centripetal

progression, and leading to thinning the fingers, nail changes and contractures. In addition,

the terms progrediens and transgrediens, are used to define some aspects of the natural

history of hyperkeratosis, which may worsen by age (progrediens) and/or contiguously

extend to the dorsal surfaces of hands and feet, wrists and Achille tendon (transgrediens)

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 (Fig. 1). Hyperkeratosis may also involve non-contiguous skin areas such as elbows, knees

and periorificial regions.

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Besides purely clinical criteria laying on the tissue-specific or pleiotropic nature of disorder

and the overall pattern of cutaneous involvement, the advancing knowledge in the field of

medical genetics is helping us in understanding the molecular milieu leading to PPK. This

information is discovering PPK as a common clinical sign for disruption of different but often

converging molecular pathways, such as those related to epithelial intercellular adhesion via

desmosomal components, cell-cell communication via gap junction connexins, and

mechanical cell stability via the keratin cytoskeleton. A strict genotype-phenotype correlation

is not possible in all PPK cases. However, a mixed clinical-genetic classification can be

outlined.

Here, we review the nosology of hereditary non-syndromic isolated and complex PPKs

(Table 1). The classification of syndromic PPKs is reviewed in the second part of this 2-part

article, where other nosologically well-defined genetic diseases, such as inherited

epidermolysis bullosa, ichthyosis, or ectodermal dysplasia, which may present PPK among

their phenotypic manifestations, are also briefly summarized.

1. ISOLATED PALMOPLANTAR KERATODERMAS

1.1 DIFFUSE PALMOPLANTAR KERATODERMAS

1.1.1 Diffuse palmoplantar keratodermas due to KRT1/KRT9 mutations

Heterozygous mutations in KRT1 and KRT9, encoding for the suprabasal keratins 1 (K1) and

9 (K9)3,4 (Table S1), have been reported to cause three different forms of diffuse hereditary

PPKs: epidermolytic PPK (EPPK) Thost-Unna/Vörner5-7 and Greither’s8 types and a

nonepidermolytic PPK (NEPPK) type9 due to KRT1 mutation. PPKs associated with

KRT1/KRT9 mutations represent the commonest forms of hereditary PPKs. PPKs caused by

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 KRT9 mutations usually associate with severe phenotypes but mostly confined to palms and

soles, where K9 is exclusively expressed. Conversely, PPKs due to KRT1 mutations may also
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involve other body regions, as K1 expression is not site-restricted. Of note, KRT1

heterozygous mutations also cause epidermolytic ichthyosis that affects the entire body

surface.10 Perinuclear vacuolization, granular degeneration of keratinocytes in the spinous

and granular layer and large irregularly shaped keratohyalin granules are the distinctive

histopathological findings of EPPKs.11 However, typical features may not be easily

detectable and NEPPK due to KRT1 mutation is also possible.9 Fungal infections are frequent

in almost all these PPK subtypes. The common histopathological findings and pathogenetic

mechanisms support grouping of all KRT1/KRT9-related PPKs in a single entity.

The Thost-Unna-Vörner PPKs,5-7 due to KRT9 mutations,11,12 manifest with autosomal

dominant inheritance and onset soon after birth. They are characterized by yellowish thick

hyperkeratosis of the entire surface of palms and soles (Fig. 2a,b) with a sharp demarcation at

the volar border and an erythematous margin (Fig. 2c,d) (Table 2). Histopathological features

are typical of EPPK.11,13 Pseudoainhum and digit mutilations have been rarely described in

patients showing EPPK due to KRT9 mutations.14,15 More recently, mutations in KRT1 have

also been reported in EPPK cases16-20 (Table 2). EPPK due to KRT1 mutations may extend

over wrists (transgrediens) and present distant hyperkeratosis,15,16 or may spread onto the

dorsal aspects of hands, feet and skin over the Achilles’ tendons (progrediens and

transgrediens) in the Greither’s disease.21-25

A diffuse autosomal dominant NEPPK with a KRT1 mutation was described in a three

generation family with 13 affected individuals.9 Patients showed moderate to severe

hyperkeratosis extending over Achilles’ tendons and sometimes along the extensor tendon of

the great toes, while it remained sharply limited to palms on hands (Table 2). Additional

findings were knuckle pad-like keratoses on fingers with a slight limitation in digit extension,

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 and hyperkeratosis of the umbilicus, nipple areolae, knees and elbows. Of note, an autosomal

dominant KRT1 mutation was also reported in a single, large British family26 and is currently
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classified as striate PPK type III. Patients manifested hyperkeratosis with a striate pattern on

palms and focal on soles.

1.1.2 Diffuse transgrediens palmoplantar keratoderma due to SLURP1 mutations, mal

de Meleda and Gamborg-Nielsen/Norrbotten keratoderma

In 2001, Fisher et al.27 identified mutations in SLURP1, encoding the secreted lymphocyte

antigen 6 (LY6)/urokinase-type plasminogen activator receptor (uPAR)-related protein-128-30

(Table S1), in a diffuse PPK called mal de Meleda (MDM). MDM is an autosomal recessive

PPK first described in patients from the Croatian island of Meleda (now called Mljet). This

PPK manifests in infancy and is characterized by a sharply demarcated, transgrediens,

yellowish and waxy palmoplantar hyperkeratosis (Fig. 3a,b), surrounded by an erythematous

halo (Fig. 3c,d) (Table 3). Frequently reported findings are hyperkeratotic lesions over the

elbows and knees, perioral erythema, nail dystrophy (Fig. 3e,f) and conical tapering of

fingers31 (Fig. 3e). Pseudoainhum and spontaneous autoamputation have been rarely

described.32 Recently, mutations in SLURP1 have been also reported in the autosomal

recessive PPK of Gamborg-Nielsen/Norrbotten type,33,34 affecting Sweden patients. This form

presents a less severe phenotype compared to MDM, lacks distant keratosis and nail

dystrophy35 and is currently considered allelic to MDM or a milder variant of MDM.35,36

1.1.3 Diffuse palmoplantar keratoderma due to AQP5 mutations, Bothnian type

Mutations in AQP537-39 (Table S1), encoding the water-channel protein aquaporin-5, were

found in a rare, diffuse NEPPK with autosomal dominant inheritance38 first described in

Northern Sweden families living along the Gulf of Bothnia.40 To date, PPK due to AQP5

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 mutations was also reported in Danish,41 Swedish, British and Scottish,38,42 and Han

Chinese43 families.
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Bothnian PPK presents yellowish palmoplantar hyperkeratosis that manifests in early

childhood,38,41-43 sometimes spreading over the dorsal aspect of fingers38,42 (Table 3). A

typical feature of Bothnian PPK is the white sponge-like appearance after immersion in

water, that may be the only clinical sign of the disease.39

1.1.4 Diffuse transgrediens palmoplantar keratoderma due to SERPINB7 mutations,

Nagashima type

Loss-of-function mutations in SERPINB744,45 (Table S1), encoding the serpin peptidase

inhibitor, clade B (ovalbumin), member 70, were shown to cause the rare, recessively

inherited, Nagashima type PPK, to date described only in Chinese and Japanese patients.44

Nagashima PPK usually manifests in infancy and is characterized by a diffuse reddish

transgrediens hyperkeratosis and a white sponge-like appearance of hyperkeratotic areas after

water exposure44 (Table 3), a feature shared with PPK Bothnian type.

1.1.5 Diffuse sclerotizing palmoplantar keratoderma (sclerotylosis, Huriez syndrome)

Huriez syndrome is a very rare diffuse and transgrediens PPK with an autosomal dominant

inheritance. It is characterized by the triad of scleroatrophy of distal estremities, mild

palmoplantar hyperkeratosis and hypoplastic nail changes46 (Table 4). A specific feature of

this genodermatosis is the early onset of aggressive, highly metastasizing, squamous cell

carcinomas (SCCs) on the scleroatrophic skin.47 The still unknown gene maps at

chromosome 4q23.48 Of note, a clinically similar phenotype is shared by a peculiar

syndromic PPK form associated with XX-sex reversal and caused by RSPO1 mutations.49

This disorder is described in the second part of this 2-part article.

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 1.1.6 Keratolytic winter erythema (KWE), Oudtshoorn skin disease, erythrokeratolysis

hiemalis
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KWE50 is a rare autosomal dominant condition mostly occurring among South African

Afrikaans-speaking Caucasoid populations of the Eastern Cape and Oudtshoorn districts. It

has also been described in British51 and American52 families with South African or Norvegian

ancestors as well as in Germany and Denmark.53,54 The KWE critical region has been mapped

to chromosome 8p23.1-p22.53,55 Very recently, two overlapping tandem duplications

segregating with the disease have been detected in the KWE critical region in South African

and Norvegian families.56 Within the overlapping duplicated region, an active enhancer exists

whose activity strongly correlates with expression of the downstream CTSB (cathepsin B)56

(Table S1) in differentiating keratinocytes. The link between this finding and KWE is

supported by cathepsin B accumulation in the epidermis of KWE patients, a phenomenon that

probably causes an imbalance between the protease and its inhibitors.56 KWE usually begins

in infancy to early childhood and its onset and recurrences are strictly related to the cold

weather. It manifests with cycles of diffuse palmoplantar erythema, followed by epidermal

thickening and formation of dry blisters, from where centrifugal peeling of palm and sole

skin develops (Table 4). Annular erythema involving the dorsum of the hands, forearms,

lower extremities and buttocks also occurs.57 Triggering or exacerbating factors are water

exposure, moist conditions, infections or fever, topical steroids and antibiotics, mechanical

trauma. The condition usually improves with age.

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 1.2 OTHER PATTERNS OF PALMOPLANTAR KERATODERMAS

1.2.1 FOCAL PALMOPLANTAR KERATODERMA

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Focal PPK is characterized by hyperkeratotic patches usually appearing at weight-bearing

areas (Fig. 4). Focal PPKs are usually caused by mutations in KRT6c or KRT16. However,

mutations in DSG1 and TRPV3 genes have also been identified in rare cases (see paragraphs

1.2.2.1 and 2.2, respectively).

1.2.1.1 Focal palmoplantar keratoderma due to KRT6c or KRT16 mutations

Autosomal dominant mutations of KRT6C58-60 and KRT1661,62 (Table S1), encoding the site-

specific keratins 6c (K6c) and 16 (K16)63-65 (Table S1), cause focal PPK usually with

prominent friction-related patchy hyperkeratosis on soles and limited or even absent palm

involvement (Table 5). Histopathological features are hypergranulosis, acanthosis and

hyperkeratosis without epidermolytic changes.61 Rarely, minimal nail changes

(onychocorneal bands, hypertrophy of the fifth toenail, splinter hemorrhages) and oral

leukokeratosis may also occur. PPKs due to KRT6C mutations may diffusely affect the soles

in individuals with high occupational mechanical stress,59 a fact that highlights the role of

environmental factors in modulating disease phenotypic expression. Of note, mutations in

KRT6A, KRT6B, KRT6C, KRT16 and KRT17 cause pachyonychia congenita, a group of

autosomal dominant disorders of keratinization, characterized by PPK, severe nail dystrophy,

oral leukokeratosis, pilosebaceous cysts, steatocysts, and natal teeth (i.e. teeth already present

at birth).66 Whether focal PPKs due to KRT6C and KRT16 mutations should be regarded as

separate entities or included in the wide spectrum of pachyonychia congenita could be a

matter for a future international consensus meeting on diagnosis and classification of PPK.

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 1.2.2 STRIATE PALMOPLANTAR KERATODERMA

Striate PPKs have usually linear distribution on palms (Fig. 5) and focal or diffuse
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presentation on soles. They are mostly due to mutations in the desmoglein 1 (DSG1) and

desmoplakin (DSP) genes67-72 (Table S1). Haploinsufficiency (the presence of a loss-of-

function allele) is considered the molecular mechanism underlying this type of PPK.

Desmogleins (Dsg) are desmosomal transmembrane cadherins crucial to ensure intercellular

adhesion in skin (Dsg1-3), hair follicle (Dsg4) and cardiac muscle (Dsg2). Desmoplakin is a

member of the plakin family linking desmosomal core proteins (plakophillins and

plakoglobin) to cytoskeleton intermediate filaments in skin, hair follicle and heart.68

Mutations in DSG1 result in impaired function of desmosomes at sites where these are most

stressed, i.e. palms and soles. On the other hand, DSP mutations can lead to isolated PPKs

with a similar mechanism, but also to syndromic PPKs with hair, teeth and cardiac

manifestations73,74 as well as to epidermolysis bullosa subtypes, such as the acantholytic

epidermolysis bullosa simplex75 and the skin fragility-woolly hair syndrome.76,77 Such a

heterogeneous clinical presentation may depend on mutation type and site, epigenetic or

genetic modifiers and still unknown factors. Histopathological features of PPKs due to DSG1

or DSP mutations consist in widening of intercellular spaces and disruption of cell-cell

connection (acantholysis) within the suprabasal epidermal cell layers.

1.2.2.1 Striate palmoplantar keratoderma type I, due to DSG1 mutations

Striate PPK type I is an autosomal dominant condition due to DGS1 heterozygous mutations

and is characterized by linear hyperkeratosis on the palms extending along the length of

fingers and by patches of hyperkeratosis on the soles78 (Table 6). It may associate with

plantar pain. A transgrediens phenotype has also been reported in two patients.79,80 Clinical

features differ among patients, even within the same family.81 Digenic inheritance of DSG1

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 and SERPINB7 mutations was demonstrated in a patient presenting striate PPK and

erythematous lesions on the dorsal aspect of fingers.80

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Autosomal dominant DSG1 mutations have been also reported in focal PPK in a Lybian

family and diffuse PPK in a Jewish Yemenite family,82,83 a fact which illustrates that different

patterns of palmoplantar involvement can result from mutations in the same gene.

Noteworthy, biallelic DSG1 mutations have been recently identified in the severe SAM

syndrome, characterized by PPK, erythroderma, multiple allergies and metabolic wasting,

with heterozygous mutation carriers only presenting hyperkeratotic palmoplantar lesions.84

1.2.2.2 Striate palmoplantar keratoderma type II, due to DSP mutations

Striate PPK type II is caused by heterozygous mutations in DSP and characterized by linear

hyperkeratosis on palms and palmar aspect of fingers and focal hyperkeratosis at trauma-

prone sites on soles85,86 (Table 6). DSP mutations lead to impaired desmosomal function in

response to mechanical stress and this may explain the phenotype.85,86

1.2.3 PUNCTATE PALMOPLANTAR KERATODERMAS (PPPK)

PPPK manifests with symmetrical hyperkeratotic papules which usually occur isolated on

palms but confluent on soles (Fig. 6). All known PPPKs show an autosomal dominant mode

of inheritance and mutations in AAGAB87-91 and COL14A192,93 (Table S1) are the unique

identified to date.

1.2.3.1 Punctate palmoplantar keratoderma type I, Buschke-Fisher-Brauer type, due to

AAGAB or COL14A1 mutations

Buschke-Fisher-Brauer PPPK is a rare disorder manifesting in late childhood to adulthood

and characterized by hyperkeratotic, centrally depressed papular lesions, irregularly

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 distributed on palms and soles (Table 7). Lesions sometimes coalesce into yellowish plaques

at sites of greater pressure and friction or acquire a verrucous aspect resembling cutaneous
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horns. Worsening of papules upon exposure to water is a typical feature.91 Unusual

associations, such as familial occurrence of sensineural hearing loss and ichthyosis vulgaris,94

congenital hip dysplasia95 and nail dystrophy90 have also been described.

Monoallelic mutations have been described in the AAGAB gene encoding for the alpha-and

gamma-adaptin-binding protein p34.87-91 Recently, a heterozygous mutation in the COL14A1

gene, encoding for the collagen type XIV, has been detected in a four generation Chinese

family96 first described by Zhang et al.97

1.2.3.2 Punctate palmoplantar keratoderma type II, porokeratosis punctata palmaris

and plantaris (PPPP)

The very rare PPPP is characterized by multiple keratotic lesions of palms and soles,98,99

variously described as filiform, spiked, spiculate, spiny, minute digitate, minute aggregate

and music-box like (Fig. 7) (Table 7). Lesions manifest around puberty and slowly progress.

Cornoid lamellae, i.e. well-demarcated columns of parakeratosis within the horny layer,

resting on an epidermal depression where the granular layer is reduced or absent, are the

typical histological feature. The disease gene has not been identified to date.

1.2.3.3 Punctate palmoplantar keratoderma type III, acrokeratoelastoidosis (AKE)

AKE is a rare PPK characterized by small, firm papules with a translucent, sometimes

umbilicated, surface mostly in a linear distribution along the edges of hands and feet100

(Table 8). A decreased number of thinned or thickened, visibly fragmented, elastic fibers

(elastorrhexis) is a pathognomonic histological finding.101

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 1.2.3.4 Focal acral hyperkeratosis (FAH)

FAH is a rare autosomal dominant PPK characterized by multiple keratotic papules located
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on the borders of palms and soles that may aggregate into plaques102,103 (Table 8). It appears

in the second or third decade of life and gradually worsens. Lack of elastorrhexis helps in

distinguishing FAH from AKE.

1.2.3.5 Hereditary papulotranslucent acrokeratoderma (HPA)

The very rare HPA104 manifests with numerous asymptomatic, smooth, translucent small

papules that may coalesce to form plaques, mainly located over the margins of palms and

soles (Table 8). Exacerbation of papular lesions after water exposure is typical. Association

with fine-textured scalp hair and atopic diathesis has been reported.104,105

2. COMPLEX PALMOPLANTAR KERATODERMAS

2.1 Diffuse mutilating palmoplantar keratoderma due to LOR mutations (loricrin

keratoderma, Vohwinkel syndrome variant with ichthyosis, Camisa variant of

Vohwinkel syndrome)

Gain-of-function heterozygous mutations in the LOR gene, encoding the cornified envelope

protein loricrin106-109 (Table S1), cause loricrin keratoderma, also known as ichthyosiform

variant of Vohwinkel syndrome or Camisa syndrome.110-112 This rare autosomal dominant

disorder is characterized by a distinctive honeycomb-like transgrediens and progrediens PPK

(Fig. 8a,b), associated with a mild generalized ichthyosis (Table 9) (Fig. 8c). Pseudoainhum

(constricting fibrous bands on the digits) and autoamputations are frequent (Fig. 8a,b). Mouse

disease models showed that loricrin keratoderma is caused by the synthesis of a mutant

loricrin rather than by the absence of wild-type loricrin.113 The mutant loricrin is not

incorporated into the cornified envelope, but translocates into the keratinocyte nucleus,

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 specifically into the nucleoli, and strongly interferes with keratinocyte differentiation.106,107

Currently, loricrin keratoderma is classified as non-syndromic ichthyosis, due to the presence

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of generalized mild skin scaling.10

2.2 Palmoplantar keratodermas due to TRPV3/MBTPS2 mutations (Olmsted syndrome)

Autosomal dominant gain-of-function114,115 or recessive116,117 mutations in TRPV3114,118,119

(Table S1), encoding the cation channel transient receptor potential vanilloid 3, cause the rare

Olmsted syndrome, a diffuse mutilating PPK first described by Olmsted120 in 1927. This

transgrediens and progrediens PPK manifests at birth or in early childhood and classically

associates with periorificial keratotic plaques, pseudoainhum and autoamputations (Table 9).

In addition, patients frequently show hair alterations such as alopecia, hypotrichosis, woolly

or dystrophic hair. Nail dystrophies are often present. Extracutaneous manifestations, such as

growth delay, hearing loss for high tones, abnormal dentition, bone deformities, high IgE

levels, chronic eosinophilia, elevated follicular T cells in peripheral blood have been reported

in a few patients.119 In the last few years, 8 families with less severe phenotype have been

described, presenting focal PPK and autosomal dominant TRPV3 mutations.121-123 All these

cases are considered as “atypical Olmsted syndrome forms” for the focal, friction-related,

aspect of PPK, absence or transient presence of periorificial hyperkeratosis, absence or only

mild hair and nail abnormalities, usually no pseudoaihnum or autoamputations. Ni et al.123

also described the sclerodactyly-like appearance and the cone-shape of fingers, a feature

reminiscent of Huriez syndrome.

A X-linked recessive mutation in MBTPS2 (Table S1), encoding the membrane-bound

transcription factor protease site 2,124 has been recently identified in an Iranian family

suffering from Olmsted syndrome,125 originally described by Yaghoobi et al.126 (Table 9).

MBTPS2 mutations are also responsible of other genodermatoses that share several features

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 with Olmsted syndrome, specifically ichthyosis follicularis with atrichia and photophobia

(IFAP) syndrome,127,128 its BRESEK/BRESHECK variant129 and keratosis follicularis

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spinulosa decalvans.130

2.3 Striate palmoplantar keratoderma with woolly hair (PPKWH), due to KANK2

mutation

PPKWH is due to a homozygous mutation in the KN motif- and ankyrin repeat domain-

containing protein 2 (KANK2) gene (Table S1), encoding the steroid receptor coactivator

(SRC)-interacting protein (SIP).131 SIP sequesters SRCs in the cytoplasm, thus modulating

their availability within the cell. SRCs act as coactivators of a large number of steroid

receptors,132 including the vitamin D receptor (VDR) and are implicated in keratinocyte and

hair follicle differentiation. Patients suffering from PPKWH are born with woolly and sparse

scalp and body hair (Table 10). In childhood, they develop striate PPK and leukonychia more

severe on fingernails. Pseudoainhum manifests later and aggravates with age.131,133 Follicular

keratosis of extensor limbs, cheeks and back has also been described.133

2.4 Palmoplantar keratoderma and congenital alopecia 1 (PPKCA1), Stefanovic type

(keratoderma-hypotrichosis-leukonychia totalis syndrome, KHLS), due to GJA1

mutation

PPKCA1 or KHLS134 is a rare autosomal dominant disorder manifesting with congenital

alopecia, focal PPK on weight-bearing areas with linear distribution on fingers and spreading

over the dorsal aspects of hands and feet, leukonychia totalis, hyperkeratotic lesions also

involving trunk and extremities and diffuse keratosis pilaris (Table 10). In 2015, Wang et

al.135 identified a heterozygous mutation in the gap junction protein alpha 1 (GJA1) gene,

encoding connexin 43 (Cx43),136 in two unrelated patients suffering from KHLS. Cx43 is

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 important in gap junction channel formation and allows intercellular passage of small

molecules and ions. The gain-of-function effect of the Cx43 mutation is the formation of
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functional gap junction channels with increased hemichannel activity, membrane current and

Ca2+ influx, that may cause keratinocyte apoptosis and hyperkeratosis.

2.5 Palmoplantar keratoderma and congenital alopecia 2 (PPKCA2), Wallis type

(cataract-alopecia-sclerodactyly syndrome, CASS)

PPKCA2 or CASS137,138 is a rare autosomal recessive disorder manifesting with congenital

alopecia (Fig. 9a), PPK on lateral and medial aspects of palms and soles, spreading over the

dorsal aspects of hands and feet, mild nail dystrophy and perionyxis-like lesions (Fig. 9b-d),

diffuse keratosis pilaris and ulerythema ophryogenes (inflammatory keratotic facial

papules)139,140 (Table 10). Progressive hyperkeratosis results in sclerodactyly (Fig. 9e), digit

contractures, pseudoahinum and mutilating deformities of fingers. The involved gene is still

unknown.

2.6 Hyperkeratosis-hyperpigmentation syndrome (HHS)

The very rare HHS141,142 is characterized by hyperpigmented maculae arising in sun exposed

areas in early childhood to adolescence and a mild papular PPK that manifests some years

later (Table 11). Both types of lesions gradually increase in size and number.

2.7 Palmoplantar keratoderma with pigmentation defects and skin carcinoma, due to

SASH1 mutation

Recently, Courcet et al.143 described two siblings, born to unaffected consanguineous parents,

showing a diffuse PPK associated with progressive alopecia and generalized hypo- and

hyperpigmented maculae (Table 11). Nail dystrophies and teeth abnormalities were also

This article is protected by copyright. All rights reserved.

 present. The development of multiple, aggressive squamous cell carcinomas is a distinctive

feature shared with Huriez syndrome. Authors found a homozygous mutation in SASH1
Accepted Article
(SAM- and SH3-domain containing 1) tumor suppressor gene in both affected patients.

Dominant SASH1 mutations are associated with dyschromatosis universalis hereditaria or

multiple lentigines phenotypes, characterized by generalized mottled pigmentation and

generalized lentiginosis, respectively.144-147 Of note, SASH1 has been also identified as a

tumour suppressor gene involved in the development of several solid cancers with somatic

mutations.148-150

REFERENCES

1. Patel S, Zirwas M, English JC 3rd. Acquired palmoplantar keratoderma. Am J Clin

Dermatol 2007; 8: 1-11.

2. Has C, Technau-Hafsi K. Palmoplantar keratodermas: clinical and genetic aspects. J

Dtsch Dermatol Ges 2016; 14: 123-139.

3. Knöbel M, O'Toole EA, Smith FJ. Keratins and skin disease. Cell Tissue Res 2015;

360: 583-589.

4. Toivola DM, Boor P, Alam C, Strnad P. Keratins in health and disease. Curr Opin Cell

Biol 2015; 32: 73-81.

5. Thost A. Ueber erbliche ichthyosis palmaris et plantaris cornea. Dissertation:

Heidelberg (pub.) 1880.

6. Unna PG. Ueber das keratoma palmare et plantare hereditarium. Vierteljahresschr

Derm Syph 1883; 15: 231-270.

7. Vorner H. Zur kenntniss des keratoma hereditarium palmare et plantare. Arch Derm

Syph 1901; 56: 3-31.

This article is protected by copyright. All rights reserved.

 8. Greither A. Keratosis extremitatum hereditaria progrediens mit dominantem. Erbgang

Hautarzt 1952; 3: 198-203.

Accepted Article
9. Kimonis V, DiGiovanna JJ, Yang JM, Doyle SZ, Bale SJ, Compton JG. A mutation in

the V1 end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma. J

Invest Dermatol 1994; 103: 764-769.

10. Oji V, Tadini G, Akiyama M et al. Revised nomenclature and classification of inherited

ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am

Acad Dermatol 2010; 63: 607-641.

11. Küster W, Reis A, Hennies HC. Epidermolytic palmoplantar keratoderma of Vörner:

re-evaluation of Vörner's original family and identification of a novel keratin 9

mutation. Arch Dermatol Res 2002; 294: 268-272.

12. Reis A, Hennies HC, Langbein L et al. Keratin 9 gene mutations in epidermolytic

palmoplantar keratoderma (EPPK). Nat Genet 1994; 6: 174-179.

13. Küster W, Becker A. Indication for the identity of palmoplantar keratoderma type

Unna-Thost with type Vörner. Thost's family revisited 110 years later. Acta Derm

Venereol 1992; 72: 120-122.

14. Funakushi N, Mayuzumi N, Sugimura R, Ikeda S. Epidermolytic palmoplantar

keratoderma with constriction bands on bilateral fifth toes. Arch Dermatol 2009; 145:

609-610.

15. Umegaki N, Nakano H, Tamai K et al. Vörner type palmoplantar keratoderma: novel

KRT9 mutation associated with knuckle pad-like lesions and recurrent mutation causing

digital mutilation. Br J Dermatol 2011; 165: 199-201.

16. Hatsell SJ, Eady RA, Wennerstrand L et al. Novel splice site mutation in keratin 1

underlies mild epidermolytic palmoplantar keratoderma in three kindreds. J Invest

Dermatol 2001; 116: 606-609.

This article is protected by copyright. All rights reserved.

 17. Terron-Kwiatkowski A, Paller AS, Compton J, Atherton DJ, McLean WH, Irvine AD.

Two cases of primarily palmoplantar keratoderma associated with novel mutations in

Accepted Article
keratin 1. J Invest Dermatol 2002; 119: 966-971.

18. Terron-Kwiatkowski A, Terrinoni A, Didona B et al. Atypical epidermolytic

palmoplantar keratoderma presentation associated with a mutation in the keratin 1 gene.

Br J Dermatol 2004; 150: 1096-1103.

19. Terron-Kwiatkowski A, van Steensel MA, van Geel M, Lane EB, McLean WH,

Steijlen PM. Mutation S233L in the 1B domain of keratin 1 causes epidermolytic

palmoplantar keratoderma with "tonotubular" keratin. J Invest Dermatol 2006; 126:

607-613.

20. Grimberg G, Hausser I, Müller FB et al. Novel and recurrent mutations in the 1B

domain of keratin 1 in palmoplantar keratoderma with tonotubules. Br J Dermatol

2009; 160: 446-449.

21. Sybert VP, Dale BA, Holbrook KA. Palmar-plantar keratoderma. A clinical,

ultrastructural, and biochemical study. J Am Acad Dermatol 1988; 18: 75-86.

22. Beylot-Barry M, Taieb A, Surleve-Bazeille JE, Maleville J. Inflammatory familial

palmoplantar keratoderma: Greither’s disease? Dermatology 1992; 185: 210-214.

23. Fluckiger R, Itin PH. Keratosis extremitatum (Greither’s disease): clinical features,

histology, ultrastructure. Dermatology 1993; 187: 309-311.

24. Grilli R, Aguilar A, Escalonilla P et al. Transgrediens et progrediens palmoplantar

keratoderma (Greither's disease) with particular histopathologic findings. Cutis 2000;

65: 141-145.

25. Gach JE, Munro CS, Lane EB, Wilson NJ, Moss C. Two families with Greither's

syndrome caused by a keratin 1 mutation. J Am Acad Dermatol 2005; 53: S225-S230.

This article is protected by copyright. All rights reserved.

 26. Whittock NV, Smith FJ, Wan H et al. Frameshift mutation in the V2 domain of human

keratin 1 results in striate palmoplantar keratoderma. J Invest Dermatol 2002; 118: 838-
Accepted Article
844.

27. Fischer J, Bouadjar B, Heilig R et al. Mutations in the gene encoding SLURP-1 in Mal

de Meleda. Hum Mol Genet 2001; 10: 875-880.

28. Mastrangeli R, Donini S, Kelton CA et al. ARS Component B: structural

characterization, tissue expression and regulation of the gene and protein (SLURP-1)

associated with Mal de Meleda. Eur J Dermatol 2003; 13: 560-750.

29. Allan CM, Procaccia S, Tran D et al. Palmoplantar keratoderma in Slurp2-deficient

mice. J Invest Dermatol 2016; 136: 436-443.

30. Lyukmanova EN, Shulepko MA, Kudryavtsev D et al. Human secreted Ly-6/uPAR

related protein-1 (SLURP-1) is a selective allosteric antagonist of α7 nicotinic

acetylcholine receptor. PLoS One 2016; 11: e0149733.

31. Perez C, Khachemoune A. Mal de Meleda: A focused review. Am J Clin Dermatol

2016; 17: 63-70.

32. Wajid M, Kurban M, Shimomura Y, Christiano AM. Mutations in the SLURP-1 gene

underlie Mal de Meleda in three Pakistani families. J Dermatol Sci 2009; 56: 27-32.

33. Gamborg Nielsen P. Two different clinical and genetic forms of hereditary

palmoplantar keratoderma in the northernmost county of Sweden. Clin Genet 1985; 28:

361-366.

34. Kastl I, Anton-Lamprecht I, Gamborg Nielsen P. Hereditary palmoplantar keratosis of

the Gamborg Nielsen type. Clinical and ultrastructural characteristics of a new type of

autosomal recessive palmoplantar keratosis. Arch Dermatol Res 1990; 282: 363-370.

This article is protected by copyright. All rights reserved.

 35. Zhao L, Vahlquist A, Virtanen M et al. Palmoplantar keratoderma of the Gamborg-

Nielsen type is caused by mutations in the SLURP1 gene and represents a variant of
Accepted Article
Mal de Meleda. Acta Derm Venereol 2014; 94: 707-710.

36. Nellen RG, Steijlen PM, van Geel M, van Steensel MA. Comment on Zhao et al.

"Palmoplantar keratoderma of the Gamborg-Nielsen type is caused by mutations in the

SLURP1 gene and represents a variant of Mal de Meleda". Acta Derm Venereol 2015;

95: 1034-1035.

37. King LS, Kozono D, Agre P. From structure to disease: the evolving tale of aquaporin

biology. Nat Rev Mol Cell Biol 2004; 5: 687-698.

38. Blaydon DC, Lind LK, Plagnol V et al. Mutations in AQP5, encoding a water-channel

protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar

keratoderma. Am J Hum Genet 2013; 93: 330-335.

39. Blaydon DC, Kelsell DP. Defective channels lead to an impaired skin barrier. J Cell Sci

2014; 127: 4343-4350.

40. Lind L, Lundström A, Hofer PA, Holmgren G. The gene for diffuse palmoplantar

keratoderma of the type found in northern Sweden is localized to chromosome 12q11-

q13. Hum Mol Genet 1994; 3: 1789-1793.

41. Krøigård AB, Hetland LE, Clemmensen O, Blaydon DC, Hertz JM, Bygum A. The first

Danish family reported with an AQP5 mutation presenting diffuse non-epidermolytic

palmoplantar keratoderma of Bothnian type, hyperhidrosis and frequent

Corynebacterium infections: a case report. BMC Dermatol 2016; 16: 7.

42. Abdul-Wahab A, Takeichi T, Liu L et al. Autosomal dominant diffuse

nonepidermolytic palmoplantar keratoderma due to a recurrent mutation in aquaporin-

5. Br J Dermatol 2016; 174: 430-432.

This article is protected by copyright. All rights reserved.

 43. Cao X, Yin J, Wang H et al. Mutation in AQP5, encoding aquaporin 5, causes

palmoplantar keratoderma Bothnia type. J Invest Dermatol 2014; 134: 284-287.

Accepted Article
44. 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: 945-956.

45. Kubo A. Nagashima-type palmoplantar keratosis: a common Asian type caused by

SERPINB7 protease inhibitor deficiency. J Invest Dermatol 2014; 134: 2076-2079.

46. Huriez C, Agache P, Bombart M, Souilliart F. Spinocellular epitheliomas in congenital

cutaneous atrophy in 2 families with high cancer morbidity. Bull Soc Fr Dermatol

Syphiligr 1963; 70: 24-28.

47. Hamm H, Traupe H, Brocker EB, Schubert H, Kolde G. The scleroatrophic syndrome

of Huriez: a cancer-prone genodermatosis. Br J Dermatol 1996; 134: 512-518.

48. Lee YA, Stevens HP, Delaporte E, Wahn U, Reis A. A gene for an autosomal dominant

scleroatrophic syndrome predisposing to skin cancer (Huriez syndrome) maps to

chromosome 4q23. Am J Hum Genet 2000; 66: 326-330.

49. Parma P, Radi O, Vidal V et al. R-spondin1 is essential in sex determination, skin

differentiation and malignancy. Nat Genet 2006; 38: 1304-1309.

50. Findlay GH, Nurse GT, Heyl T et al. Keratolytic winter erythema or ‘Oudtshoorn skin’

a newly recognized inherited dermatosis prevalent in South Africa. S Afr Med J 1977;

52: 871-874.

51. Amin AN, DeGiovanni CV, Farrant PB, Hull PR, Woollons A. Photodynamic therapy

for the treatment of keratolytic winter erythema. Clin Exp Dermatol 2011; 36: 668-669.

52. Huntington MK, Jassim AD. Genetic heterogeneity in keratolytic winter erythema

(Oudtshoorn skin disease). Arch Dermatol 2006; 142: 1073-1074.

This article is protected by copyright. All rights reserved.

 53. Starfield M, Hennies HC, Jung M et al. Localization of the gene causing keratolytic

winter erythema to chromosome 8p22-23and evidence for a founder effect in South

Accepted Article
Africa Afrikaans-speakers. Am J Hum Genet 1997; 61: 370-378.

54. Danielsen AG, Weismann K, Thomsen HK. Erythrokeratolysis hiemalis (keratolytic

winter erythema): a case report from Denmark. J Eur Acad Dermatol Venereol 2001;

15: 255-256.

55. Appel S, Filter M, Reis A et al. Physical and transcriptional map of the critical region

for keratolytic winter erythema (KWE) on chromosome 8p22-p23 between D8S550 and

D8S1759. Eur J Hum Genet 2002; 10: 17-25.

56. Ngcungcu T, Oti M, Sitek JC et al. Duplicated enhancer region increases expression of

CTSB and segregates with keratolytic winter erythema in South African and Norwegian

Families. Am J Hum Genet 2017; 100: 737-750.

57. Hull PR, Hobbs A, Aron S, Ramsay M. The elusive gene for keratolytic winter

erythema. S Afr Med J 2013; 103: 961-965.

58. Wilson NJ, Messenger AG, Leachman SA et al. Keratin K6c mutations cause focal

palmoplantar keratoderma. J Invest Dermatol 2010; 130: 425-429.

59. Akasaka E, Nakano H, Nakano A et al. Diffuse and focal palmoplantar keratoderma

can be caused by a keratin 6c mutation. Br J Dermatol 2011; 165: 1290-1292.

60. Kubo A, Oura Y, Hirano T et al. Collapse of the keratin filament network through the

expression of mutant keratin 6c observed in a case of focal plantar keratoderma. J

Dermatol 2013; 40: 553-557.

61. Shamsher MK, Navsaria HA, Stevens HP et al. Novel mutations in keratin 16 gene

underlay focal non-epidermolytic palmoplantar keratoderma (NEPPK) in two families.

Hum Mol Genet 1995; 4: 1875-1881.

This article is protected by copyright. All rights reserved.

 62. Smith FJ, Fisher MP, Healy E et al. Novel keratin 16 mutations and protein expression

studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma. Exp

Accepted Article
Dermatol 2000; 9: 170-177.

63. Koster MI. Building models for keratin disorders. J Invest Dermatol 2012; 132: 1324-

1326.

64. Lessard JC, Coulombe PA. Keratin 16-null mice develop palmoplantar keratoderma, a

hallmark feature of pachyonychia congenita and related disorders. J Invest Dermatol

2012; 132: 1384-1391.

65. Plassais J, Guaguère E, Lagoutte L et al. A spontaneous KRT16 mutation in a dog

breed: a model for human focal non-epidermolytic palmoplantar keratoderma

(FNEPPK). J Invest Dermatol 2015; 135: 1187-1190.

66. Shah S, Boen M, Kenner-Bell B, Schwartz M, Rademaker A, Paller AS. Pachyonychia

congenita in pediatric patients: natural history, features, and impact. JAMA Dermatol

2014; 150: 146-153.

67. Brooke MA, Nitoiu D, Kelsell DP. Cell-cell connectivity: desmosomes and disease. J

Pathol 2012; 226: 158-171.

68. Petrof G, Mellerio JE, McGrath JA. Desmosomal genodermatoses. Br J Dermatol 2012;

166: 36-45.

69. Broussard JA, Getsios S, Green KJ. Desmosome regulation and signaling in disease.

Cell Tissue Res 2015; 360: 501-512.

70. Ishida-Yamamoto A, Igawa S. Genetic skin diseases related to desmosomes and

corneodesmosomes. J Dermatol Sci 2014; 74: 99-105.

71. Bolling MC, Jonkman MF. Skin and heart: une liaison dangereuse. Exp Dermatol 2009;

18: 658-668.

This article is protected by copyright. All rights reserved.

 72. Li J. Alterations in cell adhesion proteins and cardiomyopathy. World J Cardiol 2014;

6: 304-313.
Accepted Article
73. Norgett EE, Hatsell SJ, Carvajal-Huerta L et al. Recessive mutation in desmoplakin

disrupts desmoplakin-intermediate filament interactions and causes dilated

cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 2000; 9: 2761-2766.

74. Norgett EE, Lucke TW, Bowers B, Munro CS, Leigh IM, Kelsell DP. Early death from

cardiomyopathy in a family with autosomal dominant striate palmoplantar keratoderma

and woolly hair associated with a novel insertion mutation in desmoplakin. J Invest

Dermatol 2006; 126: 1651-1654.

75. Jonkman JF, Pasmooij AM, Pasmans SG et al. Loss of desmoplakin tail causes lethal

acantholytic epidermolysis bullosa. Am J Hum Genet 2005; 77: 653-660.

76. Whittock NV, Wan H, Morley SM et al. Compound heterozygosity for non-sense and

mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome. J

Invest Dermatol 2002; 118: 232-238.

77. Smith FJ, Wilson NJ, Moss C, Dopping-Hepenstal P, McGrath J. Compound

heterozygous mutations in desmoplakin cause skin fragility and woolly hair. Br J

Dermatol 2012; 166: 894-896.

78. Rickman L, Simrak D, Stevens HP et al. N-terminal deletion in a desmosomal cadherin

causes the autosomal dominant skin disease striate palmoplantar keratoderma. Hum

Mol Genet 1999; 8: 971-976.

79. Nomura T, Mizuno O, Miyauchi T et al. Striate palmoplantar keratoderma: Report of a

novel DSG1 mutation and atypical clinical manifestations. J Dermatol Sci 2015; 80:

223-225.

This article is protected by copyright. All rights reserved.

 80. Fukaura R, Takeichi T, Okuno Y et al. Striate Palmoplantar keratoderma showing

transgrediens in a patient harbouring heterozygous nonsense mutations in both DSG1

Accepted Article
and SERPINB7. Acta Derm Venereol 2017; 97: 399-401.

81. Lovgren ML, McAleer MA, Irvine AD et al. Mutations in desmoglein-1 cause diverse

inherited palmoplantar keratoderma phenotypes: implications for genetic screening. Br

J Dermatol 2017; 176: 1345-1350.

82. Milingou M, Wood P, Masouyé I, McLean WH, Borradori L. Focal palmoplantar

keratoderma caused by an autosomal dominant inherited mutation in the desmoglein 1

gene. Dermatology 2006; 212: 117-122.

83. Keren H, Bergman R, Mizrachi M, Kashi Y, Sprecher E. Diffuse nonepidermolytic

palmoplantar keratoderma caused by a recurrent nonsense mutation in DSG1. Arch

Dermatol 2005; 141: 625-628.

84. Samuelov L, Sarig O, Harmon RM et al. Desmoglein 1 deficiency results in severe

dermatitis, multiple allergies and metabolic wasting. Nat Genet 2013; 45: 1244-1248.

85. Armstrong DK, McKenna KE, Purkis PE et al. Haploinsufficiency of desmoplakin

causes a striate subtype of palmoplantar keratoderma. Hum Mol Genet 1999; 8: 143-

148.

86. Whittock NV, Ashton GH, Dopping-Hepenstal PJ et al. Striate palmoplantar

keratoderma resulting from desmoplakin haploinsufficiency. J Invest Dermatol 1999;

113: 940-946.

87. Giehl KA, Eckstein GN, Pasternack SM et al. Nonsense mutations in AAGAB cause

punctate palmoplantar keratoderma type Buschke-Fischer-Brauer. Am J Hum Genet

2012; 91: 754-759.

This article is protected by copyright. All rights reserved.

 88. Pohler E, Mamai O, Hirst J et al. Haploinsufficiency for AAGAB causes clinically

heterogeneous forms of punctate palmoplantar keratoderma. Nat Genet 2012; 44: 1272-
Accepted Article
1276.

89. Pöhler E, Zamiri M, Harkins CP et al. Heterozygous mutations in AAGAB cause type 1

punctate palmoplantar keratoderma with evidence for increased growth factor

signaling. J Invest Dermatol 2013; 133: 2805-2808.

90. Kiritsi D, Chmel N, Arnold AW, Jakob T, Bruckner-Tuderman L, Has C. Novel and

recurrent AAGAB mutations: clinical variability and molecular consequences. J Invest

Dermatol 2013; 133: 2483-2486.

91. Giehl KA, Herzinger T, Wolff H et al. Eight novel mutations confirm the role of

AAGAB in punctate palmoplantar keratoderma type 1 (Buschke-Fischer-Brauer) and

show broad phenotypic variability. Acta Derm Venereol 2016; 96: 468-472.

92. Ansorge HL, Meng X, Zhang G et al. Type XIV collagen regulates fibrillogenesis:

premature collagen fibril growth and tissue dysfunction in null mice. J Biol Chem

2009; 284: 8427-8438.

93. Agarwal P, Zwolanek D, Keene DR et al. Collagen XII and XIV, new partners of

cartilage oligomeric matrix protein in the skin extracellular matrix suprastructure. J

Biol Chem 2012; 287: 22549-22559.

94. Bchetnia M, Charfeddine C, Kassar S et al. Clinical, histological and genetic

investigation of Buschke-Fischer-Brauer's disease in Tunisian families. J Dermatol Sci

2009; 54: 54-56.

95. Eytan O, Sarig O, Israeli S, Mevorah B, Basel-Vanagaite L, Sprecher E. A novel splice-

site mutation in the AAGAB gene segregates with hereditary punctate palmoplantar

keratoderma and congenital dysplasia of the hip in a large family. Clin Exp Dermatol

2014; 39: 182-186.

This article is protected by copyright. All rights reserved.

 96. Guo BR, Zhang X, Chen G et al. Exome sequencing identifies a COL14A1 mutation in

a large Chinese pedigree with punctate palmoplantar keratoderma. J Med Genet 2012;
Accepted Article
49: 563-568.

97. Zhang XJ, Li M, Gao TW et al. Identification of a locus for punctate palmoplantar

keratodermas at chromosome 8q24.13-8q24.21. J Invest Dermatol 2004; 122: 1121-

1125.

98. Brown FC. Punctate keratoderma. Arch Dermatol 1971; 104: 682-683.

99. Sakas EL, Gentry RH. Porokeratosis punctata palmaris et plantaris (punctate

porokeratosis). Case report and literature review. J Am Acad Dermatol 1985; 13: 908-

912.

100. Costa OG. Acrokerato-elastoidosis; a hitherto undescribed skin disease. Dermatologica

1953; 107: 164-168.

101. Abulafia J, Vignale RA. Degenerative collagenous plaques of the hands and

acrokeratoelastoidosis: pathogenesis and relationship with knuckle pads. Int J Dermatol

2000; 39: 424-432.

102. Dowd PM, Harman RR, Black MM. Focal acral hyperkeratosis. Br J Dermatol 1983;

109: 97-103.

103. Lee EA, Kim HS, Kim HO, Park YM. A Case of focal acral hyperkeratosis. Ann

Dermatol 2009; 21: 426-428.

104. Onwukwe MF, Mihm MC Jr, Toda K. Hereditary papulotranslucent acrokeratoderma.

A new variant of familial punctate keratoderma? Arch Dermatol 1973; 108: 108-110.

105. Sracic JK, Krishnan RS, Nunez-Gussman JK, Orengo IF, Hsu S. Hereditary

papulotranslucent acrokeratoderma: a case report and literature review. Dermatol

Online J 2005; 11: 17.

This article is protected by copyright. All rights reserved.

 106. Ishida-Yamamoto A, Kato H, Kiyama H et al. Mutant loricrin is not crosslinked into

the cornified cell envelope but is translocated into the nucleus in loricrin keratoderma. J
Accepted Article
Invest Dermatol 2000; 115: 1088-1094.

107. Ishida-Yamamoto A. Loricrin keratoderma: a novel disease entity characterized by

nuclear accumulation of mutant loricrin. J Dermatol Sci 2003; 31: 3-8.

108. Schmuth M, Fluhr JW, Crumrine DC et al. Structural and functional consequences of

loricrin mutations in human loricrin keratoderma (Vohwinkel syndrome with

ichthyosis). J Invest Dermatol 2004; 122: 909-922.

109. Yoneda K, Demitsu T, Manabe M et al. Expression of wild-type, but not mutant,

loricrin causes programmed cell death in HaCaT keratinocytes. J Dermatol 2010; 37:

956-964.

110. Maestrini E, Monaco AP, McGrath JA et al. A molecular defect in loricrin, the major

component of the cornified cell envelope, underlies Vohwinkel's syndrome. Nat Genet

1996; 13: 70-77.

111. Gedicke MM, Traupe H, Fischer B, Tinschert S, Hennies HC. Towards characterization

of palmoplantar keratoderma caused by gain-of-function mutation in loricrin: analysis

of a family and review of the literature. Br J Dermatol 2006; 154: 167-171.

112. Song S, Shen C, Song G et al. A novel c.545-546insG mutation in the loricrin gene

correlates with a heterogeneous phenotype of loricrin keratoderma. Br J Dermatol

2008; 159: 714-719.

113. Suga Y, Jarnik M, Attar PS et al. Transgenic mice expressing a mutant form of loricrin

reveal the molecular basis of the skin diseases, Vohwinkel syndrome and progressive

symmetric erythrokeratoderma. J Cell Biol 2000; 151: 401-412.

114. Lin Z, Chen Q, Lee M et al. Exome sequencing reveals mutations in TRPV3 as a cause

of Olmsted syndrome. Am J Hum Genet 2012; 90: 558-564.

This article is protected by copyright. All rights reserved.

 115. Lai-Cheong JE, Sethuraman G, Ramam M, Stone K, Simpson MA, McGrath JA.

Recurrent heterozygous missense mutation, p.Gly573Ser, in the TRPV3 gene in an

Accepted Article
Indian boy with sporadic Olmsted syndrome. Br J Dermatol 2012; 167: 440-442.

116. Duchatelet S, Guibbal L, de Veer S et al. Olmsted syndrome with erythromelalgia

caused by recessive transient receptor potential vanilloid 3 mutations. Br J Dermatol

2014; 171: 675-678.

117. Eytan O, Fuchs-Telem D, Mevorach B et al. Olmsted syndrome caused by a

homozygous recessive mutation in TRPV3. J Invest Dermatol 2014; 134: 1752-1754.

118. Nilius B, Bíró T, Owsianik G. TRPV3: time to decipher a poorly understood family

member! J Physiol 2014; 592: 295-304.

119. Duchatelet S, Hovnanian A. Olmsted syndrome: clinical, molecular and therapeutic

aspects. Orphanet J Rare Dis 2015; 10: 33.

120. Olmsted HC. Keratodermia palmaris et plantaris congenitalis: report of a case showing

associated lesions of unusual location. Am J Dis Child 1927; 33: 757-764.

121. He Y, Zeng K, Zhang X et al. A gain-of-function mutation in TRPV3 causes focal

palmoplantar keratoderma in a Chinese family. J Invest Dermatol 2015; 135: 907-909.

122. Wilson NJ, Cole C, Milstone LM et al. Expanding the phenotypic spectrum of Olmsted

syndrome. J Invest Dermatol 2015; 135: 2879-2883.

123. Ni C, Yan M, Zhang J et al. A novel mutation in TRPV3 gene causes atypical familial

Olmsted syndrome. Sci Rep 2016; 6: 21815.

124. Bornholdt D, Atkinson TP, Bouadjar B et al. Genotype-phenotype correlations

emerging from the identification of missense mutations in MBTPS2. Hum Mutat 2013;

34: 587-94.

This article is protected by copyright. All rights reserved.

 125. Haghighi A, Scott CA, Poon DS et al. A missense mutation in the MBTPS2 gene

underlies the X-linked form of Olmsted syndrome. J Invest Dermatol 2013; 133: 571-
Accepted Article
573.

126. Yaghoobi R, Omidian M, Sina N, Abtahian SA, Panahi-Bazaz MR. Olmsted syndrome

in an Iranian family: report of two new cases. Arch Iran Med 2007; 10: 246-249.

127. Oeffner F, Fischer G, Happle R et al. IFAP syndrome is caused by deficiency in

MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis

and ER stress response. Am J Hum Genet 2009; 84: 459-467.

128. Mégarbané H, Mégarbané A. Ichthyosis follicularis, alopecia, and photophobia (IFAP)

syndrome. Orphanet J Rare Dis 2011; 6: 29.

129. Naiki M, Mizuno S, Yamada K et al. MBTPS2 mutation causes BRESEK/BRESHECK

syndrome. Am J Med Genet A 2011; 158A: 97-102.

130. Aten E, Brasz LC, Bornholdt D et al. Keratosis follicularis spinulosa decalvans is

caused by mutations in MBTPS2. Hum Mutat 2010; 31: 1125-1133.

131. Ramot Y, Molho-Pessach V, Meir T et al. Mutation in KANK2, encoding a sequestering

protein for steroid receptor coactivators, causes keratoderma and woolly hair. J Med

Genet 2014; 51: 388-394.

132. Stashi E, York B, O'Malley BW. Steroid receptor coactivators: servants and masters for

control of systems metabolism. Trends Endocrinol Metab 2014; 25: 337-347.

133. Djabali K, Martinez-Mir A, Horev L, Christiano AM, Zlotogorski A. Evidence for

extensive locus heterogeneity in Naxos disease. J Invest Dermatol 2002; 118: 557-560.

134. Stevanovic DV. Alopecia congenita. The incomplete dominant form of inheritance with

varying expressivity. Acta Genet Statist Med 1959; 9: 127-132.

This article is protected by copyright. All rights reserved.

 135. Wang H, Cao X, Lin Z et al. Exome sequencing reveals mutation in GJA1 as a cause of

keratoderma-hypotrichosis-leukonychia totalis syndrome. Hum Mol Genet 2015; 24:

Accepted Article
243-250.

136. Lilly E, Sellitto C, Milstone LM, White TW. Connexin channels in congenital skin

disorders. Semin Cell Dev Biol 2016; 50: 4-12.

137. Bhatia KK, Chaudhary S, Pahwa US, Mehrotra GC. Keratoma hereditaria mutilans

(Vohwinkel's disease) with congenital alopecia universalis (atrichia congenita). J Derm

1989; 16: 231-236.

138. Wallis C, Ip FS, Beighton P. Cataracts, alopecia, and sclerodactyly: a previously

apparently undescribed ectodermal dysplasia syndrome on the island of Rodrigues. Am

J Med Genet 1989; 32: 500-503.

139. Castori M, Valiante M, Ritelli M et al. Palmoplantar keratoderma, pseudo-ainhum, and

universal atrichia: A new patient and review of the palmoplantar keratoderma-

congenital alopecia syndrome. Am J Med Genet A 2010; 152A: 2043-2047.

140. Castori M, Morlino S, Sana ME et al. Clinical and molecular characterization of two

patients with palmoplantar keratoderma-congenital alopecia syndrome type 2. Clin Exp

Dermatol 2016; 41: 632-635.

141. Cantú JM, Sánchez-Corona J, Fragoso R, Macotela-Ruiz E, Garciá-Cruz D. A "new"

autosomal dominant genodermatosis characterized by hyperpigmented spots and

plamoplantar hyperkeratosis. Clin Genet 1978; 14: 165-168.

142. Figuera LE, Rodríguez-Catellanos MA, González-Mendoza A, Cantú JM.

Hyperkeratosis-hyperpigmentation syndrome: a confirmative case. Clin Genet 1993;

43: 73-75.

This article is protected by copyright. All rights reserved.

 143. Courcet JB, Elalaoui SC, Duplomb L et al. Autosomal-recessive SASH1 variants

associated with a new genodermatosis with pigmentation defects, palmoplantar

Accepted Article
keratoderma and skin carcinoma. Eur J Hum Genet 2015; 23: 957-962.

144. Wang J, Zhang J, Li X et al. A novel de novo mutation of the SASH1 gene in a Chinese

family with multiple lentigines. Acta Derm Venereol 2017; 97: 530-531.

145. Zhang J, Li M, Yao Z. Updated review of genetic reticulate pigmentary disorders. Br J

Dermatol 2017; 177: 945-959

146. Zhou D, Wei Z, Kuang Z et al. A novel P53/POMC/Gαs/SASH1 autoregulatory

feedback loop activates mutated SASH1 to cause pathologic hyperpigmentation. J Cell

Mol Med 2017; 21: 802-815.

147. Zhou D, Kuang Z, Zeng X et al. p53 regulates ERK1/2/CREB cascade via a novel

SASH1/MAP2K2 crosstalk to induce hyperpigmentation. J Cell Mol Med 2017; 21:

2465-2480.

148. Chen EG, Chen Y, Dong LL, Zhang JS. Effects of SASH1 on lung cancer cell

proliferation, apoptosis, and invasion in vitro. Tumour Biol 2012; 33: 1393-1401.

149. Lin S, Zhang J, Xu J et al. Effects of SASH1 on melanoma cell proliferation and

apoptosis in vitro. Mol Med Rep 2012; 6: 1243-1248.

150. Meng Q, Zheng M, Liu H et al.: SASH1 regulates proliferation, apoptosis, and invasion

of osteosarcoma cell. Mol Cell Biochem 2013; 373: 201-210.

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 Table 1. Clinicogenetic classification of non-syndromic palmoplantar keratodermas

DISEASE INHERITANCE GENE(S)

ISOLATED PPKs
Accepted Article
Diffuse PPKs
Epidermolytic PPK Thost-Unna or Vorner type* AD KRT1/KRT9
Epidermolytic PPK of Greither* AD KRT1
Diffuse nonepidermolytic PPK* AD KRT1
Mal de Meleda and Gamborg-Nielsen/Norrbotten PPK AR SLURP1
Diffuse PPK, Bothnian type AD AQP5
Diffuse PPK, Nagashima type AR SERPINB7
Sclerotylosis (Huriez syndrome) AD Unknown
Keratolytic winter erythema AD CTSB
Focal PPKs AD KRT6C/KRT16
Striate PPKs
Striate PPK type I AD DSG1
Striate PPK type II AD DSP
Punctate PPKs
Punctate PPK type I , Buschke-Fisher-Brauer AD AAGAB/COL14A1
Punctate PPK type II, porokeratosis punctata palmaris and AD Unknown
plantaris
Punctate PPK type III, acrokeratoelastoidosis AD Unknown
Focal acral hyperkeratosis AD Unknown
Hereditary papulotranslucent acrokeratoderma AD Unknown
COMPLEX PPKs
Loricrin keratoderma AD LOR
Olmsted syndrome AD, AR, XLR TRPV3/MBTPS2
Striate PPK with wooly hair AR KANK2
PPK and congenital alopecia 1 (PPKCA1), Stefanovic type AD GJA1
PPK and congenital alopecia 2 (PPKCA2), Wallis type AR Unknown
Hyperkeratosis-hyperpigmentation syndrome AD Unknown
PPK with pigmentation defects and skin carcinoma AR SASH1
PPK: palmoplantar kratoderma., AD: autosomal dominant, AR: autosomal recessive, KLR: X-linked recessive
*The common histopathological findings and pathogenetic mechanisms support grouping of all KRT1/KRT9-related
PPKs (including the striate PPK type III) in a single entity.

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ccepted Articl
Table 2. Diffuse palmoplantar keratodermas due to KRT9/KRT1 mutations*

Name/definition PPK, epidermolytic PPK, epidermolytic PPK, nonepidermolytic

(Thost-Unna or Vorner type) (Greither disease)
OMIM 144200 144200 600962
149100
Inheritance AD AD AD
Gene KRT1 KRT1 KRT1
KRT9
Onset Soon after birth to early childhood Soon after birth to childhood/adolescence At birth or soon after birth
Type of palmoplantar Diffuse yellowish thick hyperkeratosis, sharp Diffuse red/yellow moderate to severe Diffuse mild to thick hyperkeratosis, red halo/rim
involvement demarcation at the volar border, frequently red- hyperkeratosis, red-violaceous halo/rim
violaceous halo/rim
Mutilating Rare No No

Transgrediens Rare Yes Yes

Progrediens Yes Yes Yes

Involvement of other skin Knuckle pads (frequently), nail clubbing Patchy hyperkeratosis on elbows, knees, thighs, Knuckle pads, hyperkeratosis of umbilicus and
areas and/or appendages inguinal folds, antecubital fossae and axillae areolae, diffuse dry skin
Additional clinical findings Fissures, hyperhidrosis, fungal infections, acral Fissures, hyperhidrosis, fungal infections, transient Fungal infections
blisters in infancy (rare) generalized blistering and erythroderma at birth
(rare)
Laboratory findings H: epidermolytic pattern (perinuclear H: epidermolytic pattern H/EM: nonepidermolytic pattern
vacuolization and granular degeneration of
keratinocytes in the spinous and granular layer
EM: tonofilament aggregates/whorls
PPK: palmoplantar keratoderma. AD: autosomal dominant. KRT: keratin. H: histology. EM: electron microscopy.
*An autosomal dominant KRT1 mutation was also reported in a single British family and is currently classified as striate PPK type III, with patients manifesting striate hyperkeratosis on palms
and focal on soles.

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ccepted Articl
Table 3. Palmoplantar keratodermas due to SLURP1/AQP5/SERPINB7 mutations

Name/definition Mal de Meleda PPK, Bothnian type PPK, Nagashima type

(PPK transgrediens of Siemens)
OMIM 248300 600231 615598
244850 Gamborg-Nielsen/Norrbotten
Inheritance AR AD AR
Gene SLURP1 AQP5 SERPINB7
Onset Soon after birth Early childhood Mostly within infancy
Type of palmoplantar Diffuse yellow and waxy thick hyperkeratosis in a Diffuse yellowish mild to thick hyperkeratosis, red Diffuse mild reddish hyperkeratosis, red rim; white
involvement “glove-and-socks” distribution, sharp rim; white spongy appearance after water exposure spongy appearance after water exposure
demarcation, red/bluish-red rim
Mutilating Rare No No
Transgrediens Yes Yes Yes
Progrediens Yes Rare No
Involvement of other skin Knucke pads, psoriasiform or lichenoid plaques Curved nails, ragged cuticles Hyperkeratosis on elbows and knees, occasionally
areas and/or appendages on elbows and knees, perioral erythema and also on forearms, thighs, cubital and popliteal
angular cheilitis, nail dystrophy fossae andl ower legs
Additional clinical findings Hyperhidrosis, fissures, maceration, infections, Hyperhidrosis, recurrent tinea pedis and Hyperhidrosis, fungal infections, maceration, foul
foul odour, digit tapering, hand/foot joint stiffness, onychomycosis odor; multiple primary acral lentiginous melanoma
contractures, melanoma arising on PPK
Laboratory findings H: nonepidermolytic pattern; increased stratum H: nonepidermolytic pattern H: nonepidermolytic pattern
lucidum, prominent perivascular inflammatory IF: strong AQP5 membrane expression in the IHC: markedly decreased SERPINB7 expression in
infiltrate granular layer the granular and horny layers
PPK: palmoplantar keratoderma. AR: autosomal recessive. AD: autosomal dominant. SLURP1: secreted lymphocyte antigen 6 (LY6)/ urokinase-type plasminogen activator receptor (uPAR)-
related protein-1. AQP5:aquaporin-5. SERPINB7: serpin peptidase inhibitor, clade B (ovalbumin), member 70. H: histology. IF: immunofluorescence. IHC: immunohistochemistry.

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ccepted Articl
Table 4. Palmoplantar keratodermas of Huriez syndrome and keratolytic winter erythema

Name/definition Sclerotylosis (Huriez syndrome) Keratolytic winter erythema

(KWE, Oudtshoorn skin disease, erythrokeratolysis hiemalis)
OMIM 181600 148370
Inheritance AD AD
Gene Unknown CTSB
Onset Infancy Infancy to early adulthood
Type of palmoplantar Diffuse non erythematous hyperkeratosis most marked on palms Recurring cycles in winter of diffuse palmoplantar erythema, followed by
involvement than soles, scleroatrophy, dry skin epidermis thickening and superficial dry blister formation from which
centrifugal peeling develops
Mutilating No No
Transgrediens No Yes
Progrediens Yes No, improvement with age
Involvement of other skin Erythematous, atrophic parchment-like or patchy hyperkeratotic Migratory annular erythema on extremities and buttocks
areas and/or appendages lesions on the dorsa of hands, feet, finger and toes, mostly on
joints; nail hypoplasia/dystrophy
Additional clinical findings Sclerodactyly, short tapered fingers with atrophy of digit pulps, Itching, hyperhidrosis, pungent odor
hypohidrosis; early onset metastatic squamous cell carcinomas
on scleroatrophic skin; pharyngeal, gastric and esophageal
cancer (rare)
Laboratory findings H: nonepidermolytic pattern, thickened dermal collagen bundles H: nonepidermolytic pattern with acanthosis, hyperkeratosis and
and scanty elastic fibers in papillary and reticular dermis, dilated hypergranulosis, focal parakeratosis, mild spongiosis
blood vessels IHC: CSTB expression in the granular layer (not detectable in normal
skin)

AD: autosomal dominant. CTSB: cathepsin B. H: histology. IHC: immunohistochemistry.

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 Table 5. Focal palmoplantar keratodermas

Name/definition Focal PPK

Accepted Article
OMIM 615735
613000
Inheritance AD
Gene KRT6C
KRT16
Onset Childhood
Type of palmoplantar Focal, friction-related plantar hyperkeratosis, occasional palmar involvement
involvement
Mutilating No
Transgrediens No
Progrediens Yes
Involvement of other skin Minimal nail changes (hypertrophy of the fifth toenail, widening of onychocorneal bands with nail
areas and/or appendages splinter hemorrhages), follicular hyperkeratosis,
Additional clinical findings Hyperhidrosis, plantar blistering, minimal oral or orogenital leukokeratosis
Laboratory findings H: nonepidermolytic pattern with hyperkeratosis, acanthosis, hypergranulosis
EM: normal keratin filament network in suprabasal cells
PPK: palmoplantar keratoderma. AD: autosomal dominant. KRT: keratin. H: histology. EM:electron microscopy.

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ccepted Articl
Table 6. Striate palmoplantar keratodermas

Name/definition Striate PPK, type I Striate PPK, type II

OMIM 148700 612908
Inheritance AD AD
Gene DSG1 DSP
Onset Childhood to adolescence Childhood to early adulthood
Type of palmoplantar Linear hyperkeratosis on palms and palmar aspects Linear hyperkeratosis on palms and palmar aspect of fingers,
involvement of the fingers, focal hyperkeratosis at trauma-prone focal hyperkeratosis at trauma-prone sites on soles
sites on soles
Mutilating No No
Transgrediens Rare No
Progrediens Yes Yes
Involvement of other skin Knee and elbow hyperkeratosis (rare) No
areas and/or appendages
Additional clinical findings Hyperhidrosis, foul odor, plantar pain Fissures

Laboratory findings H: hyperkeratosis, widening of intercellular spaces in

H: hyperkeratosis, widening of intercellular spaces and
the spinous and granular layer condensation of the keratin filament network in suprabasal cell
EM: reduced desmosome size and number layers
EM: markedly reduced desmosome number, particularly in the
spinous layer, dense tonofilament bundles in the perinuclear
cytoplasm
PPK: palmoplantar keratoderma. AD: autosomal dominant. DSG1: desmoglein 1. DSP: desmoplakin. KRT1: keratin 1. H: histology. EM: electron microscopy.

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ccepted Articl
Table 7. Punctate palmoplantar keratodermas

Name/definition Punctate PPK, Buschke-Fisher-Brauer type I Punctate PPK, type II

(porokeratosis punctata palmaris and plantaris;
Punctate PPK, type IA Punctate PPK, type IB spiny keratoderma)
OMIM 148600 614936 175860
Inheritance AD AD AD
Gene AAGAB COL14A1 Unknown
Onset Late childhood to adulthood Late childhood to adulthood Puberty to early adulthood
Type of palmoplantar Multiple hyperkeratotic papules with Multiple hyperkeratotic papules with Multiple spiny keratoses; pits with keratotic plugs (late
involvement central indentation; worsening of central indentation onset)
papules upon exposure to water

Mutilating No No No
Transgrediens No No No
Progrediens Yes Yes Yes
Involvement of other skin Nail dystrophy (rare) No No
areas and/or appendages
Additional clinical findings Association with malignancies (rare) Colonic cancer Facial sebaceous hypoplasia in males
Laboratory findings H: hyperkeratosis and hypergranulosis H: hyperkeratosis and hypergranulosis H: columns of parakeratotic corneocytes (cornoid
with central epidermal depression with central epidermal depression lamellae) overlying an epidermal depression where the
IF: strongly reduced cytoplasmic granular layer is reduced or absent
AAGAB staining in basal and lower
spinous layer, but increased perinuclear
granular staining in spinous layer
PPK: palmoplantar keratoderma. AD: autosomal dominant. AAGAB: Alpha-and gamma-adaptin-binding protein p34. COL14A1: collagen XIV. H: histology. IF: immunofluorescence.

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ccepted Articl
Table 8. Punctate palmoplantar keratodermas

Name/definition Punctate PPK, type III Focal acral hyperkeratosis Hereditary papulotranslucent
(acrokeratoelastoidosis) acrokeratoderma

OMIM 101850 - 101840

Inheritance AD AD AD
Gene Unknown Unknown Unknown
Onset Adolescence to adulthood Adolescence to adulthood At or soon after puberty
Type of palmoplantar Translucent hyperkeratotic Multiple hyperkeratotic and crateriform Translucent, yellowish-white smooth papules,
involvement papules, sometimes umbilicated, on papules coalescing into plaques on mainly on margins of palms and soles;
lateral aspects of palms and soles dorsal and lateral aspects of hands and worsening of papules upon exposure to water
feet
Mutilating No No No
Transgrediens Rare (severe cases only) Yes Yes
Progrediens Yes Yes Yes
Involvement of other skin Nail dystrophy (very rare) Nail dystrophy (rare) Sparse, fine-textured scalp hair
areas and/or appendages
Additional clinical findings No No Worsening of papules upon water exposure,
atopy
Laboratory findings H: hyperkeratosis and H: hyperkeratosis overlying a crateriform H: hyperkeratosis and hypergranulosis; normal
hypergranulosis; decreased number depression in the epidermis, eccrine ducts
of fragmented elastic fibers hypergranulosis, mild acanthosis
(elastorrhexis) EM: normal elastic fibers and collagen
PPK: palmoplantar keratoderma. AD: autosomal dominant. H: histology. EM: electron microscopy.

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ccepted Articl
Table 9. Complex palmoplantar keratodermas due to LOR/TRPV3/MBTPS2 mutations

Name/definition Loricrin keratoderma * Olmsted syndrome

OMIM 604117 614594 300918
Inheritance AD AD, AR XLR
Gene LOR TRPV3 MBTPS2
Onset Early childhood Birth to early childhood Infancy
Type of palmoplantar Diffuse honeycomb-like hyperkeratosis Diffuse and massive yellowish-brown hyperkeratosis with Diffuse and massive yellowish-brown hyperkeratosis
involvement painful fissures, red rim with deep painful fissures, red rim
Mutilating Yes Yes No
Transgrediens Yes Yes Yes
Progrediens Yes Yes Yes
Involvement of other skin Generalized mild scaling accentuated Periorificial hyperkeratosis, hyperkeratosis on neck, upper Periorificial hyperkeratosis, verrucous and
areas and/or appendages over joints and flexural areas thorax, lower abdomen, inguinal folds, thighs, elbows and hyperkeratotic plaques on neck, knees, legs and
knees, hair involvement (from fine slow-growing hair to forearms, alopecia universalis, severe nail dystrophies
alopecia universalis), nail dystrophies
Additional clinical findings Onset as congenital ichthyosiform Hyperhidrosis or anhidrosis, infections, oral leukokeratosis, Infections, foul odor, eye abnormalities (corneal
erythroderma or rarely as colloidon corneal dystrophies, chronic blepharitis, predisposition to dystrophies, chronic blepharitis, eyelid telangiectasias)
baby malignancies in hyperkeratotic areas; growth delay,
hearing loss for high tones, abnormal dentition, bone
deformities, hyper IgE, eosinophilia (rare)
Laboratory findings H: hyperkeratosis and parakeratosis, H: psoriasiform hyperplasia, massive hyperkeratosis, H: nonepidermolytic pattern with papillomatosis
intranuclear granules in granular layer hypergranulosis with foci of hypogranulosis IF: MBTPS2 expression through the epidermis, in
EM: intranuclear electron dense contrast to limited expression in the upper granular
inclusions within keratinocytes of the layer of normal epidermis
granular layer
IF/IEM: nucleolar mutant loricrin
AD: autosomal dominant. AR: autosomal recessive. XLR: X-linked recessive. LOR: loricrin. TRPV3: transient receptor potential vanilloid 3. MBTPS2: membrane-bound transcription factor
protease site 2. H: histology. EM: electron microscopy. IF: immunofluorescence. IEM: immunoelectron microscopy.
*Currently classified as non-syndromic ichthyosis10

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ccepted Articl
Table 10. Complex palmoplantar keratodermas with hair anomalies

Name/definition PPK and woolly hair PPK and congenital alopecia 1, Stefanovic type PPK and congenital alopecia 2, Wallis type
(PPKCA1, keratoderma-hypotrichosis- (PPKCA2, cataract-alopecia-sclerodactyly
leukonychia totalis syndrome, KHLS) syndrome, CASS)
OMIM 616099 104100 212360
Inheritance AR AD AR
Gene KANK2 GJA1 Unknown
Onset Woolly hair: at birth Hypotrichosis / alopecia: at birth Alopecia: infancy
PPK: early childhood PPK: infancy PPK: late infancy to middle childhood
Type of palmoplantar Striate, more severe on Focal on weight-bearing areas, linear distribution Hyperkeratosis of lateral and medial aspects of
involvement soles on fingers, erythematous halo palms and soles, erythematous halo
Mutilating Yes No Yes
Transgrediens No Yes Yes
Progrediens Yes Yes Yes
Involvement of other skin Follicular keratosis on extensor arms, shins, Hyperkeratotic plaques on trunk, limbs and perianal Ulerythema ophryogenes, diffuse keratosis pilaris,
areas and/or appendages back, and cheeks; lichenoid papules on lower areas, diffuse keratosis pilaris, hypotrichosis with scalp alopecia, sparse eyebrows and eyelashes,
shins; woolly hair, sparse scalp and body hair as hair shaft dystrophy or congenital alopecia, mild nail dystrophy, perionyxis-like changes
well as eyelashes and eyebrows, leukonychia congenital 20-nail leukonychia
Additional clinical findings No Hypohidrosis Sclerodactyly with contractures, congenital
cataract, unilateral deafness, meningocele (rare)
Laboratory findings H: hyperkeratosis with acanthosis, normal H: hyperkeratosis with follicular plugging LM (hair shaft): trichorrhexis nodosa
granular layer LM (hair shaft): trichorrhexis nodosa, trichoptilosis
LM (hair shaft): longitudinal and oblique fractures,
tapered hairs, trichorrhexis nodosa like lesions,
pseudomonilethrix, twisted and corkscrew-like
hair
PPK: palmoplantar keratoderma. AR: autosomal recessive. AD: autosomal dominant. KANK2: ankyrin repeat domain containing protein 2. GJA1: gap junction protein alpha 1 gene. H:
histology.
LM: light microscopy.

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ccepted Articl
Table 11. Complex palmoplantar keratodermas with pigmentary anomalies

Name/definition Hyperkeratosis-hyperpigmentation syndrome PPK with pigmentation defects and skin carcinoma
OMIM 144190 None
Inheritance AD AR
Gene Unknown SASH1
Onset Pigmentary anomalies: early childhood to adolescence Infancy
PPK: years later
Type of palmoplantar Hyperkeratotic thick papules on palms and soles Diffuse hyperkeratosis with ill-defined margins and thick squamae
involvement
Mutilating No No
Transgrediens Yes No
Progrediens Yes No
Involvement of other skin Brownish spots to larger dark-brown maculae on sun exposed Hypo and hyperpigmented maculae on trunk and face, reticular hypo and
areas and/or appendages areas, particularly on face, neck and limbs; slightly dysplastic nails
hyperpigmentation on extremities, progressive alopecia of the scalp,
with transversal grooves eyelashes and eyebrows, nail dystrophy, multiple and aggressive
squamous cell carcinomas
Additional clinical findings No Conjunctival telangiectasia, occasional brittle teeth leading to complete
tooth loss
Laboratory findings H: hyperkeratosis and acanthosis, mild granular layer hyperplasia NR
PPK: palmoplantar keratoderma. AD: autosomal dominant. AR: autosomal recessive. SASH1: (SAM- and SH3-domain containing 1). H: histology. NR: not reported.

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 LEGENDS

Figure 1
Accepted Article
Transgrediens plantar keratoderma. Diffuse thick hyperkeratosis extending over the Achille’

tendon area.

Figure 2

Epidermolytic diffuse palmoplantar keratoderma due to KRT9 mutation. Yellowish thick

hyperkeratosis involving the entire surface of palms and soles (a, b), with a sharp

demarcation at the volar border and an erythematous margin (c, d).

Figure 3

Mal de Meleda. Diffuse, yellowish and waxy palmoplantar hyperkeratosis, in a glove-and-

socks distribution (a, b). Transgrediens progression of hyperkeratosis to the dorsal aspects of

hands and feet (c-f). The distal phalanges of fingers show a conical shape (c, e). Nail

dystrophy is characterized by onchyolysis, hyperconvexity and subungual hyperkeratosis (e,

f). Pigmented, possibly post-inflammatory, areas are visible on the dorsal and lateral aspects

of hands and feet, respectively (c, d).

Figure 4

Focal palmoplantar keratoderma. Hyperkeratotic patches are present at weight-bearing areas

of feet.

Figure 5

Striate palmoplantar keratoderma. Hyperkeratosis with particular prominence on the creases

of the palms and in linear streaks along the flexor aspect of the fingers.

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 Figure 6

Punctate palmoplantar keratoderma. Multiple yellowish hyperkeratotic papular lesions

Accepted Article
irregularly distributed on palms.

Figure 7

Spiny palmoplantar keratoderma. Multiple, minute, filiform, hyperkeratotic lesions

distributed on margins of palms (a, arrows) and fingers (b).

Figure 8

Loricrin keratoderma. Honeycomb-like palmoplantar hyperkeratosis (a, b) associated with a

mild ichthyosis (c). Pseudoainhum (constricting fibrous bands on the digits) (a, b: arrows)

and autoamputation (b) are visible in distal phalanges of little fingers.

Figure 9

Palmoplantar keratoderma and congenital alopecia 2 (PPKCA2). Nonscarring alopecia of the

scalp (a), hyperkeratosis involving the heel (b) and the tips of the toes (c), perionyxis-like

lesions (c, d), sclerodactyly of the fingers (e).

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Accepted Article

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