Palmoplantar keratoderma (PPK)

INTRODUCTION — 

Palmoplantar keratoderma (PPK) is a heterogeneous group of inherited or acquired disorders characterized by excessive epidermal thickening of the palms and soles. In most cases, hereditary PPK are caused by variants in genes encoding proteins that are components of the intracellular cytoskeleton (eg, keratins) or involved in intercellular adhesion (eg, desmosomal proteins), cell-to-cell communication (eg, connexins), regulation of cell adhesion (eg, proteases and protease inhibitors), and cell signaling (eg, SLURP1 protein) [1,2].

Hereditary PPK can occur in isolation (nonsyndromic PPK) or in association with extracutaneous manifestations (syndromic PPK) [1,3,4]. PPK can also be an associated feature of a broad number of genodermatoses, including inherited ichthyoses, inherited blistering diseases, and ectodermal dysplasias.

The diagnosis of a specific PPK type is challenging due to the highly heterogeneous phenotypes and genotypes and is based on a combination of clinical and histopathologic features and genetic testing [5].

This topic will discuss nonsyndromic PPK and syndromes in which PPK is a major feature. Other inherited disorders of keratinization that may present with PPK are discussed separately.

●(See "Overview and classification of the inherited ichthyoses".)

●(See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features".)

●(See "Ectodermal dysplasias".)

EPIDEMIOLOGY — 

The exact incidence and prevalence of PPK are unknown. In Northern Ireland, the estimated prevalence of epidermolytic PPK (PPK Vörner type), the most common type of PPK, was 4.4 per 100,000 [6]. In Japan and China, the estimated prevalence of PPK type Nagashima, the most common PPK in East Asia, is 1.2 per 10,000 and 3.1 per 10,000, respectively [7].

CLASSIFICATION — 

There is no unanimously accepted classification of hereditary PPK. Because of the high heterogeneity in clinical presentation, causative genetic defect, mode of inheritance, and presence or absence of associated features, the classification of PPK can be based on a variety of criteria (table 1A and table 1B), including [1,3]:

●Presence or absence of other cutaneous and extracutaneous features – PPK may be isolated (nonsyndromic), associated with other genodermatoses (eg, ichthyosis, epidermolysis bullosa, ectodermal dysplasia), associated with other organ involvement as a component of a complex syndrome (eg, Papillon-Lefèvre syndrome), or associated with more debilitating pain than expected (eg, pachyonychia congenita).

●Lesion morphology – Acral hyperkeratosis can be diffuse (involving the entire palmar and plantar surfaces) or limited to certain areas (focal, striate, punctate). PPK may be "transgrediens" (extending beyond the palms and soles) or "mutilating" (due to the development of constrictive bands around the digits).

●Histology – Cytolysis in granular layer keratinocytes may be present or absent.

●Inheritance mode – PPK can be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern. Mitochondrial inheritance has also been reported.

●Genetic defect/disrupted molecular pathway [8].

MOLECULAR PATHOGENESIS — 

PPK is caused by pathogenic variants in genes encoding structural or secreted proteins of the granular layer of the epidermis. These include:

●KRT1 and KRT9, which encode major intermediate keratin filaments of the granular layer of the keratinocyte cytoskeleton

●DSG1, encoding desmoglein 1, a major cell-cell adhesion molecule of desmosomes in the granular layer

●LOR, encoding loricrin, a major component of cornified cell envelope expressed in granular layer cells

●SERPINB7 and SERPINA12, encoding serine proteinase inhibitors probably associated with the degradation of desmoglein 1 and corneodesmosin, which are expressed in granular layer cells

●AQP5, encoding a water channel protein expressed in granular layer cells

●SLURP1, encoding a secreted protein associated with signal transduction that is expressed in granular layer cells

Variants in genes encoding proteins involved in cell proliferation are also associated with PPK. These include:

●PTEN, a tumor suppressor and cell cycle regulator

●AAGAB, a putative regulator of the turnover of the epidermal growth factor receptor (EGFR)

●RHBDF2, a regulator of epidermal growth factor signaling

DIFFUSE PPK

Overview — Diffuse PPK are characterized by epidermal thickening that involves the entire surface of the palms and soles (table 1A). The hyperkeratosis may show a sharp demarcation at the palmar or plantar border ("nontransgrediens") or may extend onto nonpalmar or nonplantar skin, such as the dorsal surfaces of the hands and feet, inner wrists, the Achilles tendon area, elbows, and knees ("transgrediens") [3,5].

Involvement beyond the palmar and plantar skin is observed in several diffuse PPK, including mal de Meleda; acral keratoderma; and PPK types Nagashima, Bothnia, Gamborg-Nielsen, Greither, and Sybert [9-17].

Diffuse epidermolytic PPK Vörner type (Unna-Thost type included) — Diffuse epidermolytic PPK Vörner type (MIM #144200) is the most common PPK in White persons.

●Genetics – Vörner type PPK is caused by heterozygous pathogenic variants in the keratin genes KRT1 or KRT9 that disrupt the formation of keratin intermediate filaments. This results in structural weakness of the keratinocyte cytoskeleton and vacuolar cell degeneration (epidermolysis) [18]. Diffuse epidermolytic PPK Vörner type is inherited in an autosomal dominant pattern. De novo variants have also been reported [19].

The finding that variants in descendants of the original families described by Vörner and by Unna and Thost are located on the coil-1A segment at the beginning of the central rod domain of KRT9 supports the theory that PPK Vörner type and PPK Unna-Thost type are not different entities [18,20].

●Genotype-phenotype correlation – Because KRT9 is exclusively expressed in the keratinocytes of the palms and soles, the epidermolytic hyperkeratosis involves only the palms and soles in patients with mutated KRT9. In contrast, as KRT1 is expressed in the keratinocytes of the entire skin, distinct heterozygous variants in KRT1 cause generalized epidermolytic hyperkeratosis with diffuse PPK. This condition is called epidermolytic ichthyosis (MIM #113800) and is considered allelic to Vörner disease. (See "Keratinopathic ichthyoses", section on 'Epidermolytic ichthyosis'.)

●Histopathology – Histology shows hyperkeratosis and vacuolar degeneration of cells in the granular and spinous layers of the epidermis (epidermolytic hyperkeratosis). However, because the epidermolysis is induced by physical stimuli to the skin on a background weakness of keratin cytoskeleton, histologic examination may not consistently show epidermolysis.

Unna-Thost PPK (MIM #600962), which is caused by variants in KRT1, was formerly classified as nonepidermolytic diffuse PPK. However, based on histologic re-evaluation of skin biopsies from offspring of the original family described by Unna and Thost showing epidermolytic hyperkeratosis, it was concluded that the designation "Unna-Thost" is misleading and should be avoided [20,21]

●Clinical presentation – PPK Vörner type becomes apparent at birth or in early childhood and presents with diffuse, compact, yellowish hyperkeratosis limited to the palms and soles, with sharp demarcation at the volar border (nontransgrediens) and a surrounding erythematous margin (picture 1 and picture 2). Hyperhidrosis is a frequent associated symptom.

Diffuse nonepidermolytic PPK

Mal de Meleda — Mal de Meleda (keratosis palmoplantaris transgrediens, MIM #248300), first described on the Croatian island of Mljet (Meleda) in 1826, is an autosomal recessive PPK caused by biallelic variants in SLURP1 (encoding the secreted Ly6/uPAR related protein-1) [22]. In Europe and Mediterranean countries, the prevalence of the three most common variants (c.82delT, p.R96X, and p.W15R) shows a marked geographic demarcation, suggesting a founder effect [23].

●Clinical presentation – Mal de Meleda presents at birth or in early infancy with diffuse erythema and hyperkeratosis of the palms and soles that extends to the dorsal surface of the feet and hands and gradually progresses to involve the knuckles, wrists, and ankles in a characteristic "gloves and socks" distribution (picture 3A and picture 4). This distribution beyond the palmoplantar area is called "transgrediens".

Circumferential hyperkeratosis of the fingers may result in constriction bands (pseudoainhum), spontaneous amputations, and flexion contractures. Hyperhidrosis, maceration, odor, and secondary fungal infection are common. Hyperkeratotic plaques may be present on the elbows and knees. Nails are also affected and may show thickening and koilonychia.

Secondary fungal infection may cause severe exacerbation of symptoms (picture 5).

Gamborg-Nielsen type — PPK Gamborg-Nielsen type (also called Norrbotten type, MIM #244850) was first described in Norrbotten, the northernmost county of Sweden. It is caused by variants of SLURP1 and can be considered a milder subtype of mal de Meleda [24]. The palmoplantar hyperkeratosis is less severe, and there are no nail deformities or distant hyperkeratotic plaques, except for knuckle pads [25].

Nagashima type — Nagashima type PPK (MIM #615598) is an autosomal recessive form of diffuse, nonepidermolytic PPK and the most common PPK in Eastern Asian populations, with prevalence rates of 1.2 per 10,000 in Japan and 3.1 per 10,000 in China [7].

●Genetics – Nagashima type PPK is caused by biallelic loss of function variants in SERPINB7, which encodes a proteinase inhibitor expressed in the upper layers of the epidermis [7]. Due to a highly prevalent founder variant of SERPINB7 (c.796C>T) in East Asia, the overall prevalence of SERPINB7 variant carriers is estimated to be approximately 1 in 50 in Japanese and Chinese populations [7].

Nagashima type PPK has also been identified in White patients in Finland due to the presence of a founder mutation in Finnish populations [26]. A genome-wide association study suggested that the deleterious variant of SERPINB7 is associated with susceptibility to atopic dermatitis [27].

Digenic inheritance of SERPINB7 and SERPINA12 has been hypothesized in 12 Chinese patients with the Nagashima type phenotype [28].

●Clinical features – PPK Nagashima type presents with a nonprogressive, mild hyperkeratosis with skin redness that extends to the dorsal surfaces of the hands and feet, inner wrists, ankles, and the Achilles tendon area (picture 6A and picture 6B) [12,29]. After exposure to water, the palms and soles show a characteristic whitish, spongy appearance. Hyperhidrosis, secondary fungal infection, and odor are common. Co-occurrence of atopic dermatitis during childhood has been reported [30,31].

SERPINA12-associated PPK

●Genetics – Diffuse PPK associated with SERPINA12 variants is a rare autosomal recessive form of diffuse nonepidermolytic PPK caused by biallelic loss of function variants in SERPINA12, which encodes vaspin (visceral adipose tissue-derived serine protease) inhibitor expressed in the upper layers of the epidermis and adipose tissues. Two patients of Arab descent and Jewish descent were identified in 2020 [32]. Six additional cases caused by novel variants in SERPINA12 were subsequently identified in five unrelated families in China [33]. Biallelic SERPINA12 variants were also identified in three nonconsanguineous Finnish patients [34]. Of note, all three patients also carried a heterozygous SERPINB7 variant.

●Clinical features – Clinical features resemble PPK Nagashima type, including erythematous, diffuse hyperkeratosis of the palms and soles with peripheral peeling extending to the inner wrist area, the Achilles tendon area, and the anterior part of the leg.

Bothnia type — PPK Bothnia type has a high prevalence (0.3 to 0.55 percent) in the two northernmost provinces of Sweden around the Gulf of Bothnia [13].

●Genetics – PPK Bothnia type (MIM #600231) is an autosomal dominant form of diffuse nonepidermolytic PPK caused by variants in AQP5 (encoding the water-channel protein aquaporin 5) [35,36].

●Clinical presentation – Clinically, Bothnia type PPK resembles Nagashima type PPK, with mild transgrediens redness, hyperkeratosis, and whitish changes upon water exposure (picture 7 and picture 8) [13].

Transgrediens et progrediens PPK (Greither disease) — Transgrediens et progrediens PPK (Greither disease) is an autosomal dominant form of diffuse PPK caused by KRT1 variants [37,38]. It becomes apparent in infancy and is characterized by diffuse hyperkeratosis of the palms and soles extending to the dorsal surface of the hands and feet and the Achilles tendon area and by a tendency to worsen with age.

Of note, variants in KRT1 are associated with multiple keratinization disorders with widely heterogeneous clinical phenotypes. These include Vörner type PPK (MIM #144200), striate PPK, epidermolytic ichthyosis (MIM #113800), ichthyosis hystrix Curth-Macklin type (MIM #146590), and cyclic ichthyosis with epidermolytic hyperkeratosis (MIM #607602).

Diffuse PPK associated with FLG variants — Diffuse PPK with erythema, palmar hyperlinearity, transgrediens features, and generalized dry skin has been described in 22 patients with monoallelic or biallelic pathogenic variants in FLG, encoding filaggrin, in the absence of other pathogenic variants in all known genes associated with PPK [39]. In most cases, PPK was mild or moderate.

Diffuse PPK caused by DSG1 variants — Autosomal dominant variants in the desmoglein 1 gene (DSG1), which cause striate PPK type 1 (see 'Striate PPK types 1, 2, and 3' below), have also been associated with a form of diffuse nonepidermolytic PPK in an Israeli family [40].

Biallelic DSG1 variants with complete loss of functional DSG1 present with PPK and SAM (severe dermatitis, multiple allergies, and metabolic wasting) syndrome (MIM #615508) [41].

Certain heterozygous missense variants in the transmembrane domain of DSG1 cause autosomal dominant SAM syndrome (picture 9A-B) [42]. (See "Peeling skin syndromes", section on 'SAM syndrome'.)

FOCAL PPK — 

Focal PPK are characterized by painful, circumscribed hyperkeratosis resembling calluses on the weight-bearing areas of the soles (picture 10).

Pachyonychia congenita — Painful focal PPK with underlying blisters is a major manifestation of pachyonychia congenita (picture 11), an autosomal dominant disorder caused by heterozygous variants in KRT6A, KRT6B, KRT6C, KRT16, or KRT17 and characterized by hypertrophic nail dystrophy [43]. (See "Pachyonychia congenita".)

Focal nonepidermolytic PPK

●Genetics – Focal nonepidermolytic PPK is a genetically heterogeneous disorder.

•Specific autosomal dominant variants in keratin genes KRT6C and KRT16 (MIM #615735 and #613000) are associated with focal nonepidermolytic PPK [44-48].

•Specific autosomal dominant variants in DSG1, encoding desmoglein 1, cause phenotypically heterogeneous focal PPK type 1 (MIM #148700), with or without minimal changes in the nails and other ectodermal tissues [40,49-53].

•A missense heterozygous variant in TRPV3 (encoding a transient receptor potential cation channel, subfamily V, member 3) has been reported in a Chinese family with focal nonepidermolytic PPK type 2 (MIM #616400) (picture 12) [54].

Several variants in TRPV3 have also been reported as the cause of Olmsted syndrome (MIM #614594), which shows focal or mutilating diffuse PPK and perioral hyperkeratotic plaques [54,55]. (See 'Olmsted syndrome' below.)

•Mitochondrial PPK caused by the specific variant m.7445A>G shows focal nonepidermolytic PPK. (See 'Mitochondrial PPK with deafness' below.)

●Clinical presentation – Areas of keratoderma are present on the soles at sites of recurrent friction with limited or even absent palm involvement or nail dystrophy (picture 12).

STRIATE PPK

Striate PPK types 1, 2, and 3

●Genetics – Striate PPK type 1 (MIM #148700), type 2 (MIM #612908), and type 3 (MIM #607654) are autosomal dominant PPK caused by heterozygous variants in DSG1, DSP, and KRT1, respectively [50,56,57].

●Clinical presentation – Striate PPK presents with prominent hyperkeratosis in a linear pattern along the flexor aspects of the fingers (picture 13) and over pressure points on the soles.

Striate PPK and woolly hair — PPK and woolly hair (MIM #616099) is a rare autosomal recessive PPK caused by homozygous variants in the KANK2 gene [58]. Members of two affected consanguineous families presented with a variable degree of striate PPK, leukonychia, sparse scalp and body hair, and, in some cases, woolly hair [58].

PUNCTATE PPK — 

Punctate PPK is characterized by multiple tiny, hyperkeratotic papules on the palms and soles (picture 14). The syndromic type includes Cowden syndrome 1, Cole disease, and PLACK (peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads) syndrome. (See 'Syndromic PPK' below.)

Punctate PPK types 1A and 1B — Punctate PPK type 1A, also called PPK type Buschke-Fischer-Brauer (MIM #148600), is an autosomal dominant PPK caused by heterozygous variants in AAGAB (encoding alpha- and gamma-adaptin-binding protein p34) [59-62]. It appears during late childhood to adolescence with multiple tiny, punctate keratoses on the palms and soles that increase in number and size with age (picture 14).

A heterozygous variant in COL14A1 (encoding collagen 14) has been identified in a large Chinese family with punctate PPK type 1B [62].

It is unclear whether punctate PPK type 1A is associated with an increased risk of cancer [63,64].

Punctate PPK type 2 — Punctate PPK type 2, also called porokeratosis punctate palmaris et plantaris, is an autosomal dominant disorder with uncertain penetrance that presents with numerous tiny, keratotic spines on the palms and soles. Histologic studies showed distinct epidermal depressions containing cornoid lamellae [65,66].

Pathogenic variants in five genes encoding enzymes of the mevalonate pathway and distal mevalonate pathway for cholesterol biosynthesis have been identified as the cause of porokeratosis [67-69] (see "Porokeratosis"). One of the five genes associated with porokeratosis, MVD, has been reported to be associated with punctate PPK type 2 [70].

Punctate PPK type 3 (acrokeratoelastoidosis) — Punctate PPK type 3, also called acrokeratoelastoidosis (MIM #101850), is an autosomal dominant disorder characterized by papular, yellowish or brown lesions with a hyperkeratotic surface on the lateral and dorsal aspects of the palms and soles (picture 15A-D) [71]. Histologic findings include hyperkeratosis, mild acanthosis, and degeneration of the elastic fibers. The causative gene is unknown.

SYNDROMIC PPK — 

Syndromic PPK include a large number of conditions characterized by PPK and extracutaneous abnormalities [4]. PPK may also be a feature of certain genodermatoses, including some forms of ichthyosis and ectodermal dysplasias and some subtypes of epidermolysis bullosa.

PPK with deafness — Heterozygous variants in GJB2 (which encodes the gap junction protein connexin 26) cause a number of autosomal dominant disorders characterized by diffuse PPK with hearing impairment and various associated extracutaneous features [1,2,4,72,73]. Allelic mutations in GJB2 are also known to cause autosomal dominant and autosomal recessive forms of nonsyndromic congenital hearing loss. (See "Hearing loss in children: Etiology".)

A rare type of PPK associated with deafness is caused by mitochondrial variants. (See 'Mitochondrial PPK with deafness' below.)

Vohwinkel syndrome — Classic Vohwinkel syndrome (MIM #124500), also called mutilating PPK, is a rare autosomal dominant condition caused by variants in GJB2.

It is characterized by [74]:

●Congenital deafness or hearing impairment

●Diffuse PPK with a characteristic honeycomb pattern (picture 16)

●Starfish-shaped, hyperkeratotic plaques on knuckles (picture 17)

●Mutilating digital constriction rings around fingers and toes (pseudoainhum) that result in spontaneous autoamputation (picture 18)

PPK with sensory deafness — PPK with deafness (MIM #148350) is an autosomal dominant condition caused by variants in GJB2. It is characterized by mild to severe neurosensory hearing impairment and diffuse or focal palmoplantar hyperkeratosis [73,75,76].

Autosomal dominant KID syndrome — Autosomal dominant KID (keratitis-ichthyosis-deafness) syndrome (MIM #148210) is a rare disease caused by heterozygous variants in GJB2. It presents in infants with striking ichthyosiform erythroderma (picture 19). Later, patients may develop transgrediens PPK with a characteristic "stippled" appearance (picture 20 and picture 21), recurrent fungal infections, granuloma formation with secondary fungal or microbial infection, characteristic corneal redness, alopecia, nail dystrophy, and increased risk of squamous cell carcinoma [2]. (See "Overview and classification of the inherited ichthyoses", section on 'KID syndrome'.)

Autosomal recessive KID syndrome — Autosomal recessive KID (keratitis-ichthyosis-deafness) syndrome (MIM #242150) is a rare disorder caused by pathogenic homozygous or compound heterozygous loss of function variants in the AP1B1 gene [77,78]. It presents in the neonatal period with ichthyosis, erythroderma, PPK, keratitis, developmental delay, and failure to thrive [79].

HID syndrome — HID (hystrix-like ichthyosis with deafness) syndrome (MIM #602540) is an exceedingly rare autosomal dominant disorder that shares some features with KID syndrome and is caused by the same variant in GJB2 [72].

Bart-Pumphrey syndrome — Bart-Pumphrey syndrome, also called knuckle pads, leukonychia, and sensorineural deafness (MIM #149200), is an autosomal dominant disorder caused by variants in GJB2 and characterized by diffuse, focal, or punctate PPK appearing in early childhood and congenital deafness [2,80]. Knuckle pads are nodular or plaque-like skin thickenings overlying the metacarpophalangeal and proximal interphalangeal joints (picture 22) [81].

Mitochondrial PPK with deafness — The A7445G variant in mitochondrial deoxyribonucleic acid (DNA) has been associated with nonepidermolytic PPK with sensorineural hearing loss as well as with nonsyndromic deafness [82,83]. This type of PPK is maternally inherited with variable penetrance and expressivity. Mitochondrial PPK presents as focal PPK (picture 23 and picture 24). Hearing loss in childhood is very mild and progresses gradually; thus, it is important not to overlook it.

PPK with ichthyosis and normal hearing

Vohwinkel syndrome with ichthyosis (loricrin keratoderma) — Vohwinkel syndrome with ichthyosis (MIM #604117), also called loricrin keratoderma, is an autosomal dominant disorder caused by variants in LOR, encoding loricrin (a major protein of the cornified envelope). A severe form shows mutilating PPK (as in classic Vohwinkel syndrome) and generalized ichthyosis; a mild type shows only dry skin and PPK [2,84]. There is no associated hearing loss.

KLICK syndrome — KLICK (keratosis linearis with ichthyosis congenita and sclerosing keratoderma) syndrome (MIM #601952) is a very rare autosomal recessive disorder caused by variants in proteasome maturation protein gene (POMP) [85]. It shows [86]:

●Diffuse, transgressive PPK

●Linear, hyperkeratotic plaques around the wrists and in the antecubital and popliteal folds

●Constricting bands around the fingers

●Flexural deformities

●Congenital ichthyosis

PPK with periodontitis

Papillon-Lefèvre syndrome — Papillon-Lefèvre syndrome (MIM #245000) is a rare autosomal recessive disorder caused by variants in CTSC (encoding cathepsin C) [87]. It shows diffuse PPK in a transgrediens pattern (picture 25 and picture 26 and picture 27) with keratoderma plaques often present on the extensor aspect of the elbows and knees, early-onset periodontitis leading to premature loss of both milk and permanent teeth (picture 28), and recurrent cutaneous and systemic infections [88-90]. (See "Periodontal disease in children: Associated systemic conditions", section on 'Papillon-Lefèvre syndrome'.)

Haim-Munk syndrome — Haim-Munk syndrome (MIM #245010) is an autosomal recessive disorder caused by variants in CTSC and, thus, allelic to Papillon-Lefèvre syndrome [91]. Haim-Munk syndrome has been described only among descendants of a religious isolate originally from Cochin, India, and is characterized by PPK, severe periodontitis, arachnodactyly, acroosteolysis, pes planus, and finger deformities.

PPK and congenital alopecia — PPK and congenital alopecia-1 (MIM #104100) is a rare autosomal dominant disorder caused by heterozygous variants in the GJA1 gene and characterized by severe hyperkeratosis and congenital alopecia [92].

PPK and congenital alopecia-2 is an autosomal recessive disorder of unknown genetic alteration. Biallelic variants in LSS, encoding lanosterol synthase, have been found in two unrelated patients [93].

PPK associated with cardiomyopathy and woolly hair

Carvajal syndrome — Carvajal syndrome, also called PPK with left ventricular cardiomyopathy and woolly hair (MIM #605676), is an autosomal recessive disorder caused by variants in DSP, encoding desmoplakin (an intracellular scaffold protein of desmosome) [94,95]. It shows striate PPK, cardiomyopathy, and woolly hair [96].

An autosomal dominant variant of Carvajal syndrome is associated with tooth agenesis (MIM #615821) [97,98]. (See "Inherited syndromes associated with cardiac disease", section on 'Naxos disease and Carvajal syndrome'.)

Naxos disease — Naxos disease (MIM #601214) is an autosomal recessive disorder caused by variants in JUP, encoding plakoglobin (an intracellular scaffold protein of desmosome) [99]. It shows diffuse PPK, arrhythmogenic right ventricular dysplasia, and woolly hair. (See "Inherited syndromes associated with cardiac disease", section on 'Naxos disease and Carvajal syndrome'.)

Arrhythmogenic right ventricular dysplasia with mild PPK — Arrhythmogenic right ventricular dysplasia associated with mild PPK and woolly hair (MIM #610476) due to homozygous variants in DSC2, encoding desmocollin 2 (an intracellular scaffold protein of desmosome), has also been reported [100].

PPK associated with ectodermal dysplasia

Clouston syndrome — Clouston syndrome (MIM #129500) is an autosomal dominant disorder caused by variants in GJB6, encoding connexin 30 (a gap junction protein) [101]. It shows moderate to severe diffuse PPK (picture 29) with nail dystrophy (picture 30) and hair abnormalities. In contrast with KID syndrome due to GJB2 variants, patients with Clouston syndrome do not have neurosensory deafness. (See "Ectodermal dysplasias", section on 'Ectodermal dysplasia 2, Clouston type'.)

Naegeli-Franceschetti-Jadassohn syndrome — Naegeli-Franceschetti-Jadassohn syndrome (MIM #161000) is an autosomal dominant disorder caused by variants in KRT14 [102]. It shows diffuse PPK, nail dystrophies, anhidrosis, dental defects, and reticulate hyperpigmentation (picture 31) [2]. (See "Congenital and inherited hyperpigmentation disorders", section on 'Naegeli-Franceschetti-Jadassohn syndrome'.)

Odonto-onycho-dermal dysplasia — Odonto-onycho-dermal dysplasia (MIM #257980) is an autosomal recessive disorder caused by variants in WNT10A [103,104]. The WNT gene family is a group of related genes encoding signaling molecules involved in the differentiation of various cell lineages through the canonical Wnt/beta-catenin signaling pathway. Odonto-onycho-dermal dysplasia is characterized by diffuse PPK, hyperhidrosis, hypodontia, smooth tongue, hypotrichosis, and dystrophic nails.

Schöpf-Schulz-Passarge syndrome — Schöpf-Schulz-Passarge syndrome (MIM #224750) is an autosomal recessive disorder caused by variants in WNT10A [105]. It resembles odonto-onycho-dermal dysplasia but is complicated by eyelid cysts (hidrocystomas) and an increased risk of skin tumors [2,55].

PPK associated with skin fragility syndromes — Skin fragility diseases are considered subtypes of suprabasal epidermolysis bullosa simplex and are characterized by a variable constellation of clinical findings, including generalized skin fragility, diffuse PPK with painful fissures, hypotrichosis or woolly hair, and growth retardation (table 2). (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Epidermolysis bullosa simplex'.)

Ectodermal dysplasia/skin fragility syndrome and skin fragility/woolly hair syndrome are rare autosomal recessive disorders caused by variants in PKP1, encoding plakophilin 1 (MIM #604536) (picture 32), or in DSP, encoding desmoplakin (MIM #607655), respectively [106-108]. Although these disorders primarily cause skin fragility, PPK is thought to be a compensatory response.

A phenotype characterized by mild skin fragility, woolly hair, and mild PPK has been described in two siblings carrying a biallelic splice-site variant in TUFT1, encoding the desmosome-associated protein tuftelin-1 [109]. Tuftelin-1 localizes to the peripheral cell membranes of keratinocytes and is involved in desmosomal organization and signaling [110].

PPK associated with peeling skin/blistering and leukonychia

PLACK syndrome — PLACK (peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads) syndrome (MIM #616295) is a rare autosomal recessive disorder caused by variants in CAST, encoding calpastatin, a calcium-dependent protease [111]. (See "Peeling skin syndromes", section on 'PLACK syndrome'.)

PPK associated with guttate hypopigmentation

Cole disease — Cole disease (MIM #615522) is a rare autosomal dominant disorder caused by heterozygous variants in ENPP1 [112,113]. It shows congenital or early-onset, punctate PPK associated with irregularly shaped, guttate hypopigmentation distributed over the arms and legs but not on the trunk or acral regions. Some patients exhibit calcinosis cutis or early-onset calcific tendinopathy.

PPK associated with increased risk of cancer

Tylosis with esophageal cancer — Tylosis with esophageal cancer (MIM #148500), also known as Howel-Evans syndrome, is an extremely rare autosomal dominant disorder caused by variants in RHBDF2, encoding a protein that interacts with ADAM metallopeptidase domain 17 and regulates epidermal growth factor signaling [114]. It is characterized by focal PPK, increased risk of esophageal cancer, and oral precursor lesions (eg, leukoplakia) [114,115]. (See "Epidemiology and risk factors for esophageal cancer", section on 'Tylosis'.)

In the absence of molecular diagnosis, the use of a targeted family history is useful to detect the presence of oral and/or esophageal cancer-affected family members. Those patients with tylosis and a personal or family history of esophageal or oral cancer warrant further screening.

Huriez syndrome — Huriez syndrome, also known as sclerotylosis, is a very rare autosomal dominant genodermatosis characterized by diffuse and transgrediens PPK, scleroatrophy of the distal extremities, hypoplastic nails, and increased risk of developing aggressive squamous cell carcinoma in the affected areas [2,116]. Based on whole genome sequencing studies, it has been proposed that Huriez syndrome is caused by haploinsufficiency of SMARCAD1, encoding human helicase 1 (involved in high-fidelity homologous recombination repair of DNA double-strand breaks) [117].

Cowden syndrome 1 — Cowden syndrome 1 (MIM #158350) is an autosomal dominant disorder caused by variants in PTEN and characterized by overgrowth, evidenced by macrocephaly and especially hamartomas (which can involve any organ), and an increased risk of internal cancers [118]. Mucocutaneous lesions include punctate acral keratoses (picture 33); facial trichilemmomas; papillomatous oral lesions; lipomas; hemangiomas; and pigmented, speckled macules of the glans penis in males [119]. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)

Olmsted syndrome — Olmsted syndrome is a rare keratinizing disorder inherited in an autosomal dominant, autosomal recessive, or X-linked mode.

●Genetics – Autosomal dominant Olmsted syndrome 1 (MIM #614594) is caused by gain-of-function variants in TRPV3, encoding transient receptor potential vanilloid 3, a temperature-sensitive ion channel highly expressed in keratinocytes that result in the activation of the epidermal growth factor receptor (EGFR) [55].

Olmsted syndrome 2 is caused by variants in PERP, encoding a desmosomal component [120,121]. X-linked Olmsted syndrome (MIM #300918) is caused by variants in MBTPS2, encoding a membrane-bound zinc metalloprotease [122].

●Clinical presentation – Olmsted syndrome is characterized by the combination of bilateral, diffuse, painful, mutilating PPK with transgrediens features; periorificial hyperkeratotic plaques; and severe pruritus [123]. Associated features may include diffuse alopecia, nail dystrophy, oral leukokeratosis, corneal dystrophy, recurrent infections, erythromelalgia, and susceptibility to develop squamous cell carcinomas in keratotic areas [124,125].

There are several reports of successful use of the EGFR inhibitor erlotinib for the treatment of Olmsted syndrome [126-130]. (See 'Experimental therapies' below.)

DIAGNOSIS — 

The diagnosis of specific inherited PPK may be challenging due to the considerable clinical and genetic heterogeneity of this group of diseases. A careful physical examination, including the entire skin surface, mucous membranes, nails, eyes, and hair, and a detailed personal and family history, especially for the presence or absence of esophageal and oral cancers, are the first steps in the diagnostic approach [2,4,5]. A multidisciplinary approach may be needed if extracutaneous abnormalities are detected or suspected on physical examination. Histopathologic and, if available, ultrastructural examination of a skin biopsy can be of value in supporting the clinical diagnosis and directing genetic testing.

The approach to the diagnosis of PPK based on the clinical phenotype is illustrated in the algorithm (algorithm 1) [131].

●Physical examination – Relevant clinical features that may orient the diagnosis include the distribution and morphology of lesions and associated signs and symptoms:

•Diffuse versus focal, striate, or punctate PPK

•Presence or absence of transgrediens hyperkeratosis (affected skin area does or does not extend onto the dorsal surfaces of the hands and feet, inner wrists, and the Achilles tendon area)

•Aspect of hyperkeratosis (waxy, compact with fissures and associated erythema, desquamation, and stippling)

•Changes upon water exposure

•Presence of acral, sclerotic changes or digit constrictions

•Presence of palmoplantar hyperhidrosis

•Significant pain

•Presence of additional cutaneous findings (erythroderma, generalized ichthyosis, skin fragility)

•Nail, hair, mucosal, and dental abnormalities

•Major extracutaneous findings (hearing loss, cardiac manifestations, internal malignancies, ocular keratitis)

●History – Onset in infancy or early childhood, a positive family history, or parental consanguinity support the diagnosis of inherited PPK.

●Histopathology – Routine histopathologic examination may show, in addition to unspecific findings such as hyperkeratosis and acanthosis, the presence of epidermolysis (cytolysis of granular layer keratinocytes), which helps in distinguishing epidermolytic from nonepidermolytic PPK.

●Genetic testing – The identification of the causative variant in candidate genes allows a precise diagnosis in many cases (algorithm 1). Founder variants or hot spot variants are known in several types of PPK. In such cases, Sanger sequencing to check the candidate variants is first recommended.

Types of PPK caused by widespread founder variants include mal de Meleda in the Adriatic region (p.W15R of SLURP1) and PPK type Nagashima in East Asian countries (p.R266*). Hot spot variants at p.163Arg in KRT9 cause PPK type Vörner.

For types of PPK that defy a clinical diagnosis based on the clinical presentation, exome sequencing is a valuable technique to identify pathogenic variants. One strategy is to request a panel type blood test that includes sequencing and deletion/duplication testing of candidate genes well known to cause PPK, if available. If standard panel testing does not reveal pathogenic variants, then whole exome sequencing offers a next-step option when available.

DIFFERENTIAL DIAGNOSIS

Acquired PPK — PPK may be a feature of a broad range of acquired skin disorders and is more commonly seen in clinical practice than hereditary PPK. Underlying causes include [132]:

●Contact dermatitis (picture 34) and chronic hand eczema (picture 35). (See "Chronic hand eczema".)

●Psoriasis (picture 36A-B). (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

●Pityriasis rubra pilaris (picture 37A-B). (See "Pityriasis rubra pilaris: Pathogenesis, clinical manifestations, and diagnosis".)

●Keratoderma climactericum – Keratoderma climactericum (Haxthausen disease) is an acquired keratoderma with painful fissuring described in some postmenopausal females [133,134]. It initially develops on the soles at the pressure points and then becomes confluent. Later, it may extend to the palms. The cause is unknown. Associated factors include obesity and hypertension.

●Exposure to certain chemicals, such as arsenic and chlorinated hydrocarbons (picture 38). (See "Arsenic exposure and chronic poisoning", section on 'Dermatologic'.)

●Drug reactions – An example is hand-foot skin reaction in patients with cancer treated with multitargeted tyrosine kinase inhibitors. (See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)

●Infections and infestations – Fungal infection, especially from Trichophyton rubrum, may cause hyperkeratosis of the palms and/or soles that is typically unilateral but may be symmetric (picture 39). Crusted scabies (Norwegian scabies) can be associated with massive hyperkeratosis of the palms and soles (picture 40). (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Crusted scabies'.)

●Systemic disease, such as myxedema or chronic lymphedema. (See "Clinical manifestations of hypothyroidism", section on 'Skin' and "Clinical features, diagnosis, and staging of peripheral lymphedema".)

●Mycosis fungoides – Hyperkeratosis of the palms and soles may occur in association with, or even precede, mycosis fungoides. Rarely, it can be the only manifestation of the disease. (See "Variants of mycosis fungoides", section on 'Mycosis fungoides palmaris et plantaris'.)

●Internal malignancies – PPK may occur as a paraneoplastic manifestation in a variety of internal cancers, including lung, esophageal, bladder, breast, and colon cancer. (See "Cutaneous manifestations of internal malignancy", section on 'Hyperkeratotic and proliferative dermatoses'.)

●Bullous pemphigoid – Transient PPK has been reported in some patients with bullous pemphigoid [135,136]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

Acquired PPK usually does not develop during infancy, and there is no associated family history. However, several hereditary PPK do not manifest in early childhood, and family history may be negative in patients affected by hereditary PPK due to de novo autosomal dominant variants and in those with autosomal recessive forms who have unaffected carrier parents.

In contrast with hereditary PPK, usually showing a symmetric distribution of skin lesions, acquired PPK tends to show left-right asymmetric involvement. Acquired PPK usually improves and may resolve with the treatment of the underlying condition. Examples include PPK due to contact dermatitis, which may respond to topical corticosteroids and avoidance of the offending allergen, and PPK associated with psoriasis, which may improve with topical psoralen plus ultraviolet A (PUVA) treatment of the soles and palms. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Topical PUVA'.)

Other genodermatoses associated with PPK — PPK can be a feature in a number of genodermatoses, including:

●Darier disease (picture 41) (see "Darier disease")

●Acrokeratosis verruciformis of Hopf (picture 42) (see "Darier disease", section on 'Acrokeratosis verruciformis of Hopf')

●Epidermodysplasia verruciformis (picture 43) (see "Epidermodysplasia verruciformis")

●Epidermolysis bullosa simplex (picture 44A-B) (see "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features")

MANAGEMENT — 

The treatment of hereditary PPK is difficult. Major goals of treatment are softening the hyperkeratotic skin, reducing its thickness and making it less noticeable, and controlling discomfort and pain. However, in most cases, treatment results in limited and temporary improvement.

Patients with syndromic PPK require an individualized, multidisciplinary approach based on the type and severity of associated clinical signs and symptoms.

Because of its rarity and clinical heterogeneity, there is a lack of high-quality clinical studies on PPK. The approach to the management of these patients is based on clinical experience and very limited evidence from case reports and small case series [137].

General measures — Patients with certain types of PPK will benefit from daily to weekly bath soaks followed by gentle mechanical scale removal with tools chosen according to patient preference. Examples of useful tools include pumice stones, synthetic polyurethane pumice bars (which are softer), or a callus file. Professional foot and hand care may be appropriate for some patients. Frequent and liberal use of emollients is advisable.

Physical therapy may be useful if unreducible contractures of the fingers or palms are present.

Secondary bacterial and fungal infections, often presenting with worsening of pain, maceration, and odor, should be treated with appropriate topical or systemic antimicrobial therapy. Patients with mal de Meleda, PPK Nagashima type, and KID (keratitis-ichthyosis-deafness) syndrome are especially predisposed to fungal infection and benefit from antifungal treatment.

Pharmacologic therapies — Pharmacologic therapies that can be used for the treatment of PPK include topical keratolytics, topical retinoids, and systemic retinoids. None of these treatments provide a long-term benefit, and recurrence is common when they are discontinued.

●Keratolytics – Topical creams or ointments containing urea, lactic acid, salicylic acid, or propylene glycol at various concentrations and in various combinations are used to soften the hyperkeratotic stratum corneum. Concentrations of urea greater than 20% and up to 40% may be required for thick hyperkeratosis. Patients with unsatisfactory response to single keratolytics may benefit from using ointments containing a combination of keratolytics, such as 5% lactic acid with 10% urea or 2% salicylic acid with 20% urea. Keratolytic preparations should be used with caution in children due to the risk of systemic absorption.

●Topical retinoids – Topical retinoids, such as tazarotene (at 0.05% or 0.1% cream) or topical tretinoin (at 0.025% to 0.1% cream), may be a treatment option for mild cases of PPK. They should be tried gradually (eg, applied once per week, starting with a small area of the hand or foot) to ensure irritation is not excessive. The treatment area and frequency of application can then be increased as tolerated.

●Systemic retinoids – In patients with thick keratodermas or punctate keratodermas that are causing debilitating pain with walking or hand contractures that limit dexterity or activities of daily living, a trial of oral retinoids may be attempted [138-141]. Systemic retinoids include acitretin, isotretinoin, etretinate, and alitretinoin. Etretinate is not available in the United States, Europe, and Canada but is still marketed in Japan. Isotretinoin is available in the United States and is an additional option. Alitretinoin (9-cis-retinoic acid), a systemic retinoid approved in Europe and Canada for the treatment of chronic hand eczema, has shown some efficacy in a single patient with diffuse nonepidermolytic PPK (mal de Meleda) [142] and in a few patients with punctate PPK [143,144]. (See "Inherited ichthyosis: Overview of management", section on 'Retinoids'.)

•Administration – Oral retinoids can be started at 0.5 mg/kg per day and adjusted up or down depending on clinical response and tolerability. Treatment should be continued for several months. If improvement is noted, the dose can be tapered to the lowest effective dose.

•Efficacy – Data from a retrospective study of 30 patients with pachyonychia congenita treated with systemic retinoids indicate that acitretin is more effective than isotretinoin and that low doses (less than or equal to 25 mg per day) of systemic retinoids are as beneficial as higher doses in thinning plantar calluses and reducing pain [145]. In a few case reports, low-dose acitretin (at 10 to 25 mg per day) in combination with topical salicylic acid and topical corticosteroids was effective in inducing regression of punctate PPK lesions [139,146].

•Adverse effects – Common adverse effects of retinoids include mucocutaneous dryness, cheilitis, hair loss, and elevation of serum triglyceride levels. Oral retinoids are teratogenic. Extreme caution is recommended for use of acitretin in females of childbearing age and prior to childbearing age due to concern for teratogenicity and its longer half-life in comparison with isotretinoin. Pregnancy is contraindicated for three years after discontinuing acitretin.

Surgical treatment — Several case reports describe successful treatment of pseudoainhum by specialized hand surgery [147]. Successful treatment of digital constriction band using a distant abdominal skin flap has been reported in a patient with Vohwinkel syndrome [148].

Experimental therapies — Therapeutic strategies that are being investigated for the treatment of autosomal dominant disorders include:

●Inhibition of cell proliferation signals – In Olmsted syndrome, aberrant TRPV3 signaling due to TRPV3 variant leads to epidermal growth factor receptor (EGFR) transactivation. Nearly complete remission of severe palmoplantar keratosis was obtained in several patients by blocking EGFR transactivation with the EGFR inhibitor erlotinib hydrochloride [126-130].

●Allele-specific ribonucleic acid (RNA) interference – In autosomal dominant PPK, patients' skin expresses both wild-type and mutated proteins. Gain of function of the mutated protein or dominant negative effect to the wild-type protein cause the phenotype. Therefore, specific suppression of the expression of mutated protein is being investigated. Mutated allele-specific RNA interference is one of the candidate methods [149,150].

●Readthrough of nonsense variant – It is known that gentamicin induces readthrough of nonsense variants, and topical use of gentamicin has been tried in PPK Nagashima type, in which the major founder variant is a nonsense variant [151,152].

GENETIC COUNSELING — 

Referral to a genetic counselor or clinical geneticist should be offered to patients and their families once a hereditary condition has been diagnosed. Genetic counseling provides patients and families with psychosocial support and information regarding the mode of inheritance, risk for the offspring, genetic testing, and availability of prenatal diagnosis. (See "Genetic counseling: Family history interpretation and risk assessment".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ichthyosis".)

SUMMARY AND RECOMMENDATIONS

●Definition and classification – Hereditary palmoplantar keratodermas (PPK) are a clinically and genetically heterogeneous group of uncommon disorders characterized by excessive epidermal thickening of the palms and soles. There are multiple classification systems for PPK based on lesion morphology (diffuse, focal, striate, or punctate), presence of associated cutaneous or extracutaneous symptoms, or genetic defect (table 1A-B). (See 'Introduction' above and 'Classification' above.)

●Diffuse PPK – Diffuse PPK include some of the most common types of PPK. They are characterized by epidermal thickening that involves the entire surface of the palms and soles. The hyperkeratosis may show a sharp demarcation at the palmar or plantar border ("nontransgrediens"), such as PPK Vörner type (picture 1), or may extend onto the dorsal surfaces of the hands and feet, inner wrists, and the Achilles tendon area ("transgrediens"), such as mal de Meleda (picture 3A-B) and PPK Nagashima type (picture 6A-B). (See 'Diffuse PPK' above and 'Diffuse epidermolytic PPK Vörner type (Unna-Thost type included)' above and 'Mal de Meleda' above and 'Nagashima type' above.)

●Focal, striate, and punctate PPK – Focal, striate, and punctate PPK are uncommon and are characterized, respectively, by:

•Circumscribed hyperkeratosis resembling calluses on the weight-bearing areas of the soles (picture 10) (see 'Focal PPK' above)

•Prominent hyperkeratosis in a linear pattern along the flexor aspects of the fingers or pressure points on the soles (picture 13) (see 'Striate PPK' above)

•Multiple tiny, hyperkeratotic papules on the palms and soles (picture 14)

●Syndromic PPK – Syndromic PPK encompass a large number of conditions characterized by PPK and involvement of extracutaneous organs. Examples include PPK with deafness, PPK with periodontitis, PPK associated with cardiomyopathy, and PPK associated with ectodermal dysplasias and skin fragility syndromes. (See 'Syndromic PPK' above.)

●Diagnostic approach – The diagnosis of inherited PPK may be challenging due to considerable clinical and genetic heterogeneity of this group of diseases (algorithm 1). It is based on careful physical examination, including the entire skin surface, mucous membranes, nails, and hair, and a detailed personal and family history. Routine histopathology may be helpful in distinguishing epidermolytic from nonepidermolytic PPK. Genetic testing demonstrating a causative variant in candidate genes is required for a precise diagnosis. (See 'Diagnosis' above.)

●Management – Treatment of hereditary PPK is difficult. Major goals of treatment are softening and flattening the thickened hyperkeratotic skin, improving function and cosmesis, and controlling discomfort and pain. Patients with syndromic PPK require an individualized, multidisciplinary approach, in addition to dermatologic care, based on the type and severity of associated clinical signs and symptoms.

•General measures – Most patients will benefit from daily to weekly bath soaks followed by gentle mechanical scale removal. Professional foot and hand care may be appropriate for some patients. (See 'General measures' above.)

•Pharmacologic therapies – Pharmacologic therapies include topical keratolytics, topical retinoids, and systemic retinoids. However, none of these treatments provide long-term benefit, and recurrence is common after discontinuation. (See 'Pharmacologic therapies' above.)

-Topical keratolytics – For most patients with PPK, we suggest initial treatment with topical keratolytics rather than topical or oral retinoids (Grade 2C). Keratolytics are effective in softening the hyperkeratotic stratum corneum and facilitating mechanical scale removal. Topical keratolytics, such as urea, lactic acid, salicylic acid, or propylene glycol, at various concentrations and in various combinations in cream or ointment formulations can be applied once or twice daily to the affected areas until improvement is noted. Topical keratolytics should be used with caution in children due to the risk of systemic absorption.

-Topical retinoids – Topical retinoids, such as tazarotene (at 0.05% or 0.1% cream) and tretinoin (at 0.025% to 0.1% cream), are a treatment option for mild PPK. They have a modest keratolytic effect. They should be trialed gradually (eg, starting with once- or twice-weekly application to a small area of the hand or foot) to avoid excessive irritation.

-Oral retinoids – In patients with disabling PPK, we suggest a trial of oral retinoids (Grade 2C). Oral retinoids, including acitretin, isotretinoin, etretinate, and alitretinoin, can be started at a dose of 0.5 mg/kg per day and adjusted up or down depending on response and tolerability. If improvement is noted, the dose can be tapered to the lowest effective dose. Caution is recommended for use of acitretin in females of childbearing age due to concern for teratogenicity and its longer half-life in comparison with isotretinoin. Pregnancy is contraindicated for three years after discontinuing acitretin. (See "Inherited ichthyosis: Overview of management", section on 'Retinoids'.)