Palmoplantar keratoderma

INTRODUCTION — Palmoplantar keratoderma (PPK) is a heterogeneous group of inherited or acquired disorders characterized by excessive epidermal thickening of the palms and soles. Hereditary PPKs are in most cases caused by mutations 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), and cell signaling (eg, SLURP1) [1,2].

Hereditary PPKs can occur in isolation (nonsyndromic PPK) or in association with extracutaneous manifestations (syndromic PPK) [1,3,4]. PPK can also be a manifestation of a broad number 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 focus on inherited nonsyndromic PPKs 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 PPKs 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 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 PPKs can be based on a variety of criteria, 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), or associated with other organ involvement as a component of a complex syndrome (eg, Papillon-Lefèvre syndrome).

●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 — Mutations in genes encoding structural proteins supporting the granular layer of the epidermis cause hyperkeratotic diseases, including PPK. The PPK-causative genes include KRT1 and KRT9, which encode major intermediate filaments of granular layer keratinocytes; DSG1, a major cell-cell adhesion molecule of desmosomes in the granular layer; LOR, a major component of cornified cell envelope expressed in granular layer cells; SERPINB7 and SERPINA12, serine proteinase inhibitors associated with degradation of DSG1 and CDSN that are expressed in granular layer cells; AQP5, a water channel protein expressed in granular layer cells; and SLURP1, a secreted protein associated with signal transduction that is expressed in granular layer cells.

Mutations in genes encoding proteins expressed in basal layer cells and associated with cell proliferation cause acanthosis and hyperkeratosis and result in PPK. They include PTEN, a tumor suppressor and a cell cycle regulator; AAGAB, a putative regulator of the turnover of epidermal growth factor receptor; and RHBDF2, a regulator of epidermal growth factor processing.

DIFFUSE PALMOPLANTAR KERATODERMA — Diffuse PPKs are characterized by epidermal thickening that involves the entire surface of 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 plantar 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 PPKs, including mal de Meleda; acral keratoderma; and PPK types Nagashima, Bothnia, Gamborg-Nielsen, Greither, and Sybert [9-17].

Diffuse epidermolytic palmoplantar keratoderma (Vörner type, Unna-Thost type included) — Diffuse epidermolytic PPK Vörner type (MIM #144200) is the most common PPK in White persons and is caused by a heterozygous pathogenic mutation in keratin gene KRT1 or KRT9 [18]. The mutations in KRT1 or KRT9 disrupt the formation of keratin intermediate filaments, which causes physical weakness of cytoskeletons. The vacuolar degeneration of cells (epidermolysis) is a result of physical cell damage caused by the weakness of cytoskeletons.

Because KRT9 is exclusively expressed in the keratinocytes of the palms and soles, the epidermolytic hyperkeratosis appears only on the palms and soles in KRT9-mutated patients. In contrast, KRT1 is expressed in the keratinocytes of the entire skin. Distinct heterozygous mutations of 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'.)

The mode of inheritance of diffuse epidermolytic PPK Vörner type is autosomal dominant. De novo mutations have been reported [19]. In autosomal dominant de novo mutations, both parents are unaffected with the disease, but each of the affected patients' future offspring have a 50 percent risk to inherit the disease.

PPK Vörner type becomes apparent at birth or 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 1A-B). Hyperhidrosis is a frequent associated symptom.

The histologic examination of a skin biopsy 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 also caused by mutations in KRT1 and was formerly classified as nonepidermolytic diffuse PPK, is likely a misdiagnosis of PPK Vörner type, due to inconsistent presence of epidermolysis on histologic examination. The re-evaluation of skin histology from offspring of the original family described by Unna and Thost showed, in fact, epidermolytic hyperkeratosis [20,21].

Moreover, the finding that mutations 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 further supports the theory that PPK Vörner type and PPK Unna-Thost type are not different types of PPK [18,21]. The designation "Unna-Thost" is thus misleading and should be avoided, while the term "PPK Vörner type" should be used for accurate description of epidermolytic hyperkeratosis.

Diffuse nonepidermolytic palmoplantar keratoderma

Diffuse palmoplantar keratoderma caused by DSG1 mutations — Autosomal dominant mutations in the desmoglein 1 gene (DSG1), which cause striate PPK type 1 (MIM #148700), have also been associated with a form of diffuse nonepidermolytic PPK [22]. (See 'Striate palmoplantar keratoderma types 1, 2, and 3' below.)

The histologic examination of a skin biopsy shows hyperkeratosis and acantholysis (disruption of desmosomal cell-cell adhesions caused by haploinsufficiency of desmoglein 1) in the granular layer of the epidermis [22].

Patients who inherit two DSG1 mutations in a homozygous manner present with PPK and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome [23]. This suggests that while heterozygous carriers of DSG1 have limited PPK, complete loss of functional DSG1 from both alleles results in a complex syndrome. (See "Peeling skin syndromes", section on 'SAM syndrome'.)

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 mutations in SLURP1 (encoding the secreted Ly6/uPAR related protein-1) [24]. In Europe and Mediterranean countries, the prevalence of the three most common mutations (c.82delT, p.R96X, and p.W15R) shows a marked geographic demarcation, suggesting a founder effect [25].

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 feet and hands and gradually progress to involve the wrists and ankles (picture 2A-B). 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.

Palmoplantar keratoderma Gamborg-Nielsen/Norrbotten type — PPK Gamborg-Nielsen type (also called Norrbotten type, MIM #244850) was first described in Norrbotten, the northernmost county of Sweden. It shows a morphologic phenotype similar to mal de Meleda but with less severe hyperkeratosis and no nail deformities or distant keratosis, except for knuckle pads [26]. Genetic investigation revealed that Gamborg-Nielsen/Norrbotten PPK is an autosomal recessive PPK caused by distinct mutations of SLURP1 [27].

Palmoplantar keratoderma Nagashima type — PPK Nagashima type (MIM #615598) is an autosomal recessive form of diffuse nonepidermolytic PPK caused by mutations in SERPINB7, which encodes a proteinase inhibitor expressed in the upper layers of the epidermis [7]. PPK Nagashima type is the most common PPK in Asian populations, with a widely spread founder mutation of SERPINB7 (c.796C>T). The prevalence of SERPINB7 mutation carriers is estimated to be approximately 1 in 50 in Japanese and Chinese populations, with prevalence rates of PPK Nagashima type in Japan and China of 1.2 per 10,000 and 3.1 per 10,000, respectively [7].

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 3A-B) [12,28]. After exposure to water, the palms and soles show a characteristic whitish, spongy appearance. Hyperhidrosis, secondary fungal infection, and odor are common.

Palmoplantar keratoderma with SERPINA12 mutations — Diffuse PPK with SERPINA12 mutations is an autosomal recessive form of diffuse nonepidermolytic PPK caused by mutations 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 Muslim Arab descent and Jewish descent were identified in 2020 [29]. Six additional cases caused by novel variants in SERPINA12 were subsequently identified in five unrelated families in China [30].

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.

Palmoplantar keratoderma Bothnia type — PPK Bothnia type (MIM #600231) is an autosomal dominant form of diffuse nonepidermolytic PPK caused by mutations in AQP5 (encoding the water-channel protein aquaporin 5) [31,32]. PPK Bothnia type has a high prevalence of 0.3 to 0.55 percent in the two northernmost provinces of Sweden around the Gulf of Bothnia [13]. PPK Bothnia type resembles PPK Nagashima type, with mild transgrediens redness and hyperkeratosis and whitish changes upon water exposure (picture 4A-B) [13].

Transgrediens et progrediens palmoplantar keratoderma (Greither disease) — Transgrediens et progrediens PPK (Greither disease) is an autosomal dominant form of diffuse PPK caused by a KRT1 mutation [33,34]. 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 over the Achilles tendon, and a tendency to worsen with age.

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

FOCAL PALMOPLANTAR KERATODERMA — Focal PPKs are characterized by painful, circumscribed hyperkeratosis resembling calluses on the weight-bearing areas of the soles (picture 5).

Pachyonychia congenita — Painful focal PPK with underlying blisters is a major manifestation of pachyonychia congenita (picture 6), an autosomal dominant disorder caused by heterozygous mutations in KRT6A, KRT6B, KRT6C, KRT16, or KRT17 and characterized by hypertrophic nail dystrophy [35]. (See "Pachyonychia congenita".)

Focal nonepidermolytic palmoplantar keratoderma — Distinct autosomal dominant mutations in KRT6C and KRT16 cause focal nonepidermolytic PPK (MIM #615735 and #613000) [36-40]. Areas of keratoderma are present on the soles at sites of recurrent friction, with limited or even absent palm involvement or nail dystrophy.

Specific autosomal dominant mutations in DSG1 (encoding desmoglein 1) cause phenotypically heterogeneous focal PPK type 1, with or without minimal changes in the nails and other ectodermal tissues [22,41-45].

A missense heterozygous mutation in TRPV3 (encoding a transient receptor potential cation channel, subfamily V, member 3) has been reported to cause focal nonepidermolytic PPK type 2 (MIM #616400) [46]. Several mutations in TRPV3 have also been reported as the cause of Olmsted syndrome (MIM #614594), which shows mutilating diffuse PPKs and perioral hyperkeratotic plaques [46,47]. (See "Pachyonychia congenita", section on 'Olmsted syndrome'.)

STRIATE PALMOPLANTAR KERATODERMA — Striate PPK shows hyperkeratosis prominent in a linear pattern along the flexor aspects of the fingers (picture 7) and over pressure points on the soles.

Striate palmoplantar keratoderma types 1, 2, and 3 — Striate PPK type 1 (MIM #148700), type 2 (MIM #612908), and type 3 (MIM #607654) are autosomal dominant PPKs caused by heterozygous mutations in DSG1, DSP, and KRT1, respectively [42,48,49].

Patients with homozygous DSG1 mutations via consanguineous parents present with an autosomal recessive condition with severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome (MIM #615508) [23]. Additional findings include congenital ichthyosiform erythroderma, focal and striate PPK, hypotrichosis, and hyper-immunoglobulin E (IgE).

Palmoplantar keratoderma and woolly hair — PPK and woolly hair (MIM #616099) is a rare autosomal recessive PPK caused by homozygous mutation in the KANK2 gene [50]. Members of two affected families presented with variable degree of striate PPK, leukonychia, sparse scalp and body hair, and, in some cases, woolly hair.

PUNCTATE PALMOPLANTAR KERATODERMA — Punctate PPK shows multiple tiny, hyperkeratotic papules on the palms and soles. The syndromic type includes Cowden syndrome 1, Cole disease, and PLACK (peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads) syndrome. (See 'Syndromic palmoplantar keratoderma' below.)

Punctate palmoplantar keratoderma type 1 — Punctate PPK type 1A, also called PPK type Buschke-Fischer-Brauer (MIM #148600), is an autosomal dominant PPK caused by heterozygous mutations in AAGAB (encoding alpha- and gamma-adaptin-binding protein p34) [51-54]. 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 8).

A heterozygous mutation in COL14A1 (encoding collagen 14) has been identified in a large Chinese family with punctate PPK type 1B [54].

Punctate palmoplantar keratoderma type 2 — Punctate PPK type 2, also called porokeratosis punctate palmaris et plantaris, is probably an autosomal dominant disorder that presents with numerous tiny, keratotic spines on the palms and soles. Histologic studies showed distinct epidermal depressions containing cornoid lamellae [55,56]. The causative gene is unknown.

Punctate palmoplantar keratoderma 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 palms and soles (picture 9A-D) [57]. Histologic findings include hyperkeratosis, mild acanthosis, and degeneration of the elastic fibers. The causative gene is unknown.

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

Palmoplantar keratodermas with deafness — Heterozygous mutations 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 [1,2,4,58,59]. These include classic Vohwinkel syndrome, PPK with neurosensory deafness, keratitis-ichthyosis-deafness (KID) syndrome, Bart-Pumphrey syndrome, and hystrix-like ichthyosis with deafness (HID) syndrome. 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".)

Another rare PPK associated with deafness is caused by mitochondrial mutations.

Vohwinkel syndrome — Classic Vohwinkel syndrome (MIM #124500), also called mutilating PPK, is a rare autosomal dominant condition caused by mutations in GJB2. It is characterized by congenital deafness or hearing impairment; diffuse PPK with a characteristic honeycomb pattern (picture 10); starfish-shaped, hyperkeratotic plaques on knuckles (picture 11); and mutilating digital constriction rings around fingers and toes (pseudoainhum) that result in spontaneous autoamputation (picture 12) [60].

Palmoplantar keratoderma with deafness — PPK with deafness (MIM #148350) is an autosomal dominant condition caused by mutations in GJB2 and characterized by mild to severe neurosensory hearing impairment and diffuse or focal palmoplantar hyperkeratosis [59,61,62].

KID syndrome — Keratitis-ichthyosis-deafness (KID) syndrome (MIM #148210) is a rare disease caused by mutations in GJB2. It presents in infants with striking ichthyosiform erythroderma (picture 13); later, patients may develop PPK (picture 14), recurrent fungal infections, 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'.)

HID syndrome — Hystrix-like ichthyosis with deafness (HID) syndrome (MIM #602540) is an exceedingly rare autosomal dominant disorder that shares some features with KID syndrome and is caused by the same mutation in GJB2 [58].

Bart-Pumphrey syndrome — Bart-Pumphrey syndrome, also called knuckle pads, leukonychia, and sensorineural deafness (MIM #149200), is an autosomal dominant disorder caused by mutations in GJB2 and characterized by diffuse, focal, or punctate PPK appearing in early childhood and congenital deafness [2,63]. Knuckle pads are nodular or plaque-like skin thickenings overlying the metacarpophalangeal and proximal interphalangeal joints (picture 15) [64].

Mitochondrial palmoplantar keratoderma with deafness — The A7445G mutation in mitochondrial DNA has been associated with nonepidermolytic PPK with sensorineural hearing loss, as well as with nonsyndromic deafness [65,66]. This type of PPK is maternally inherited with variable penetrance and expressivity.

Palmoplantar keratoderma with ichthyosis and normal hearing

Vohwinkel syndrome with ichthyosis — Vohwinkel syndrome with ichthyosis (MIM #604117), also called loricrin keratoderma, is an autosomal dominant disorder caused by mutations 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 [2,67]. There is no associated hearing loss.

KLICK syndrome — Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome (MIM #601952) is a very rare autosomal recessive disorder caused by mutations in proteasome maturation protein gene (POMP) [68]. It shows diffuse, transgressive PPK; linear, hyperkeratotic plaques around the wrists and in the antecubital and popliteal folds; constricting bands around the fingers; flexural deformities; and congenital ichthyosis [69].

Palmoplantar keratoderma with periodontitis

Papillon-Lefèvre syndrome — Papillon-Lefèvre syndrome (MIM #245000) is a rare autosomal recessive disorder caused by mutations in CTSC (encoding cathepsin C) [70]. It shows diffuse PPK in a transgrediens pattern (picture 16), early-onset periodontitis leading to premature loss of both milk and permanent teeth (picture 17), and recurrent cutaneous and systemic infections [71-73]. (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 mutations in CTSC and, thus, allelic to Papillon-Lefèvre syndrome [74]. 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.

Palmoplantar keratoderma 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 mutations in DSP, encoding desmoplakin (an intracellular scaffold protein of desmosome) [75,76]. It shows striate PPK, cardiomyopathy, and woolly hair [77].

An autosomal dominant variant of Carvajal syndrome is associated with tooth agenesis (MIM #615821) [78,79]. (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 mutations in JUP, encoding plakoglobin (an intracellular scaffold protein of desmosome) [80]. 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 palmoplantar keratoderma — Arrhythmogenic right ventricular dysplasia associated with mild PPK and woolly hair (MIM #610476) due to homozygous mutations in DSC2, encoding desmocollin 2 (an intracellular scaffold protein of desmosome), has also been reported [81].

Palmoplantar keratoderma associated with ectodermal dysplasia

Clouston syndrome — Clouston syndrome (MIM #129500) is an autosomal dominant disorder caused by mutations in GJB6, encoding connexin 30 (a gap junction protein) [82]. It shows moderate to severe diffuse PPK (picture 18) with nail dystrophy (picture 19) and hair abnormalities. In contrast with KID syndrome due to GJB2 mutations, 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 mutations in KRT14 [83]. It shows diffuse PPK, nail dystrophies, anhidrosis, dental defects, and reticulate hyperpigmentation (picture 20) [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 mutations in WNT10A [84,85]. 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 mutations in WNT10A [86]. It resembles odonto-onycho-dermal dysplasia but is complicated by eyelid cysts (hidrocystomas) and an increased risk of skin tumors [2,47].

Skin fragility syndromes — Ectodermal dysplasia/skin fragility syndrome and skin fragility/woolly hair syndrome are rare autosomal recessive disorders caused by mutations in PKP1, encoding plakophilin 1 (MIM #604536), or in DSP, encoding desmoplakin (MIM #607655), respectively [87-89]. Although these disorders primarily cause skin fragility, PPK is thought to be a compensatory response. These skin fragility diseases are considered variants 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'.)

Palmoplantar keratoderma associated with peeling skin/blistering and leukonychia

PLACK syndrome — PLACK (peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads; MIM #616295) syndrome is a rare autosomal recessive disorder caused by mutations in CAST. It shows peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads [90]. (See "Peeling skin syndromes", section on 'PLACK syndrome'.)

Palmoplantar keratoderma associated with guttate hypopigmentation

Cole disease — Cole disease (MIM #615522) is a rare autosomal dominant disorder caused by heterozygous mutations in ENPP1 [91,92]. 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.

Palmoplantar keratoderma 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 mutations in RHBDF2, the protein product of which interacts with ADAM metallopeptidase domain 17 (ADAM17, also called TACE) and regulates epidermal growth factor processing [93]. It is characterized by focal PPK, increased risk of esophageal cancer, and oral precursor lesions, such as leukoplakia [93,94]. (See "Epidemiology and pathobiology of esophageal cancer", section on 'Tylosis'.)

In the absence of molecular diagnosis, 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 [2,95]. 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) [96].

Cowden syndrome 1 — Cowden syndrome 1 (MIM #158350) is an autosomal dominant disorder caused by mutations in PTEN and characterized by overgrowth, especially hamartomas that can involve any organ and an increased risk of internal cancers [97]. Mucocutaneous lesions include punctate acral keratoses (picture 21), facial trichilemmomas, papillomatous oral lesions, lipomas, hemangiomas, and pigmented, speckled macules of the glans penis in males [98]. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)

Olmsted syndrome — Olmsted syndrome is a rare keratinizing disorder characterized by the combination of bilateral mutilating transgrediens PPK and periorificial hyperkeratotic plaques with severe pruritus [99]. Associated features include diffuse alopecia, nail dystrophy, oral leukokeratosis, corneal dystrophy, recurrent infections, and susceptibility to develop squamous cell carcinomas in the keratotic areas.

Olmsted syndrome is inherited in an autosomal dominant, autosomal recessive, or X-linked mode. Autosomal dominant Olmsted syndrome (MIM #614594) is caused by mutations in TRPV3 [47], and X-linked Olmsted syndrome (MIM #300918) is caused by a mutation in MBTPS2 [2]. Olmsted syndrome shows diffuse and mutilating PPK and perioral hyperkeratotic plaques with severe pruritus. Diffuse alopecia, constriction of the digits, and onychodystrophy have been reported [2,78].

DIAGNOSIS — The diagnosis of specific inherited PPKs may be challenging due to 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 step 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) [100]:

●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 extends 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, with associated erythema and desquamation)

•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 mutation in candidate genes allows a precise diagnosis in most cases (algorithm 1). Founder mutations or hot spot mutations are known in several PPKs. In such cases, Sanger sequencing to check the candidate mutations is first recommended. PPK caused by widespread founder mutations includes mal de Meleda in the Adriatic region (p.W15R of SLURP1) and PPK type Nagashima in Asian countries (p.R266*). Hot spot mutations at p.163Arg in KRT9 cause PPK type Vörner.

For forms of PPK that defy a clinical diagnosis based on the clinical presentation, exome sequencing is a valuable technique to identify disease-causative mutations. 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 causative mutation(s), then whole exome sequencing offers a next-step option when available.

DIFFERENTIAL DIAGNOSIS

Acquired palmoplantar keratoderma — 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 [101]:

●Contact dermatitis (picture 22) and chronic hand eczema (picture 23). (See "Chronic hand eczema".)

●Psoriasis (picture 24A-B). (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

●Pityriasis rubra pilaris (picture 25A-B). (See "Pityriasis rubra pilaris: Pathogenesis, clinical manifestations, and diagnosis".)

●Keratoderma climactericum – Keratoderma climactericum (Haxthausen's disease) is an acquired keratoderma with painful fissuring described in some postmenopausal women [102,103]. It develops initially 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 26). (See "Arsenic exposure and chronic poisoning", section on 'Dermatologic'.)

●Drugs – An example is hand-foot skin reaction in cancer patients 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 palms and/or soles that is typically unilateral but may be symmetric. (picture 27). Crusted scabies (Norwegian scabies) can be associated with massive hyperkeratosis of palms and soles (picture 28). (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 and diagnosis of peripheral lymphedema".)

●Mycosis fungoides – Hyperkeratosis of 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 [104,105]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

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

In contrast with hereditary PPK, usually showing a left-right 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 palmoplantar keratoderma — PPK can be a feature in a number of genodermatoses, including:

●Darier disease (picture 29) (see "Darier disease")

●Acrokeratosis verruciformis of Hopf (picture 30) (see "Darier disease", section on 'Acrokeratosis verruciformis of Hopf')

●Epidermodysplasia verruciformis (picture 31) (see "Epidermodysplasia verruciformis")

●Epidermolysis bullosa simplex (picture 32A-B) (see "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features")

MANAGEMENT — 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.

General measures — Patients with certain types of PPK will benefit from daily to weekly bath soaks followed by gentle mechanical scale removal with tools that are chosen according to patient preference. Examples of useful tools include a pumice stone, a synthetic polyurethane pumice bar (which is 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 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 keratitis-ichthyosis-deafness (KID) 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 tazarotene (0.05% or 0.1% cream) or topical tretinoin (0.025% to 0.1% cream), may be a treatment option for mild cases of PPK. They should be trialed gradually (eg, applied once per week starting with a small area of the hand or foot) to be sure 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 [106-109]. 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) [110] and in a few patients with punctate PPK [111,112].

Oral retinoids can be started at a dose of 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.

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 (≤25 mg per day) of systemic retinoids are as beneficial as higher doses in thinning plantar calluses and reducing pain [113]. In a few case reports, low-dose acitretin (10 to 25 mg per day) in combination with topical salicylic acid and topical corticosteroids was effective in inducing regression of punctate PPK lesions [107,114].

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 women of childbearing age and girls 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 [115].

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 mutation leads to epidermal growth factor receptor (EGFR) transactivation. Nearly complete remission of severe palmoplantar keratosis was obtained by blocking EGFR transactivation with the EGFR inhibitor erlotinib hydrochloride [116].

●Allele-specific RNA interference – In autosomal dominant PPKs, 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 [117,118].

●Readthrough of nonsense mutation – It is known that gentamicin induces readthrough of nonsense mutations, and topical use of gentamicin has been tried in PPK Nagashima type, in which the major founder mutation is a nonsense mutation [119].

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

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

●Diffuse PPK includes some of the most common types of PPK. They are characterized by epidermal thickening that involves the entire surface of palms and soles. The hyperkeratosis may show a sharp demarcation at the palmar or plantar border ("nontransgrediens"), such as PPK Vörner type (picture 1A), 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 2A-B) and PPK Nagashima type (picture 3A-B). (See 'Diffuse palmoplantar keratoderma' above and 'Diffuse epidermolytic palmoplantar keratoderma (Vörner type, Unna-Thost type included)' above and 'Mal de Meleda' above and 'Palmoplantar keratoderma Nagashima type' above.)

●Syndromic PPKs encompass a large number of conditions characterized by PPK and involvement of extracutaneous organs. Examples include PPK with deafness, PPK with periodontitis, and PPK associated with cardiomyopathy. (See 'Palmoplantar keratodermas with deafness' above and 'Palmoplantar keratoderma with periodontitis' above and 'Palmoplantar keratoderma associated with cardiomyopathy and woolly hair' above.)

●PPK is a feature of some types of ectodermal dysplasias, such as Clouston syndrome, odonto-onycho-dermal dysplasia, and ectodermal dysplasia/skin fragility syndrome. (See 'Palmoplantar keratoderma associated with ectodermal dysplasia' above.)

●PPK is also a feature of several syndromes associated with an increased risk of cutaneous and internal cancers. (See 'Palmoplantar keratoderma associated with increased risk of cancer' above.)

●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 mutation in candidate genes is required for a precise diagnosis. (See 'Diagnosis' above.)

●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. 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 therapy includes 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, 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, such as tazarotene (0.05% or 0.1% cream) and tretinoin (0.025% to 0.1% cream), are a treatment option for mild PPK. 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.

•In patients with disabling PPK, a trial of oral retinoids, including acitretin, isotretinoin, etretinate, and alitretinoin, may be attempted. Oral retinoids 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.

●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. (See 'Syndromic palmoplantar keratoderma' above.)