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Palmoplantar keratoderma

Palmoplantar keratoderma (PPK), also known as keratosis palmaris et plantaris, encompasses a diverse group of disorders marked by persistent hyperkeratosis leading to abnormal thickening of the epidermal layer on the palms and soles.^[1] PPK is rare, with prevalence varying by subtype but generally estimated at about 1-4 per 100,000 population. These conditions can manifest as diffuse, focal/striate, or punctate patterns of skin involvement, often causing pain, fissuring, and impaired function due to the rigid, scaly plaques that form. PPK may occur in isolation or as part of syndromic features, such as hearing loss or alopecia, and affects individuals across all ages, with varying severity that can significantly impact quality of life.^[2]^[3] PPK is broadly classified into inherited (epidermolytic or nonepidermolytic) and acquired forms.^[1] Inherited PPK arises from monogenic mutations, predominantly autosomal dominant, in genes encoding keratins (e.g., KRT9 for epidermolytic PPK), connexins (e.g., GJB2 in Vohwinkel syndrome), or other structural proteins like desmosomes, leading to early-onset hyperkeratosis often present at birth or in infancy.^[2] Notable subtypes include diffuse nonepidermolytic PPK (Unna-Thost disease), striate PPK, and punctate PPK (e.g., due to AAGAB mutations), with some associated with extracutaneous risks like esophageal carcinoma in Howel-Evans syndrome.^[3] In contrast, acquired PPK develops later in life without genetic predisposition and is often secondary to underlying factors.^[4] Causes of acquired PPK include chronic friction or contact dermatitis, systemic diseases (e.g., myxedema in hypothyroidism), malignancies (e.g., paraneoplastic associations with lung cancer, esophageal cancer, or mycosis fungoides), infections (e.g., human papillomavirus), nutritional deficiencies, or medication side effects (e.g., arsenic exposure).^[3]^[5] In diffuse forms, clinical features typically involve yellowish, hyperkeratotic plaques covering more than 50% of the palmar or plantar surfaces, sometimes with erythema, hyperhidrosis, or secondary bacterial infections; in inflammatory variants, blistering or erosions may occur.^[4] Diagnosis relies on clinical examination, family history, and histopathological findings such as orthokeratotic or epidermolytic hyperkeratosis depending on the subtype, with genetic testing (e.g., next-generation sequencing) essential for inherited cases to identify specific mutations.^[2]^[1] Management focuses on symptom relief and addressing underlying etiologies, as no curative therapy exists for inherited forms.^[1] Topical keratolytics such as urea, salicylic acid, or lactic acid creams soften plaques and reduce thickness, while emollients prevent fissuring; oral retinoids (e.g., acitretin) offer benefit for severe or widespread disease but carry risks like hyperlipidemia.^[3]^[5] For acquired PPK, treating the primary cause—such as malignancy resection or infection eradication—can lead to resolution, supplemented by mechanical debridement or phototherapy in refractory cases.^[4] Emerging approaches, including gene-targeted therapies like CRISPR, show promise in preclinical studies for monogenic subtypes as of 2025.^[1] Long-term monitoring is crucial, particularly for syndromic PPK with malignancy risks.^[3]

Overview

Definition and characteristics

Palmoplantar keratoderma (PPK) is a heterogeneous group of disorders characterized by abnormal thickening, or hyperkeratosis, of the stratum corneum on the palms and soles, resulting in skin that can become fragile, rigid, or prone to fissuring.^[1] This hyperkeratosis leads to a rough, hardened texture on the affected areas, often impairing mobility and causing discomfort due to pressure or friction.^[6] The condition manifests primarily on the palmar surfaces of the hands and the plantar surfaces of the feet, though in some cases it may extend to adjacent areas such as the nails, knuckles, elbows, or dorsa of the hands and feet.^[7] Onset typically occurs congenitally or during early childhood, with many forms presenting within the first year of life, although acquired variants can develop later in adulthood.^[1] Progression generally worsens with age, exacerbated by mechanical friction or trauma, leading to more pronounced thickening and potential complications like painful cracks or secondary infections, though the course can vary from stable to relentlessly advancing.^[6] Histologically, PPK features orthokeratotic or parakeratotic hyperkeratosis, often accompanied by acanthosis and papillomatosis, but without significant underlying inflammation.^[1]^[8] PPK is not a single disease entity but rather a clinical phenotype shared across multiple etiologies, including hereditary and acquired forms, and is broadly classified into diffuse, focal, and punctate types based on the pattern of involvement.^[1] This distinction helps differentiate it from other hyperkeratotic conditions, such as calluses from mechanical stress or ichthyosis variants, emphasizing its role as a descriptive term for a spectrum of palm and sole-specific dermatoses.^[9]

Epidemiology

Palmoplantar keratoderma (PPK) encompasses a heterogeneous group of rare dermatological disorders, with an overall global prevalence estimated at less than 1 in 100,000 individuals, though this varies significantly by subtype and population. Specific inherited forms, such as epidermolytic PPK (Vörner type), have a reported prevalence of at least 4.4 per 100,000 in Northern Ireland, while the Bothnian type (Unna-Thost) reaches 0.3-0.55% in isolated northern Swedish communities. In South India, the prevalence of hereditary PPK has been documented at 5.2 per 10,000, highlighting higher rates in certain regional or ethnic groups due to founder effects. Acquired forms are generally less common than inherited ones but can occur secondary to underlying conditions, contributing to the overall rarity of the disorder.^[1]^[10] Demographically, hereditary PPK typically manifests in infancy or early childhood, with autosomal dominant forms like Unna-Thost and Vörner showing onset by age 3-4 years, while recessive variants such as Mal de Meleda present in the first months of life. Autosomal recessive subtypes are more prevalent in consanguineous populations, where inbreeding increases homozygosity for causative mutations, as observed in Algerian and Slovenian families with high rates of first-degree cousin marriages. There is no strong overall sex bias, though some acquired PPK cases show a slight male predominance, potentially linked to occupational exposures. Punctate forms appear more frequently among Europeans compared to diffuse types in other groups.^[1]^[11]^[12]^[13] Geographically, PPK exhibits notable variations, with higher incidence in specific regions tied to genetic isolates. Mal de Meleda, an autosomal recessive form, has an estimated worldwide prevalence of 1 in 100,000 but is more common in the Mediterranean basin, including the Balkans (originally described on the Adriatic island of Mljet), North Africa, and the Middle East due to historical consanguinity. In East Asia, Nagashima-type PPK shows elevated rates of 1.2 per 10,000 in Japan and 3.1 per 10,000 in China, reflecting founder mutations in SERPINB7. Risk factors for inherited PPK include family history and consanguinity, while acquired variants are associated with environmental triggers like chronic friction or heat exposure.^[14]^[15]^[16] Recent genetic studies from 2024-2025 have enhanced recognition of PPK through expanded testing, potentially increasing reported incidence in diverse populations due to migration and improved diagnostics. For instance, novel mutations in genes like SERPINA12 have been identified in European cases, previously thought limited to Asian cohorts, underscoring emerging patterns in multicultural settings. These advancements highlight the disorder's public health impact in isolated communities while emphasizing the need for targeted screening in high-risk groups.^[17]^[18]^[19]

Classification

Diffuse forms

Diffuse palmoplantar keratoderma is characterized by symmetrical, uniform hyperkeratosis that covers most or all of the palms and soles, resulting from excessive epidermal proliferation and altered cornification. This form typically manifests as thick, yellowish plaques with sharply demarcated erythematous borders, often beginning in infancy or early childhood and reaching full expression by age 3–4 years.^[20] Subtypes of diffuse palmoplantar keratoderma are broadly classified into epidermolytic and nonepidermolytic variants based on histopathological features. The epidermolytic subtype, exemplified by the Vörner type, presents with severe blistering and a characteristic "dirty snakeskin" appearance due to hyperkeratosis and epidermolysis; it is associated with mutations in the KRT9 gene, which encodes a palmoplantar-specific keratin. In contrast, the nonepidermolytic subtype, such as the Unna-Thost type, features smoother, waxy yellow plaques with minimal or absent blistering and is linked to mutations in the KRT1 gene, providing mechanical stability to keratinocytes.^[20]^[2] Clinically, diffuse forms often initiate with localized redness and fine scaling on weight-bearing areas, progressing to rigid, diffuse plaques that impair mobility and function. High-friction sites are particularly susceptible to fissuring, secondary infections, pain, and excessive sweating or odor, with a median onset age of around 5 years and symptoms worsening in about 23% of cases over time.^[21]^[2] Inheritance is primarily autosomal dominant, facilitating vertical transmission within families, though rare autosomal recessive cases occur, particularly in consanguineous populations. These genetic patterns underscore the role of keratin filament disruptions in the palmoplantar epidermis.^[20]^[2]

Focal forms

Focal palmoplantar keratoderma refers to a subtype of hereditary palmoplantar keratodermas characterized by discrete areas of hyperkeratotic thickening confined to specific sites of mechanical stress on the palms and soles, such as the balls of the feet, heels, and thenar eminence of the hands, while sparing the central portions of the palms and soles.^[2] These lesions typically manifest as yellow-brown, callus-like plaques that can be painful and are often induced by friction or pressure.^[20] Clinical features may also include associated blistering, minor nail abnormalities, and follicular hyperkeratosis in some cases, with the plaques appearing nummular-shaped and primarily affecting the plantar skin.^[20] The condition usually presents with onset in childhood or adolescence, though it can vary by subtype, and is less common than diffuse forms of palmoplantar keratoderma.^[1] Inheritance is typically autosomal dominant, with affected individuals having a 50% chance of passing the trait to offspring.^[22] Genetic mutations associated with focal forms include those in keratin genes such as KRT6A, KRT16, and desmosomal genes like DSG1, though detailed molecular mechanisms are beyond the scope here.^[2] Progression of focal palmoplantar keratoderma often worsens with repeated trauma or mechanical stress, leading to deeper fissures that increase the risk of secondary bacterial infections.^[20] Unlike more widespread variants, these localized lesions do not typically lead to spontaneous complications like autoamputation but can significantly impair mobility due to pain.^[2] Representative examples include Jadassohn-Lewandowsky syndrome, also known as pachyonychia congenita type 1, which features focal hyperkeratotic plaques on weight-bearing areas of the soles, accompanied by nail dystrophy affecting over 90% of toenails and oral leukokeratosis, with onset often before age 5 upon weight-bearing.^[2] Another example is Richner-Hanhart syndrome, a tyrosinemia type II-related disorder presenting with painful focal keratotic lesions on palms and soles starting in infancy or early childhood, though it is metabolic in nature rather than purely structural.^[23] Isolated non-syndromic focal forms, such as striate palmoplantar keratoderma, show linear hyperkeratotic bands on palms and discrete plantar plaques, emphasizing the localized pattern at friction sites.^[2]

Punctate forms

Punctate palmoplantar keratoderma is a rare subtype of hereditary palmoplantar keratoderma characterized by multiple discrete, small hyperkeratotic papules, typically measuring 1-5 mm in diameter, resembling raindrops or seeds, primarily affecting the palms and soles and occasionally extending to the digits. These lesions are usually asymptomatic and non-painful in their initial presentation, though they may cause mild discomfort with prolonged pressure or friction. The condition manifests as scattered, firm keratotic plugs that do not involve the entire palmoplantar surface, distinguishing it from more generalized forms.^[20]^[24] Several subtypes of punctate palmoplantar keratoderma have been identified based on clinical presentation, age of onset, and genetic associations. Type 1, also known as the Buschke-Fischer-Brauer type, is the most common and features an autosomal dominant inheritance pattern with early onset during late childhood or adolescence; it is linked to the 15q22.33-q23 locus and mutations in the AAGAB gene, which encodes a protein involved in epidermal growth factor receptor recycling. Type 2, often described as the spiny or porokeratotic variant, typically presents with late onset in early adulthood and is characterized by small, spiny keratotic projections or plugs that may resemble porokeratoses, also following autosomal dominant inheritance, though specific genetic loci remain less well-defined in some cases. Type 3, referred to as acral hyperkeratosis or the acrokeratoelastoidosis type, predominantly involves the margins of the hands and feet, including the toes, with keratotic papules appearing in adolescence or adulthood and autosomal dominant transmission.^[20]^[24]^[2] The inheritance of punctate palmoplantar keratoderma is predominantly autosomal dominant, with affected individuals having a 50% chance of passing the mutation to offspring, though rare autosomal recessive forms exist in specific variants. Clinically, the lesions may progress over time by increasing in number and size, potentially coalescing into larger plaques, particularly in areas subject to mechanical stress; exacerbation is commonly noted with exposure to moisture, such as water immersion, or occupational pressure, leading to worsening in manual laborers. The Buschke-Fischer-Brauer type exemplifies this progression, with lesions often becoming more prominent with age. While the global prevalence is estimated at approximately 1 in 100,000 individuals, higher rates have been observed in certain ethnic groups, including those of European, African, and Asian descent, reflecting varied genetic penetrance across populations.^[20]^[24]^[2]

Other variants

Striate palmoplantar keratoderma, also known as the Brunauer-Fohs-Siemens type, is an autosomal dominant disorder characterized by linear or striate hyperkeratosis primarily along the volar aspects of the fingers and toes, often extending to the palms and soles without significant involvement elsewhere.^[25] This variant typically manifests in infancy or early childhood with longitudinal ridges of thickened skin that may cause discomfort but rarely leads to mutilation.^[26] It is caused by mutations in the desmoglein 1 (DSG1) gene, which encodes a desmosomal protein essential for epidermal adhesion.^[27] Mutilating variants, such as Vohwinkel syndrome, represent severe progressive forms featuring diffuse honeycombed palmoplantar hyperkeratosis accompanied by constricting fibrous bands that can result in autoamputation of digits.^[28] Distinctive starfish-shaped keratotic plaques often appear on the dorsal aspects of hands and feet, with onset in early childhood and autosomal dominant inheritance due to mutations in the GJB2 gene encoding connexin 26, a gap junction protein.^[29] These bands, known as pseudoainhum, arise from circumferential constriction and may necessitate surgical intervention to prevent tissue loss.^[30] Loricrin keratoderma serves as a syndromic overlap, presenting with honeycomb-like palmoplantar hyperkeratosis, mild erythroderma, and pseudoainhum, often resembling a progressive symmetric erythrokeratoderma variant but with predominant acral involvement.^[31] This autosomal dominant condition stems from frameshift mutations in the LORICRIN gene, leading to truncated loricrin protein accumulation that disrupts the cornified envelope.^[32] Non-classic features may include subtle ichthyosiform scaling on the limbs, distinguishing it from purely mutilating types.^[33] Among rare forms, Nagashima-type palmoplantar keratoderma is an autosomal recessive disorder prevalent in East Asian populations, marked by well-demarcated, transgressive hyperkeratosis of palms and soles that extends to the wrists and ankles, often with periorificial erythema around the eyes, nose, and mouth.^[16] It arises from biallelic mutations in the SERPINB7 gene, which encodes a protease inhibitor crucial for epidermal homeostasis, and features a nonprogressive course without epidermolysis.^[34] In contrast, aquagenic palmoplantar keratoderma is an acquired or transient variant triggered by water exposure, causing rapid edematous wrinkling, whitish papules, and burning pain on the palms within minutes of immersion, sometimes linked to underlying conditions like cystic fibrosis.^[35] This form lacks persistent hyperkeratosis and resolves spontaneously, highlighting its distinct environmental provocation.^[36] Recent genetic studies from 2024 and 2025 have identified biallelic DSG1 splice-site variants causing mixed phenotypes, including non-syndromic striate palmoplantar keratoderma with transgressive features and variable severity across families.^[37] These reports expand the spectrum of DSG1-related disorders, previously associated mainly with milder dominant forms, to include recessive presentations with hyperkeratotic plaques and occasional nail dystrophy.^[38] A 2024 cohort analysis of 76 families confirmed DSG1 variants in multiple mixed phenotypes, underscoring the gene's role in diverse morphological expressions.^[17]

Etiology

Genetic causes

Palmoplantar keratoderma (PPK) encompasses a heterogeneous group of hereditary disorders primarily caused by mutations in genes encoding structural proteins essential for epidermal integrity, such as keratins, desmosomal components, and gap junction proteins. These mutations lead to abnormal keratinization and hyperproliferation of keratinocytes in the palmoplantar epidermis. Most hereditary forms follow an autosomal dominant inheritance pattern, though autosomal recessive and rare X-linked modes also occur.^[20]^[17] Mutations in keratin genes represent a major genetic cause, particularly for nonepidermolytic and epidermolytic diffuse PPK variants. For instance, heterozygous mutations in KRT1 (OMIM 139350) are associated with nonepidermolytic diffuse PPK, where missense variants in the rod domain disrupt keratin filament assembly, causing cytoskeletal instability and compensatory epidermal thickening. Similarly, mutations in KRT9 (OMIM 607606), specific to palmoplantar epidermis, underlie epidermolytic palmoplantar keratoderma (EPPK1; OMIM 144200), with over 30 reported variants, many in the helix initiation motif, leading to clumping of keratin intermediate filaments. Overlap with pachyonychia congenita occurs in cases of KRT16 (OMIM 148067) mutations, where focal palmoplantar keratoderma accompanies nail dystrophy due to impaired keratin 6/16 heterodimer formation.^[20]^[39] Other non-keratin genes contribute to syndromic and nonsyndromic PPK through diverse molecular mechanisms. Biallelic mutations in GJB2 (OMIM 121011), encoding connexin 26, cause Vohwinkel syndrome (OMIM 124300), an autosomal dominant disorder with mutilating keratoderma and hearing loss, resulting from impaired gap junction communication and cellular homeostasis. Autosomal recessive Mal de Meleda (OMIM 248300) arises from SLURP1 (OMIM 606398) variants, which encode a secreted protein modulating cholinergic signaling and desquamation. TRPV3 (OMIM 601627) gain-of-function mutations lead to Olmsted syndrome (OMIM 614594), featuring severe mutilating PPK and periorificial keratoses due to dysregulated calcium influx and inflammation. Rare X-linked forms, such as Olmsted syndrome variants, involve MBTPS2 (OMIM 300294) mutations affecting proteolytic processing of epidermal transcription factors.^[20] Autosomal recessive inheritance predominates in certain subtypes, exemplified by Nagashima-type PPK (OMIM 615598), caused by SERPINB7 (OMIM 608955) mutations that inhibit serine protease activity, leading to unchecked desmosomal degradation and transgressive hyperkeratosis. Recent genetic studies have expanded the spectrum, including 2024 findings of 8 DSG1 (OMIM 125670) variants, including 5 novel alleles such as splice variants, in diverse nonpunctate PPK phenotypes across families, emphasizing variable expressivity and the need for targeted sequencing. These mutations in desmoglein 1, a desmosomal cadherin, compromise cell adhesion and intercellular cohesion in the suprabasal epidermis. Overall, mutations disrupt intermediate filament networks or cell-cell junctions, precipitating cytoskeletal instability and aberrant differentiation.^[20]^[17]

Acquired causes

Acquired palmoplantar keratoderma (PPK) refers to non-hereditary forms of excessive epidermal thickening on the palms and soles, often triggered by external environmental exposures, underlying diseases, or secondary systemic conditions, in contrast to genetic forms that typically present with early onset and familial patterns.^[4] These cases usually develop later in life and may resolve upon addressing the underlying cause.^[40] Reactive forms of acquired PPK arise from chronic mechanical irritation, thermal exposure, or chemical contact, commonly observed in occupational settings such as farmers exposed to soil and friction or athletes subjected to repeated pressure on the feet.^[4] For instance, prolonged immersion in water can lead to aquagenic PPK, characterized by transient wrinkling and keratotic plaques shortly after exposure.^[40] Chemical agents like arsenic or chloracnegens have also been implicated in inducing hyperkeratosis through direct toxic effects on the skin.^[40] Paraneoplastic PPK manifests as a cutaneous sign of internal malignancies, most frequently associated with bronchial carcinoma, esophageal cancer, or breast tumors, where the hyperkeratosis often regresses following tumor treatment.^[4] Specific variants include acrokeratosis paraneoplastica (Bazex syndrome) and tripe palms, presenting with psoriasiform or velvety thickening.^[40] Recent case reports from 2024 document resolution of diffuse PPK after surgical excision of a mixed serous neuroendocrine tumor of the pancreas, highlighting the reversible nature when the malignancy is addressed.^[41] A reported instance linked PPK to renal cell carcinoma, emphasizing the need to screen for occult cancers in atypical presentations.^[42] Endocrine disorders, such as hypothyroidism leading to myxedema, can also cause acquired PPK.^[43] Inflammatory dermatoses frequently cause secondary hyperkeratosis resembling PPK, with psoriasis leading to diffuse or central palmoplantar involvement marked by scaly plaques, while eczema and lichen planus variants produce localized thickening due to chronic inflammation.^[40] Pityriasis rubra pilaris can induce yellow-orange hyperkeratosis on the palms and soles as part of its erythrodermic features.^[40] These conditions differ from primary PPK by their pruritic or erythematous components and response to anti-inflammatory therapies.^[4] Infectious etiologies are rare but include human papillomavirus (HPV) inducing punctate lesions, fungal overgrowth such as tinea pedis causing hyperkeratotic borders, and other pathogens like scabies, syphilis, or mycobacterial infections leading to reactive epidermal proliferation in predisposed individuals.^[40] For example, leprosy has been reported to cause focal PPK through granulomatous inflammation.^[4] Drug-induced PPK occurs as an adverse reaction to various medications, with lithium commonly implicated in producing psoriasiform hyperkeratosis that may persist during therapy but improves upon discontinuation.^[44] Other agents include chemotherapy drugs like bleomycin and hydroxyurea, as well as venlafaxine and verapamil, where cases resolve within 4-5 weeks after withdrawal.^[40] Nutritional deficiencies, particularly vitamin C scarcity in scurvy, can precipitate acquired PPK alongside gingival changes and ecchymoses, as evidenced by a 2022 case where severe palmoplantar thickening resolved after four weeks of multivitamin supplementation and dietary correction.^[45] Protein and other micronutrient deficits, often seen in malnutrition states, similarly contribute to epidermal fragility and hyperkeratosis.^[4] Emerging reports from 2023-2025 associate post-COVID-19 inflammatory triggers with new-onset PPK, including cases of palmoplantar keratosis following SARS-CoV-2 vaccination, potentially mediated by immune dysregulation.^[46] A 2023 case described diffuse hyperkeratosis triggered by COVID-19 vaccination, while aquagenic variants have been noted post-infection, underscoring viral-induced autoimmunity as a factor.^[47] Additionally, a 2025 report linked severe PPK to poorly controlled type 2 diabetes, resolving with topical keratolytics and glycemic management.^[48]

Pathophysiology

Molecular mechanisms

Palmoplantar keratoderma (PPK) arises from disruptions in keratinocyte function, primarily driven by genetic mutations that lead to abnormal keratin aggregation and compromise desmosomal integrity, thereby weakening the epidermal barrier. In hereditary forms, mutations in keratin genes such as KRT1 and KRT9 alter the structure of intermediate filaments, causing keratinocytes to aggregate improperly and fail to maintain stable cell-cell adhesions via desmosomes. This dysfunction manifests as hyperproliferation and incomplete differentiation of keratinocytes in the palmoplantar epidermis, contributing to the characteristic thickening.^[49]^[1] In epidermolytic variants of PPK, tonofilament disruption is a central mechanism, where mutations in suprabasal keratins like KRT1 or KRT9 induce clumping of keratin filaments within keratinocytes, leading to cytolysis and localized blistering beneath the hyperkeratotic areas. These aggregates destabilize the cytoskeletal network, impairing mechanical resilience and promoting compensatory epidermal hyperplasia as the skin attempts to reinforce its barrier.^[49]^[50] Signaling pathways in PPK involve dysregulated expression of cornified envelope components, including upregulation of involucrin and transglutaminase in the stratum corneum, which enhances cross-linking and rigidifies the envelope but exacerbates hyperkeratosis. In acquired forms, inflammatory mediators activate pathways such as NF-κB, amplifying keratinocyte proliferation through cytokine signaling and further disrupting epidermal homeostasis.^[49]^[1] Epidermal turnover is impaired in PPK due to alterations in cornified envelope proteins, notably loricrin mutations in variants like Vohwinkel syndrome, which reduce desquamation by forming defective, insoluble envelopes that resist shedding and perpetuate accumulation of corneocytes. This leads to a thickened, adherent stratum corneum with diminished barrier renewal.^[49] Recent insights from 2024 studies highlight the role of TRPV3 mutations in erythrokeratoderma-associated PPK, such as in Olmsted syndrome, where gain-of-function variants cause constitutive activation of calcium channels, resulting in excessive Ca²⁺ influx that triggers EGFR/PI3K/NF-κB signaling, keratinocyte apoptosis, and hyperproliferative responses culminating in severe palmoplantar hyperkeratosis.^[51]

Histopathological features

Histopathological examination of palmoplantar keratoderma (PPK) lesions reveals characteristic epidermal changes, primarily involving thickening and altered differentiation of the stratum corneum and underlying layers. The most consistent feature across subtypes is hyperkeratosis, often compact and orthokeratotic in nonepidermolytic forms, manifesting as marked thickening of the stratum corneum without parakeratosis.^[20] In epidermolytic variants, such as epidermolytic palmoplantar keratoderma (EPPK), hyperkeratosis is orthokeratotic and accompanied by vacuolization and epidermolytic changes in the suprabasal layers, reflecting disrupted keratinocyte maturation.^[20]^[2] Acanthosis, characterized by thickening of the spinous layer, and papillomatosis, with elongated rete ridges, are frequently observed, contributing to the hypertrophic appearance of the epidermis. These changes are prominent in diffuse and focal forms, such as Greither syndrome or keratosis palmoplantaris nummularis, where the epidermis shows increased cellular proliferation without significant cytolysis.^[20] In blistering subtypes like Vörner-type EPPK, epidermolysis is evident as suprabasal clefting and granular degeneration, leading to intraepidermal separation due to cytoskeletal instability.^[2] Hypergranulosis, with prominent keratohyaline granules, may also be seen in nonepidermolytic PPK, enhancing the stratum granulosum's density.^[20] Inflammation is typically minimal, with rare perivascular lymphocytic infiltrates and absence of viral inclusions unless an infectious etiology is present. Special diagnostic techniques provide further insight: electron microscopy demonstrates tonofilament aggregates and clumped keratin filaments in epidermolytic forms, correlating with mutations causing keratin clumping.^[52]^[53] Immunohistochemistry reveals altered expression of keratins, such as reduced K1 and K10 in affected suprabasal layers of epidermolytic PPK, aiding in subtype differentiation.^[2]

Clinical presentation

Symptoms and signs

Palmoplantar keratoderma (PPK) is characterized by abnormal thickening of the skin on the palms and soles, known as hyperkeratosis, which can appear diffuse, focal, or punctate depending on the variant.^[1] This hyperkeratosis often leads to painful fissuring, cracking, and bleeding, particularly at pressure points such as the heels and balls of the feet, increasing susceptibility to secondary infections.^[6] In some cases, an unpleasant odor arises from secondary bacterial overgrowth or excessive sweating within the thickened skin.^[1] The condition impairs daily function, causing difficulties with grip and walking due to the rigid, hardened skin that restricts movement and exacerbates pain during weight-bearing activities.^[2] Nail dystrophy is common, manifesting as ridging, thickening, or discoloration, which can further hinder manual dexterity.^[1] Abnormal sweating patterns, including hyperhidrosis (excessive sweating) or anhidrosis (reduced sweating), contribute to discomfort and may worsen fissuring in humid environments.^[54] Patients often experience sensory symptoms such as itching, burning sensations, or tenderness in the affected areas, with chronic pain becoming prominent in severe cases and significantly impacting quality of life.^[6] Hereditary forms typically onset in infancy or early childhood, progressing gradually with age and thickening over time, while acquired variants may exhibit seasonal flares triggered by environmental factors.^[2] Variant-specific manifestations include blistering and erosions in epidermolytic PPK, often induced by friction or trauma, and seed-like or tiny hard papules in punctate forms, which may coalesce into plaques.^[1]

Associated syndromes and conditions

Palmoplantar keratoderma (PPK) is frequently associated with various syndromic conditions that involve multisystem manifestations beyond the skin, highlighting its role in broader genetic disorders.^[1] These associations underscore the importance of evaluating patients for extracutaneous features to guide comprehensive management.^[1] Vohwinkel syndrome presents with mutilating keratoderma characterized by constricting bands on the digits that can lead to autoamputation, alongside congenital sensorineural deafness and other features such as alopecia and ichthyosiform dermatosis.^[1] Olmsted syndrome is marked by severe periorificial keratotic plaques, progressive flexion contractures of the digits, and potential autoamputation, often accompanied by alopecia, onychodystrophy, and dental anomalies.^[1] Mal de Meleda features transgressive erythema and hyperkeratosis extending beyond the palms and soles, with pachydermoperiostosis-like changes, nail dystrophy, and occasional syndactyly or high-arched palate, predominantly observed in populations of Mediterranean descent.^[1] Pachyonychia congenita involves focal palmoplantar hyperkeratosis with painful blisters, thick dystrophic nails, oral leukokeratosis, and cysts, along with follicular hyperkeratosis and hoarseness.^[1] Howel-Evans syndrome, a focal variant of PPK, is linked to a high lifetime risk of esophageal squamous cell carcinoma, approaching 95% by age 65, and includes oral leukokeratosis and follicular keratosis.^[1] Nagashima-type PPK, recognized as a nonprogressive diffuse form, may involve mild transgrediens spread to the elbows and knees, with recent reports noting perioral erythema in some cases and an elevated prevalence of malignant melanoma.^[1] Beyond syndromic features, PPK predisposes individuals to secondary bacterial and fungal infections due to fissuring and hyperkeratosis, particularly in variants like Mal de Meleda.^[1] The visible and debilitating nature of PPK can also lead to significant psychological comorbidities, including anxiety, depression, and reduced self-esteem, impacting daily activities and social interactions.^[55]

Diagnosis

Clinical assessment

The clinical assessment of palmoplantar keratoderma (PPK) begins with a detailed history to establish the onset, familial patterns, and potential triggers. Patients are queried about the age of symptom onset, which is typically in infancy or early childhood for hereditary forms but may occur later in acquired cases.^[20] Family history is crucial, as most inherited PPK follows autosomal dominant or recessive patterns, helping to differentiate genetic from sporadic or environmental etiologies.^[2] Aggravating factors such as mechanical friction, moisture exposure, or manual labor are noted, as they can exacerbate hyperkeratosis in both hereditary and acquired variants.^[6] Associated symptoms, including pain, blistering, hyperhidrosis, or systemic features like hearing loss or dental anomalies, are evaluated to identify syndromic associations.^[20] For suspected acquired PPK, additional investigations target underlying etiologies. These include laboratory tests such as thyroid function tests for myxedema, complete blood count, and nutritional assessments for deficiencies. Paraneoplastic associations warrant screening for malignancies, including chest X-ray or CT for lung cancer, endoscopy for esophageal cancer, and tumor markers where appropriate. Infections may require serology for human papillomavirus or syphilis, and dermatopathology consultation for mycosis fungoides.^[1]^[5]^[3] Physical examination focuses on inspection of the palms and soles to characterize the distribution and morphology of lesions. Hyperkeratotic plaques may appear diffuse, covering the entire palmoplantar surface, or focal/nummular, confined to pressure points; punctate or striate patterns are also possible.^[2] Texture is assessed for waxy thickening, scaling, fissuring, or blistering, with documentation of secondary infection signs like erythema or odor.^[6] Extension beyond the palms and soles—such as transgrediens spread to the Achilles tendon or involvement of nails (e.g., pachyonychia) and oral mucosa—is noted to suggest specific subtypes or syndromes.^[20] Severity is gauged through clinical documentation of lesion extent, fissuring depth, and functional impairment, supplemented by validated tools like the Dermatology Life Quality Index (DLQI) to quantify impact on daily activities, with mean scores around 7-8 indicating moderate effects.^[56] Red flags include rapid onset in adulthood, suggesting acquired or paraneoplastic forms, or syndromic clues such as hearing impairment (e.g., in PPK-deafness syndrome).^[2] Differential diagnosis relies on clinical clues to distinguish PPK from mimics: hereditary or acquired PPK often shows symmetric, non-resolving hyperkeratosis unlike mechanical calluses; psoriatic plaques may exhibit silvery scales and joint involvement; secondary syphilis can present with similar palmoplantar eruptions but typically includes generalized rash or lymphadenopathy.^[1] If clinical features are equivocal, referral for biopsy or genetic testing may follow as confirmatory steps.^[20]

Genetic testing and biopsy

Genetic testing and biopsy play crucial roles in confirming the diagnosis of palmoplantar keratoderma (PPK), particularly in distinguishing inherited forms from acquired ones and identifying associated risks. A skin biopsy is typically performed using a punch or shave technique, targeting the edge of a hyperkeratotic lesion on the palms or soles to capture representative tissue while avoiding fissured areas to minimize infection risk.^[20]^[57] Histopathological examination reveals characteristic features such as orthokeratotic hyperkeratosis, acanthosis, and, in epidermolytic subtypes, vacuolar degeneration of suprabasal keratinocytes; non-specific hyperkeratosis may be seen in acquired cases, helping to rule out mimics like malignancy or inflammatory dermatoses.^[2]^[20] For inherited PPK, genetic testing involves targeted gene panels or next-generation sequencing (NGS) focusing on keratin genes (e.g., KRT1, KRT9) and connexin genes (e.g., GJB2), with broader NGS panels for syndromic cases that may include genes like DSG1, AAGAB, or RHBDF2.^[20]^[17] A positive mutation, such as in KRT9 for epidermolytic PPK, confirms the inherited nature and specific subtype, while genetic counseling is essential to discuss autosomal dominant or recessive inheritance patterns and family implications.^[2]^[58] Interpretation of results integrates clinical history; for instance, a keratin mutation establishes hereditary etiology, whereas normal or non-specific histology in biopsy supports acquired PPK or exclusion of neoplastic processes.^[20] The utility of these tests is highlighted in recent studies, where genetic testing achieved a diagnostic yield of 83% in familial cases, aiding prognosis such as elevated esophageal cancer risk in Howel-Evans syndrome (RHBDF2 mutations) and enabling early surveillance or targeted therapies like retinoids for specific subtypes.^[17]^[58] Limitations include the fact that not all PPK cases are genetic, with acquired forms often showing only non-specific hyperkeratosis on biopsy, and phenotypic variability complicating genotype-phenotype correlations; additionally, high costs and access issues for NGS may restrict use in non-syndromic cases.^[2]^[20]

Management

Topical and systemic therapies

Topical therapies form the cornerstone of management for palmoplantar keratoderma (PPK), aiming to hydrate the skin, reduce hyperkeratosis, and alleviate symptoms such as pain and fissuring. Emollients containing urea (10-40%) or lactic acid (10%) are commonly applied to improve skin barrier function and hydration, particularly in hereditary forms like epidermolytic PPK due to KRT1 or KRT9 mutations.^[1] Keratolytics, such as salicylic acid (5-20%), promote desquamation and debridement of thickened plaques; these are often used in concentrations of 6-20% for diffuse or nonepidermolytic PPK, with application under occlusion to enhance penetration.^[59]^[1] Topical retinoids, including tazarotene gel (0.05-0.1%), are effective for epidermolytic subtypes by modulating keratinocyte differentiation, though irritation limits their use in sensitive areas.^[1] For acquired PPK, topical corticosteroids or anti-inflammatory agents like calcipotriol may reduce associated erythema and inflammation.^[59] Systemic therapies are reserved for severe, diffuse, or refractory cases where topical approaches provide insufficient relief. Oral retinoids, such as acitretin (starting at 0.5-1 mg/kg/day, up to 30-35 mg/day) or etretinate (though less commonly used due to longer half-life), induce epidermolysis and reduce hyperkeratosis in conditions like Mal de Meleda (SLURP1 mutations) or mutilating PPK (GJB2 mutations), often requiring long-term low-dose maintenance.^[59]^[1] In syndromic PPK with inflammatory components, such as in dermatomyositis-associated cases, methotrexate (7.5-15 mg/week orally or subcutaneously) has demonstrated resolution of keratoderma by targeting underlying autoimmune processes.^[60] Emerging therapies target specific molecular pathways in select PPK subtypes. Biologic agents like dupilumab (300 mg subcutaneously every two weeks) have shown marked improvement in Nagashima-type PPK (SERPINB7 mutations), particularly when associated with atopic dermatitis, with near-complete resolution of keratosis after 42 weeks in reported cases, without relapse or significant adverse effects.^[61] Treatment protocols emphasize a multimodal approach, including daily soaking in warm water followed by application of keratolytics under occlusion overnight, combined with mechanical debridement as needed.^[1] Irritation from topicals is monitored closely, with dose reductions or discontinuation if severe; in children, lower concentrations (e.g., salicylic acid 3-6%) and adjusted retinoid doses (0.25-0.5 mg/kg/day for acitretin) are recommended to minimize systemic absorption risks.^[59] Efficacy varies by subtype, with topical therapies offering short-term relief and systemic options providing more sustained control; lifelong maintenance is often necessary due to the chronic nature of PPK.^[59]^[1]

Surgical interventions

Surgical interventions for palmoplantar keratoderma (PPK) are typically reserved for severe, refractory cases where medical therapies fail to alleviate functional impairment or prevent complications such as infection. These procedures aim to remove hyperkeratotic tissue and restore skin integrity, particularly in mutilating forms like those associated with Olmsted or Vohwinkel syndromes.^[62]^[1]^[7] Debridement involves mechanical removal of hyperkeratotic masses using sharp instruments or harmonic scalpels to reach the deep dermis, providing temporary relief from pain and mobility restrictions. For focal lesions, ablative carbon dioxide (CO2) laser therapy vaporizes thickened keratin layers, promoting re-epithelialization with minimal bleeding and reduced postoperative pain compared to traditional paring. This approach has shown efficacy in limited hyperkeratoses, with sustained improvement observed in case reports up to one year post-treatment.^[62]^[63]^[64] Reconstructive surgeries address structural deformities, such as deep fissures or constrictive bands. Skin grafting, often involving full-thickness or split-thickness autografts from donor sites like the thigh, is used to cover excised areas on palms and soles, improving durability and preventing recurrence in weight-bearing regions. In Vohwinkel syndrome, surgical release of pseudoainhum constrictions—via Z-plasty or excision with flap reconstruction—prevents digital autoamputation and restores hand function, with low recurrence rates when combined with local tissue rearrangement.^[1]^[65]^[66] Indications for surgery include significant functional limitations, such as inability to walk or grip objects, recurrent infections, or sepsis risk from fissured skin. A 2024 case report on severe PPK in Olmsted syndrome reported successful outcomes with staged excision, dermal matrix application, and grafting, achieving full resolution of symptoms and restored mobility after 16 years of follow-up in a young patient previously wheelchair-bound.^[62]^[67] Risks encompass scarring, hyperkeratosis recurrence within months if incomplete excision occurs, and potential neurovascular damage during debridement. Postoperative care involves negative pressure wound therapy to support graft take, alongside topical keratolytics like urea to manage minor regrowth, emphasizing multidisciplinary monitoring to optimize healing.^[62]^[68]^[66]

Prognosis and complications

Long-term outcomes

Inherited forms of palmoplantar keratoderma (PPK) follow a lifelong trajectory, characterized by persistent hyperkeratosis that typically begins in infancy or early childhood and requires continuous management to mitigate symptoms.^[2] In contrast, acquired PPK often resolves upon addressing the underlying etiology, such as surgical resection of an associated tumor in paraneoplastic cases, leading to complete remission of skin changes.^[69] This distinction underscores the importance of identifying hereditary versus secondary causes early in the disease course to guide expectations for long-term control. Therapeutic interventions, including topical keratolytics, systemic retinoids, and emerging biologics, achieve partial symptom control in many patients, though full resolution remains uncommon in inherited variants. Genetic counseling plays a key role in long-term outcomes by facilitating informed family planning and early detection in at-risk relatives, with studies showing low uptake but high potential impact when implemented.^[70] Recent investigations, including those from 2023-2025, demonstrate enhanced responses to biologic agents targeting inflammatory pathways, with notable reductions in pain and hyperkeratosis severity—up to complete clearance in select cases—improving overall quality of life.^[71] Functional prognosis varies by subtype; mutilating forms, such as those in Vohwinkel or Olmsted syndromes, often lead to significant disability, including joint contractures, autoamputation, and impaired mobility due to progressive constriction.^[72] Punctate PPK, however, tends toward better long-term function with early intervention, as timely therapies can prevent coalescence of lesions and reduce associated pain.^[1] Ongoing monitoring is crucial, with annual dermatology follow-ups recommended to assess disease progression and adjust care, alongside targeted cancer screening for high-risk associated syndromes like Howel-Evans, where esophageal malignancy risk necessitates regular endoscopy.^[73]^[74] These measures help sustain quality of life despite the chronic nature of the disorder.

Potential complications

Palmoplantar keratoderma (PPK) can predispose affected individuals to chronic skin infections due to fissuring and hyperkeratotic barriers that impair barrier function and promote microbial colonization. Bacterial infections, such as those caused by Staphylococcus aureus, and fungal infections, including dermatophytosis, are common secondary complications, particularly in subtypes like Bothnian PPK associated with hyperhidrosis.^[75]^[76] Severe or chronic PPK lesions carry an elevated risk of malignant transformation into squamous cell carcinoma (SCC), especially in syndromic forms. In Howel-Evans syndrome (tylosis with esophageal cancer), patients face up to a 40% lifetime risk of esophageal SCC, often linked to persistent palmoplantar hyperkeratosis.^[77] Cutaneous SCC has also been reported arising directly from longstanding PPK plaques in variants like Olmsted syndrome and Bothnian PPK.^[78]^[79] Systemically, mutilating subtypes such as Olmsted and Vohwinkel syndromes can lead to autoamputation of digits through progressive constriction bands (pseudoainhum) that cause ischemia and fibrosis.^[80]^[81] Joint contractures frequently develop from chronic inflammation and fibrotic changes in the periarticular skin, limiting mobility in hereditary PPK cases.^[82]^[83] The visible and debilitating nature of PPK often results in psychological distress, including increased anxiety, depression, and social isolation due to cosmetic disfigurement and functional impairments.^[84]^[85] Affected individuals and their families report a significant psychosocial burden, with needs for mental health support highlighted in genodermatoses like PPK-associated ichthyoses.^[86] Treatment-related complications include hepatotoxicity from systemic retinoids like acitretin, which can elevate liver enzymes and, in rare cases, lead to fibrosis with prolonged use in dermatologic conditions.^[87]^[88] Prolonged application of topical corticosteroids may induce skin atrophy, thinning the epidermis in treated areas.^[89] In rare paraneoplastic presentations, acquired PPK has been documented as a cutaneous manifestation of underlying malignancies, such as metastatic carcinoma or acute myeloid leukemia, with reports from 2023 onward describing resolution following oncologic therapy like chemotherapy; however, recurrence may occur if the primary tumor persists.^[90]^[69]^[91] Early intervention can mitigate these complications, aligning with improved long-term outcomes in managed cases.

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Nov 13, 2023 · Vohwinkel syndrome is a hereditary PPK associated with starfish keratoses on the knuckles, a PPK in a honeycomb pattern, hearing impairment, and mutilating ...
[81]
Hereditary palmoplantar keratoderma (four cases in three generations)
Contractures were present on all the fingers; nevertheless, the deformity of the middle and distal interphalangeal joints of the little finger was prominent.
[82]
Partial Improvement of Olmsted Syndrome With Etretinate - PubMed
He had a sharply marginated, painful keratoderma with a red border on his palms and soles. Flexion contractures of the fingers were also observed.
[83]
Increased risk of anxiety and coping strategies in patients ... - PubMed
Apr 23, 2025 · People with genodermatoses face physical pain, social discrimination, and daily life challenges, all of which have an impact on their emotional ...
[84]
A multicenter study on quality of life of the "greater patient ... - PubMed
Oct 20, 2021 · ... palmoplantar keratoderma. Additional features include ectropion, eclabium, ear deformities, foul-smell, joints contractures and walking ...
[85]
The Burden of Autosomal Recessive Congenital Ichthyoses on ...
Jun 22, 2021 · The results of this study highlight the impact of ARCI on specific aspects of patient and family life, underlining the need for psychological ...
[86]
Liver toxicity of retinoid therapy - PubMed
Since retinoids are analogs of vitamin A, their potential to produce liver disease is reviewed. Animal and human studies of liver function tests suggest some ...
[87]
Acitretin in dermatology - PubMed
Since its use is limited by its teratogenic potential and other adverse effects, including mucocutaneous effects and hepatotoxicity, this review would summarize ...
[88]
Topical tazarotene: a review of its use in the treatment of plaque ...
... corticosteroids; it also has the potential to reduce the degree of skin atrophy associated with topical corticosteroids. The combination of tazarotene and ...Missing: palmoplantar | Show results with:palmoplantar<|separator|>
[89]
Paraneoplastic palmoplantar keratoderma secondary to metastatic ...
Palmoplantar keratoderma (PPK) is a dermatosis that presents as hyperkeratosis of the palms and soles. It may be acquired or heritable. Acquired PPK often ...
[90]
Paraneoplastic Eczematous Dermatitis With Palmoplantar ... - PubMed
Paraneoplastic Eczematous Dermatitis With Palmoplantar Keratoderma as an Initial Manifestation of Acute Myeloid Leukemia.