Keratosis Palmaris et Plantaris: Overview, Diffuse Hereditary PPK, Focal and Striate Hereditary PPK (2023)

Diffuse types without associated features

Epidermolytic PPK (Vorner PPK)

Synonyms for epidermolytic PPK (EPPK) include diffuse Vorner disease and PPK cum degeneratione granulosa. In some ethnic groups, this form is the most common type of hereditary PPK. For example, it has an estimated prevalence of at least 4.4 cases per 100,000 population in Northern Ireland. It is inherited in an autosomal dominant fashion. Onset occurs in the first few months of life, but the disease is usually well developed by age 3-4 years.

Clinical features are very similar to diffuse nonepidermolytic PPK (NEPPK). A well-demarcated, thick, yellow hyperkeratosis is present over the palms and soles. An erythematous band is frequently present at the periphery of the keratosis. The surface is often uneven and verrucous. Painful fissures and hyperhidrosis are common. Finally, it is usually nontransgredient, with a sharp demarcation of the lesions at the wrists.

Histologically, keratinocytes show epidermolysis, hyperkeratosis, acanthosis, and papillomatosis. Perinuclear vacuolization and large keratohyalin granules are seen. Cellular breakdown in the spinous and granular cell layers occurs rarely and can lead to blister formation. Several biopsy specimens may be required to confirm the changes, as they may be subtle and patchy.

This disorder is most frequently associated with mutations in keratin 9, although keratin 1 has been implicated in a small number of reported cases. Mutations in keratin 9 typically result in phenotypes confined to the palms and soles. In contrast, keratin 1 is expressed ubiquitously, thus these mutations can affect the entire body surface. ^[1]

Topical therapies that have proven useful for EPPK include salicylic acid, keratolytic agents (ie, lactic acid and urea), and 50% propylene glycol in water under plastic occlusion several nights per week. Mechanical debridement with a blade also may be useful. Oral retinoid therapy has had variable effects and may not benefit patients with certain genotype profiles, such as K1 mutations. Finally, gene editing via CRISPR/Cas9, ^[2] as well as RNA-interference-based therapy, ^[3] has shown benefit in mouse models of this disease and may represent a powerful therapeutic strategy in the future.

Nonepidermolytic PPK (Unna-Thost PPK and Bothnian-type PPK ^[1]

Synonyms include diffuse Unna-Thost disease and PPK diffusa circumscripta. Diffuse NEPPK is inherited in an autosomal dominant fashion. The condition may manifest in the first few months of life but is usually well developed by age 3-4 years. It is another common type of hereditary PPK. Bothnian-type PPK has a prevalence rate of 0.3-0.55% in Northern Sweden (near the Gulf of Bothnia).

Clinically, waxy, thick, well-demarcated hyperkeratosis is present over the palms and soles. A red band is frequently present at the periphery of the keratosis. It is usually nontransgredient, with a sharp demarcation of the lesions at the wrists. Aberrant keratotic lesions may appear in the dorsum of the hands, feet, knees, and elbows. The dorsa of the fingers may be involved with a scleroderma-like thickening of the distal digit. A cobblestone hyperkeratosis of the knuckles may be seen. Nails may be thickened. Bothnian-type PPK may be distinguishable by the spongy-white appearance of affected areas when exposed to water.

EPPK and NEPPK show considerable clinical overlap and may be indistinguishable without histologic evaluation; however, some clinical features may help differentiate the two entities. NEPPK may have a more waxy, even appearance, compared with that of EPPK. Hyperhidrosis and pitted keratolysis may be present with NEPPK. Finally, secondary dermatophyte infections are more common in NEPPK.

Histologic findings include orthokeratotic hyperkeratosis associated with hypergranulosis or hypogranulosis and moderate acanthosis. Changes are nonspecific and common to many varieties of keratoderma. An absence of epidermolysis differentiates it from EPPK.

Unna-Thost PPK and Bothnian-type PPK are both autosomal dominant, but they differ in their associated mutations. Unna-Thost PPK molecular biology features include linkage to type II keratin locus on band 12q11-13, corresponding to a keratin 1 gene mutation. Bothnian-Type PPK is marked by a monoallelic missense mutation in the aquaporin 5 gene. Aquaporin 5 is expressed in eccrine sweat glands. ^[4]

Topical treatment options for NEPPK are similar to those for EPPK. These include salicylic acid, keratolytic agents (ie, lactic acid and urea), and 50% propylene glycol in water under plastic occlusion. Mechanical debridement with a blade may also be useful. Oral retinoid therapy has had variable effects. Treatment with an antifungal agent is beneficial if dermatophyte infection coexists with the NEPPK.

Mal de Meleda ^[5]

A synonym is keratosis extremitatum hereditaria trangrediens et progrediens. Mal de Meleda is an autosomal recessive disease. Onset occurs in early infancy, but the condition is rare. The prevalence is 1 case per 100,000 population. Initially, it was described in inhabitants of the Adriatic Island of Meleda (now called Mljet). ^[1]

Clinical features of mal de Meleda include a diffuse, thick keratoderma with prominent erythematous borders. Lesions are transgradient with spreading onto the dorsa of the hands and the feet. Constricting bands are present around the digits and can result in spontaneous amputation. Well-circumscribed psoriasislike plaques or lichenoid patches may be present on the knees and the elbows. Patients may have severe hyperhidrosis, possibly accompanied by malodor. Secondary bacterial and fungal infections are common. Perioral erythema; periorbital erythema and hyperkeratosis; nail changes (eg, koilonychia, subungual hyperkeratosis); and lingua plicata, syndactyly, hair on the palms and the soles, high-arched palate, and left-handedness are other clinical features.

Histologic findings include orthokeratosis, normogranulosis, and a pronounced stratum lucidum without epidermolysis. There is a prominent perivascular lymphohistiocytic infiltration.

Molecular biology features include mutations in the gene encoding SLURP-1 found on band 8q24.3. Proteins of the SLURP family have been implicated in transmembrane signal transduction, cell activation, and cell adhesion.

Treatment is with oral retinoids and topical keratolytic agents.

Nagashima-type PPK ^[6]

This condition is inherited in an autosomal recessive fashion. Onset of disease occurs between birth and age 3 years with stable disease severity over time. To date, the approximately 30 reported cases have occurred in Japan and China.

Clinically, the disease was initially described as a milder form of mal de Meleda. Some classify this keratosis as its own distinct entity, with common involvement of other sites, including the elbows and knees. Hyperhidrosis and tinea pedis infection are associated features. Case reports have described an increased prevalence of malignant melanoma in the hyperkeratotic lesions of Japanese patients with Nagashima-type PPK. ^[7] This may be due to the lack of epidermal Langerhans cells as seen on histopathology of hyperkeratotic skin. ^[8]

Treatment options include emollients and keratolytic agents.

Whole-exome sequencing has identified the molecular basis of Nagashima-type PPK as a defect in the SERPINB7 gene. The serpin superfamily of proteins is diverse and contributes to inflammation, immunology, and metastasis. ^[9]

Progressive PPK (Greither disease)

A synonym is transgrediens et progrediens PPK. This is inherited in an autosomal dominant fashion. Onset occurs in early infancy but may occur later in childhood.

Clinically, Greither disease is a transgradient PPK with extension of plaques onto the dorsa of the hands and the feet. There is characteristic involvement of the Achilles tendon. Scaly plaques may be found on the elbows, knees, and flexural areas. Hyperhidrosis and intrafamilial phenotypic variation are common. Pseudoainhum formation with amputation of the digits has been described.

Histologic features include epidermolysis of the granular cell layer. Lipid-laden corneocytes may be seen.

Molecular biology features include mutations in the gene encoding keratin 1. ^[10]

Treatment includes emollients, topical retinoids, keratolytics, and topical steroids.

Diffuse types with associated features

Mutilating PPK (Vohwinkel or Camisa syndrome)

Synonyms include PPK mutilans, loricrin keratoderma, and keratoderma hereditaria mutilans. Mutilating PPK is inherited in an autosomal dominant fashion. Onset occurs in infancy.

Clinically, this condition manifests in infants as a honeycomblike keratosis of the palms and the soles. It becomes transgredient during childhood. Later, constricting, fibrous bands appear on the digits and can lead to progressive strangulation and autoamputation. Starfish-shaped keratoses may occur on the knuckles of the fingers and toes, which is a characteristic feature of this disorder. Alopecia, hearing loss, spastic paraplegia, myopathy, ichthyosiform dermatosis, and nail abnormalities are associated findings. Cases of epithelioma cuniculatum have been reported.

Histologic findings include hyperkeratosis, acanthosis, and a thickened granular cell layer with retained nuclei in the stratum corneum.

Molecular biological studies have confirmed that the most common mutation found in Vohwinkel syndrome involves the gene GJB2, which encodes the gap junction protein connexin 26. ^[11] This subtype is associated with hearing loss. In contrast, a mutation in the gene for loricrin, involved in epidermal differentiation, is associated with mutilating keratoderma and ichthyosis, but not deafness.

Treatment includes oral retinoids. Reconstructive plastic surgery may be necessary for treatment of digital autoamputation. ^[12]

Also see Vohwinkel Syndrome.

Bart-Pumphrey syndrome ^[13]

A synonym is PPK with knuckle pads, leukonychia, and deafness. It is inherited in an autosomal dominant fashion. Onset occurs in infancy.

Clinically, all neonates are hearing impaired from birth and develop diffuse PPK in childhood. Leukonychia and hyperkeratoses over the joints of the hand also appear.

Molecular biological studies describe a new mutation in the GJB2 gene encoding connexin 26, which explains the clinical overlap with Vohwinkel syndrome.

Diffuse NEPPK and sensorineural deafness

This condition is inherited in an autosomal dominant fashion. ^[14]

Clinical features include diffuse palmoplantar hyperkeratosis in mid childhood preceded by slowly progressive, high-frequency hearing loss in early childhood.

Molecular biology features include a connexin 26 mutation. This mutation occurs on a distinct domain from that found in Vohwinkel syndrome. A mitochondrial point mutation has also been demonstrated as the cause of this phenotype, making this the only type of keratoderma associated with a mutation in mitochondrial DNA (serine tRNA). ^[11]

PPK with sclerodactyly (Huriez syndrome) ^[15]

PPK with sclerodactyly is inherited in an autosomal dominant fashion. Onset occurs in infancy.

Clinical features include red, atrophic skin on the dorsal hands and feet at birth. Diffuse, mild keratoderma is more marked on the palms than the soles. Other clinical features include sclerodactyly and nail abnormalities (hypoplasia, fissuring, ridging, koilonychia). PPK with sclerodactyly is also associated with marked atrophy and aggressive squamous cell carcinoma in areas of atrophic skin.

Histologic findings include acanthosis, accentuation of the granular layer, and orthokeratosis; Langerhans cells are almost completely absent in the affected skin. Under electron microscopy, dermoepidermal junctions and desmosomes are normal; however, dense bundles of tonofilaments are seen in the epidermal layer. The granular layer shows large, coarse, clumped keratohyalin.

Molecular biologic findings include a mutation in the gene mapped to 4q23.

Owing to the increased risk of skin cancer, close monitoring of patients is recommended. Other treatments include emollients, keratolytics, and topical and oral retinoids.

Hidrotic ectodermal dysplasia (Clouston syndrome)

This syndrome is an autosomal dominant disorder.

Clinical features include diffuse papillomatous PPK (especially over pressure points of the palms and soles), dystrophic nails, and hypotrichosis. Thickened, hyperpigmented skin may also appear over the small and large joints, including the knuckles, elbows, and knees. Thickened, severely dystrophic nails develop, but they may be normal at birth. Universal sparsity of hair affects the scalp, eyebrows, eyelashes, and axillary and genital regions. Sensorineural deafness, polydactyly, syndactyly, clubbing of fingers, mental retardation, dwarfism, photophobia, and strabismus are associated features.

Clouston syndrome is mapped to 13q11. One form is caused by a mutation in the gene encoding connexin 30. Ultrastructural studies of the hair of these patients demonstrate disorganization of hair fibrils with loss of the cuticular cortex. Evidence reported in 2016 suggests that patients may be immunodeficient, with reduced phagocytic activity of granulocytes and monocytes. ^[16]

Mutilating PPK with periorificial keratotic plaques (Olmsted syndrome)

This type can be autosomal dominant, autosomal recessive, or X-linked recessive depending on the affected genes. Onset occurs in the first year of life.

Clinically, Olmsted syndrome begins focally in infancy and subsequently becomes diffuse. Later findings include flexion deformities and constriction of the digits, sometimes leading to spontaneous amputation. Progressive, well-defined perioral, perianal, and perineal hyperkeratotic plaques are present, as is onychodystrophy. Alopecia, deafness, nail dystrophy, and dental loss may be associated. Squamous cell carcinoma and malignant melanoma have developed in the areas of keratoderma. ^[17]

Histologic findings include hyperkeratosis without parakeratosis and mild acanthosis. Positive Ki-67 immunostaining of suprabasal keratinocytes suggests that hyperproliferation of the epidermis is a feature of this disease. ^[18]

Autosomal dominant and recessive forms have been associated with a gain-of-function mutation on the transient receptor potential vanilloid-3 (TRPV3) gene. X-linked recessive forms have been associated with mutations in the membrane-bound transcription factor protease, site 2 gene. ^[19]

Treatment includes oral and topical retinoids. Full-thickness excision and skin grafting has also been reported to result in clinical improvement. The development of a TRPV3 antagonist would provide the opportunity for targeted therapy.

PPK with periodontitis (Papillon-Lefèvre syndrome)

This condition is inherited in an autosomal recessive fashion. The prevalence of PPK with periodontitis is 4 cases per million. A variant, Haim-Munk syndrome, features, in addition to PPK and periodontitis, arachnodactyly, acroosteolysis, and onychogryphosis.

Clinically, diffuse transgredient PPK may be observed, typically developing within the first 3 years of life. Punctiform accentuation, particularly along the palmoplantar creases, may be seen. Unless treated, periodontosis results in severe gingivitis and loss of teeth by age 5 years. No significant correlation has been demonstrated between the level of periodontal infection and the severity of skin affections, which supports the concept that these major components of this syndrome are unrelated to each other. Patients exhibit increased susceptibility to cutaneous and systemic infections owing to neutrophil dysfunction. Scaly, psoriasiform lesions are often observed over the knees, elbows, and interphalangeal joints. Finally, patients may have malodorous hyperhidrosis. Reports from 2008 indicate a high prevalence of malignant melanoma in Japanese patients with Papillon-Lefèvre syndrome. ^[20]

Histologic findings include hyperkeratosis with irregular parakeratosis and moderate perivascular infiltration. Electron microscopic features include lipidlike vacuoles in corneocytes and granulocytes, a reduction in tonofilaments, and irregular keratohyalin granules.

Molecular biology findings include mutations in the CTSC gene. This gene codes for cathepsin C and mutations have been mapped to 11q14-q21. ^[21] Cathepsin C is a lysosomal protease known to activate enzymes that are vital to the body's defenses. Reports of multiple distinct mutations on the CTSC gene have been reported from consanguineous families in Turkey. ^[22]

Treatment includes oral retinoids for the PPK. Elective extraction of involved teeth may prevent excess bone resorption. Appropriate antibiotic therapy may be required for periodontitis and recurrent cutaneous and systemic infections. Early treatment with acitretin in childhood may allow patients to have normal adult dentition. Finally, in a 2018 in vitro study, introduction of recombinant cathepsin C partially restored some of the downstream immunologic functions of mutant cells and could represent an attractive therapeutic option in the future. ^[23]

Diffuse NEPPK with woolly hair and arrhythmogenic cardiomyopathy (Naxos disease) ^[24]

This condition is inherited in an autosomal recessive fashion.

Clinically, a diffuse, nontransgredient keratoderma with an erythematous border appears during the first year of life. Woolly (dense, rough, and bristly) scalp hair is present at birth. Cardiac disease, manifested by arrhythmias, heart failure, or sudden death, becomes evident during and after late puberty. Other cutaneous manifestations include acanthosis nigricans, xerosis, follicular hyperkeratosis over the zygoma, and hyperhidrosis.

Histologic findings include hyperkeratosis, hypergranulosis, and acanthosis.

Molecular biology findings include a mutation in the plakoglobin gene, mapping to 17q21, which is responsible for Naxos disease. Cardiomyopathy with alopecia and palmoplantar keratoderma (CAPK) is a subtype of Naxos disease described in a family with alopecia and right ventricular arrhythmogenic cardiomyopathy. CAPK has been linked to a mutation in the JUP gene coding for plakoglobin. ^[25] Plakoglobin is an important component of cell-to-cell and cell-to-matrix adhesion complexes of many tissues, including the skin and cardiac junctions. It also plays a role in signaling in the formation of desmosomal junctions. Mutations in the plakoglobin gene may lead to detachment of the cardiac myocytes, resulting in myocyte death. Plakoglobin mutations may also lead to desmosomal junction fragility in hair shafts, explaining the clinical phenotype of woolly hair.

Normalization of plakoglobin levels has been shown to restore cardiac function in mice and may be a viable therapeutic approach for improving the cardiac, and other, manifestations of this disease. ^[26]