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  Table of Contents  
Year : 2019  |  Volume : 10  |  Issue : 4  |  Page : 365-379  

Hereditary palmoplantar keratoderma: A practical approach to the diagnosis

1 Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh, India

Date of Web Publication28-Jun-2019

Correspondence Address:
Gomathy Sethuraman
Department of Dermatology, All India Institute of Medical Sciences, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/idoj.IDOJ_367_18

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The ridged skin of the palms and soles has several unique features: (i) presence of dermatoglyphics created by alternating ridges and grooves forming a unique pattern, (ii) presence of the highest density of eccrine sweat glands and absence of pilosebaceous units, and (iii) differential expression of keratins compared to the glabrous skin. These features explain the preferential localization of palmoplantar keratoderma (PPK) and several of its characteristic clinical features. PPK develops as a compensatory hyperproliferation of the epidermis and excessive production of stratum corneum in response to altered cornification of the palmoplantar skin due to mutations in the genes encoding several of the proteins involved in it. PPK can manifest as diffuse, focal, striate, or punctate forms per se or as a feature of several dermatological or systemic diseases. There is a wide genetic and phenotypic heterogeneity in hereditary PPK, due to which reaching an accurate diagnosis only on the basis of clinical features may be sometimes challenging for the clinicians in the absence of molecular studies. Nevertheless, recognizing the clinical patterns of keratoderma, extent of involvement, degree of mutilation, and associated appendageal and systemic involvement may help in delineating different forms. Molecular studies, despite high cost, are imperative for accurate classification, recognizing clinical patterns in resource poor settings is important for appropriate diagnosis, genetic counseling, and management. This review intends to develop a practical approach for clinical diagnosis of different types of hereditary PPK with reasonable accuracy.

Keywords: Clinical diagnosis, hereditary palmoplantar keratoderma, keratinization disorders, palmoplantar keratoderma

How to cite this article:
Dev T, Mahajan VK, Sethuraman G. Hereditary palmoplantar keratoderma: A practical approach to the diagnosis. Indian Dermatol Online J 2019;10:365-79

How to cite this URL:
Dev T, Mahajan VK, Sethuraman G. Hereditary palmoplantar keratoderma: A practical approach to the diagnosis. Indian Dermatol Online J [serial online] 2019 [cited 2021 Aug 2];10:365-79. Available from: https://www.idoj.in/text.asp?2019/10/4/365/261793

   Introduction Top

Hereditary palmoplantar keratodermas (PPK) are a heterogeneous group of keratinizing disorders characterized by hyperkeratotic thickening of the palms and soles. The molecular basis of PPK has been well established in recent years. The mutations in the genes encoding proteins involved in keratinization process, such as keratins, desmosomes, loricrin, cathepsin C, gap junction proteins, and many others have been implicated in pathogenesis of PPK. The majority of PPK manifests in infancy in isolation or in association with other abnormalities involving nails, teeth, or other organs.[1],[2] Traditionally, the diagnosis of hereditary PPKs has been based on history and clinical features combined with histopathology. Although the major histological features of palmoplantar keratosis are usually nonspecific hyperkeratosis, other histopathological characteristics such as epidermolysis may be useful in distinguishing nonepidermolytic and epidermolytic PPK. However, owing to significant clinical heterogeneity, accurate classification of PPK merely on clinical features may be challenging in the absence of molecular studies. On the other hand, recognizing the clinical patterns of keratoderma, extent of involvement, degree of mutilation, and associated appendageal and systemic involvement will help in their management. This review intends to develop a practical approach to diagnose different types of hereditary PPK clinically with reasonable accuracy.

Pathogenesis of hereditary PPK

Most of the types of PPK are inherited as autosomal dominant or autosomal recessive disorders. History of consanguinity in parents may point towards the presence of recessive variants. Medical and occupation details helps in differentiating acquired causes of palmoplantar hyperkeratosis, such as manual labor, chronic contact dermatitis, atopic dermatitis, psoriasis, HIV infection, paraneoplstic, metabolic disorders (hypothyroidism, myxedema climacteric), exposure to chemicals (arsenic, hydrocarbons), and drugs (lithium, chemotherapeutics).[3] It will also be prudent here to briefly revisit the structure and functions of various molecules and genetic mutations involved in (molecular) pathogenesis of hereditary PPK.[4],[5]

The keratins are members of intermediate filament group that maintain the structural integrity of the cells. Keratins K5 and K14 are expressed in the basal layer, while K1 and K9 are expressed in suprabasal compartment of palmoplantar skin.[6] The other keratins that are expressed in the suprabasal layers include K6a/K16 and K6b/K17. Mutation in the keratin genes results in disruption of keratin assembly leading to compensatory thickening of palmoplantar skin with varying severity depending on the mutation locus. Mutations in the highly conserved region of keratin peptides result in severe PPK, whereas involvement of variable region leads to milder phenotypes.[1],[7],[8]

Desmosomes are intercellular junctions that integrate intermediate filaments into the cell membrane and provide adhesion between the cells. Desmosomes are larger with increased expression of desmosomal proteins in palmoplantar skin as compared to rest of the skin leading to preferential localization of PPK in some of these desmosomal mutations.[9] Gap junctions are other transmembrane communicating channels between the cells that are made up of connexin proteins. Mutation in connexin protein results in defective gap junctions and intercellular trafficking, leading to accumulation of abnormal proteins and hence PPK.[10],[11]

Loricrin is another important protein involved in the formation of cornified cell envelope (CCE). Mutation in the loricrin gene leads to abnormalities in CCE formation and dysfunctional apoptosis of differentiated keratinocytes, resulting in mild ichthyosiform erythroderma and PPK.[12],[13]

Various other molecules involved in the pathogenesis of PPK are cysteine lysosomal protease, transient receptor potential vanniloid 3, secreted LY6/urokinase type plasminogen activator receptor (uPAR)-related protein 1), and many others.[14],[15]

Classification and clinical features of hereditary palmoplantar keratoderma

[Table 1] depicts comparative features of clinically classified four major types of PPK: (i) diffuse, (ii) focal, (iii) striate, and (iv) punctate.[16],[17] Diffuse type of PPK characterized by uniform waxy thickening of the palms and soles is the most commonly observed variant of PPK. A contiguous expansion of PPK to the dorsal hands, feet, inner wrists, and Achilles tendons occurs in diffuse PPK with transgrediens. Some forms of PPK also progress/improve with age (progrediens).
Table 1: Clinical features of major hereditary palmoplantar keratoderma

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Isolated Diffuse PPK

Flow chart in [Figure 1] depicts proposed approach for the clinical diagnosis of isolated diffuse PPK.
Figure 1: Flow chart showing a practical approach to cases with isolated diffuse PPK. (AD, autosomal dominant; AR, autosomal recessive; EPPK, epidermolytic palmoplantar keratoderms; NEPPK, nonepidermolytic palmoplantar keratoderma; PPK, palmoplantar keratoderma)

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PPK without transgrediens

This autosomal dominant form includes two clinically similar phenotypes epidermolytic (Vorner) and nonepidermolytic (Unna Thost) PPK.[18],[19] Keratoderma begins in early infancy as patchy hyperkeratosis and is well developed by 3–4 years of age manifesting as symmetric, diffuse, thick, yellowish palmoplantar hyperkeratosis with a sharply demarcated erythematous lateral margins that is typically nontransgrediens. Other features include hyperhidrosis, secondary dermatophyte infection, and pitted keratolysis associated with pruritus and malodor.[20],[21],[22],[23] Genetically, mutations occur in either K9 or K1 genes. Severe epidermolysis is noted in K9 mutation, while no or minimal epidermolysis occurs with K1 gene mutation.[24] K9 is palmoplantar skin-specific keratin and its mutation results in keratoderma confined to palms and soles. However, K1 is expressed on palmoplantar and glabrous skin as well as coexpressed with K9 in the former and K10 in the later alone.[7] Thus, mutations in both K1 and K10 genes lead to epidermolytic ichthyosis wherein K10 mutation will not have PPK as it is not expressed in the palms and soles and isolated K1 mutation results in generalized epidermolytic ichthyosis with severe PPK. The K1 mutations manifesting as isolated PPK along with hyperkeratosis of the umbilicus, areola, and knuckles too have been described.[22] Mutation in the highly conserved region will result in epidermolysis even in K1 mutations, while that in noncritical region will have less effect on keratin filaments and hence no epidermolysis.

PPK with transgrediens

PPK of Greither

Greither's or transgrediens et progrediens PPK manifests during infancy and develops fully during childhood and is characterized by PPK with contiguous involvement of tendo -achilles [Figure 2]a and [Figure 2]b. The severity may vary from mild to severe and hyperhidrosis is frequent, while autoamputation of digits is occasional. Molecular studies show a missense mutation in K1 gene and hence this form is considered a variant of nonepidermolytic PPK. Histologically, orthohyperkeratosis and acanthosis with prominent irregular keratohyaline granules are characteristic.[25] Autosomal dominant Sybert's PPK resembles this phenotype but shows more severe and widespread hyperkeratosis with involvement of natal cleft and groins but exact genetic locus remains unidentified.[26],[27]
Figure 2: Greither's syndrome in a 20-year-old female showing transgrediens PPK (a), and contiguous involvement of skin over tendo Achilles (b)

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Mal de Meleda PPK

Mal de Meleda PPK or keratosis palmoplantaris transgrediens of Siemens manifests clinically as bilateral thick yellow-brown PPK with prominent erythematous border, trangrediens, and progrediens in a glove and stocking pattern [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d. Inherited autosomal recessively it becomes evident at birth as palmoplantar erythema that has a progressive clinical course evolving to thick lesions during first 4 years of life. Keratoderma may be complicated by hyperhidrosis and secondary infection leading to malodor. Nails show Beau's line, subungual hyperkeratosis, onycholysis, koilonychia and onychogryphosis. Oral manifestations include high arched palate, perioral erythema, and angular chelitis.[15],[28] Psoriasiform lesions occur occasionally over elbows and knees, while severe mutilation, contractures, constricting bands around digits, pseudoainhum and amputation of the digits are the features of progressive form.
Figure 3: (a and b) Mal de Meleda PPK (mutilating PPK) showing severe hyperkeratotic, mutilating PPK with several constriction bands with nail dystrophy; (c and d) showing significant improvement in keratoderma and mutilation 6 weeks after treatment with acitretin (2 mg/kg/day). The patient did not improve with acitretin 1 mg/kg/day given for 8 weeks prompting dose escalation

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Molecular studies show improperly regulated keratinocyte apoptosis from mutation in SLURP1 protein that is primarily expressed in the stratum granulosum.[15] This protein also inhibits macrophage and keratinocyte release of TNF-α. Thus, uninhibited tumor necrosis factor (TNF)-α release in the epidermis results in inflammation and dermal inflammatory cell infiltrate.

Nagashima PPK

The autosomal recessively inherited Nagashima PPK, reported mostly from Japan and China, is similar to Mal de Meleda but with a milder phenotype manifesting as nonprogressive mild hyperkeratosis and lacks mutilation, constricting bands, spontaneous amputation, and contractures. It usually exhibits perioral erythema, occasional brachydactyly, nail abnormities, and lichenoid plaques. The white spongy appearance of the keratosis on exposure to water is considered to be a diagnostic clue.[29] Molecular studies show mutations in SERPINB7 gene that encodes the serine protease inhibitor superfamily distinguishing it from Mal de Meleda. A similar phenotype is also described in Bothnian PPK and is due to mutation in AQP5 gene that encodes a water channel protein.[30]

Diffuse PPK with associated features

Flow chart in [Figure 4] depicts proposed approach for the clinical diagnosis of diffuse PPK with associated features.
Figure 4: Flow chart showing a practical approach to cases with diffuse PPK and associated features. (AD, autosomal dominant; AR, autosomal recessive; PPK, palmoplantar keratoderma; PLS, Papillon–Lefèvre syndrome)

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PPK with honeycomb pattern

This spectrum includes the deafness-associated Vohwinkel syndrome and the ichthyosis associated loricrin PPK (Camisa's variant). Vohwinkel syndrome or keratoderma hereditaria mutilans is a rare form resulting from mutation in GJB2 gene encoding connexin 26. Inherited in autosomal dominant form it presents at birth and becomes more evident in adulthood. The honeycomb appearance of PPK with a fine discernible superficial pattern replacing normal dermatoglyphics and starfish-shaped keratotic plaques over the knuckles, wrists, elbows, and knees are highly diagnostic. Over time the affected children develop constricting fibrous bands and pseudoainhum and autoamputation of the toes and fingers particularly of the fifth digit. Other features include moderate to severe sensory neural deafness, myopathy, spastic paraplegia, mental retardation, acanthosis nigricans, ichthyosiform dermatitis, alopecia, and nail abnormalities.[31]

The children with loricrin PPK are often born with collodion membrane and present with mild nonerythrodermic ichthyosis.[32] Unlike Vohwinkel PPK they do not exhibit starfish-shaped keratosis and deafness. Alopecia may occur in few cases; however nail, teeth, and mucosae remain normal. Skin biopsy shows the pathognomonic features of marked hyperkeratosis and parakeratosis along with round retained nuclei and intranuclear granules in the upper granular layer. Immunoelectron microscopy has confirmed that these granules are mutated loricrin protein.[12],[13]

PPK with severe mutilation and periorifical plaques

Olmsted syndrome is a rare mutilating keratoderma with periorifical plaques. Most cases are inherited sporadically and PPK manifests during infancy as focal lesions, which eventually becomes diffuse and severe with transgrediens. Severe mutilation, contractures, constrictions, and autoamputation of digits occur over time [Figure 5]a. Other distinctive features are severe itching, hyperkeratotic plaques around the mouth, nostrils, ears, anogenital region [Figure 5]b, axillae, neck, and groins and histologically inflammatory infiltrate with mast cells. Corneal defects, alopecia universalis, keratosis pilaris, oral leucokeratosis, teeth abnormalities, and sensory neural deafness have been also described.[14],[33]
Figure 5: Olmsted syndrome in a 12-year-old boy: Severe mutilating PPK (a), intertriginous keratotic plaque involving natal cleft (b)

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PPK with periodontitis

Papillon Lefèvre syndrome (PLS), an autosomal recessive disorder, is characterized by the triad of symmetrical keratoderma with transgrediens, early onset severe periodontitis with loss of primary and permanent dentitions, and susceptibility to cutaneous and systemic infections.[34] PLS manifests at birth or early infancy with the appearance of the palmoplantar keratoderma, which may be preceded by erythema. Although punctate or striate keratoderma is not uncommon, a diffuse keratoderma with transgrediens is highly characteristic [Figure 6]a. Soles are affected more severely than palms and malodorous hyperhidrosis is frequent. Additionally, there will be scaly psoriasiform plaques over interphalangeal joints, elbows, knees, tendo Achilles, and external malleoli.[35]
Figure 6: Papillon–Lefévre Syndrome showing: diffuse plantar keratoderma (a), Periodontitis and loss of teeth (b), panoramic radiograph showing hypodontia, alveolar bone resorption, and a “floating in the air” appearance of teeth (c)

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Eruption of deciduous teeth is associated with gingival inflammation and severe periodontitis affecting both deciduous and permanent teeth leading to rapid destruction of periodontium and premature loss of teeth and extensive bone resorption [Figure 6]b. Once the primary teeth are lost at the age of 4–5 years, the gingiva becomes normal. However, periodontitis recurs with the eruption of permanent teeth and the child is edentulous by 14–15 years of age and gingiva becomes normal. Radiologically, there is loss or resorption of both maxillary and mandibular alveolar ridges [Figure 6]c. Another remarkable clinical feature of PLS is increased susceptibility to pyogenic skin and liver infections mostly due to Staphylococcus aureus. Ectopic calcifications of falx cerebri and choroid plexus, and mild mental retardation are also reported. Haim–Munk syndrome resembles PLS but additional features of arachnodactyly, acroosteolysis, and atrophic nail changes are present.[36]

PLS is due to loss-of-function mutation in CTSC gene for cathepsin C mapped to chromosome 11q14-q21, which is expressed in palms, soles, knees, and keratinized gingiva. The cathepsin C protein, a lysosomal protease, is essential for activation of serine proteinase, neutrophil serine protease, proteinase 3, and elastase. Deficiency of CTSC leads to dysregulation of host immune response which in turn predisposes to infections in gingiva, skin, and liver.[34],[37]

PPK with scleroatrophy

Huriez syndrome, an autosomal disorder, is characterized by a triad of PPK, congenital scleroatrophy of extremities, and hypoplastic nail changes with onset in infancy. The keratoderma is mild and diffuse with involvement of palms more than soles. The sclerodactyly is progressive and nail changes include ridging, koilonychia, fissuring, and hypoplasia. The atrophic skin plaques have an increased risk of squamous cell carcinoma in approximately 15% cases by third-fourth decade with a tendency for early metastasis. The gene for this rare syndrome has been mapped to chromosome 4q.[38]

Focal PPK

Keratosis palmoplantaris nummularis

Keratosis palmoplantaris nummularis or hereditary painful callosities is associated with mutation in KRT 6C genes encoding keratin 6c expressed predominantly on plantar skin.[39] It is autosomal dominant and manifests clinically within first 2 years of life as painful, nummular-shaped keratotic plaques located mainly over pressure points. Blistering and minor nail abnormalities may also be seen. Oral leukokeratosis or gingival keratosis as leukoplakic lesions of the labial mucosa or attached gingival surface may occur. Histologically, it is characterized by focal epidermolytic hyperkeratosis.

Pachyonychia congenita

Pachyonychia congenita (PC), an autosomal dominant disorder, is due to mutations in one of the four keratin genes, KRT6A, KRT6B, KRT16, or KRT17. Based on the specific keratin mutation, it has been classified into PC-6a, PC 6b, PC-16, PC-17, and PC-unknown. It affects skin, nails, oral mucosa, and teeth. Plantar keratoderma, plantar pain, and thickened toenails, the cardinal features [Figure 7], develop in >90% cases before 5 year of age.[40],[41] Of 254 reviewed cases, 98% had toenail thickening and 87% showed fingernail involvement.[40] The average reported age for onset of toe nail dystrophy in all types was 2.8 years with earliest average age at onset being 4 months in PC-6a, 9.5 years in PC-6b, and late in PC-17. The average number of toenail involved was 8.8 and both toenail and fingernail involvement occurred in all PC-6a cases. Whereas fewer fingernails are affected in PC-6b cases compared to other types. Plantar keratoderma was found in 91–96% cases and callosity-like thickening being the most common manifestation.[40],[41] The other features included were fissuring, blisters, and ulceration. These manifestations never resolved completely. The associated plantar pain seen in 89% significantly affects the quality of life.[40]
Figure 7: Pachyonychia congenita showing focal plantar keratoderma with heaped up tented nails in a 10-year-old female child

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Mucosal changes present at birth in 54% cases, while their onset is by 1 year of age in 73% cases.[40],[41] Oral leucokeratosis develops in 70% cases at an average age of 5.1 years. Pilosebaceous and steatocysts develop in 41% patients and chances are higher by 88% in PC-17 cases compared to other types who also tend to have natal teeth more frequently.[40]

Recently, co-occurrence of filaggrin gene mutation has been described as a genetic modifier increasing the phenotypic severity of PC in a parent–child trio where both mother and the son had PC, carrying K16 mutation (p. Leu132Pro) and the father had ichthyosis vulgaris. The son was affected more severely than the mother as he additionally had heterozygous filagrin mutation (p.R2447X) inherited from father.[42]

Linear or striate PPK

Also known as PPK striata, Wachter-type focal nonepidermolytic palmoplantar keratoderma, or Brünauer–Fuh–Siemens syndrome, is an autosomal dominant disorder. It follows mutations in desmoglein 1 gene mapped to chromosome 18q1-12 (striate PPK 1), desmoplakin gene on chromosome 6p21 (striate PPK 2), and keratin 1gene (striate PPK 3) involved in maintaining epidermal integrity that is important for friction-bearing areas.[2] Clinically, onset is in early infancy or first few years of life with marked phenotypic variability. Woolly hair and left ventricular dilated cardiomyopathy (in recessive form) may occur. In manual workers, palmar keratoderma may have linear pattern (islands of linear hyperkeraosis) and increased skin fragility from occupational friction/trauma, while others may have no or minimal changes. Histologically, hyperkeatosis, acanthosis, and hypergranulosis occur without epidermolysis.

Punctate PPK

Punctate PPK or Buschke–Fischer syndrome, an autosomal dominant disorder, presents between 12 and 30 years of age as multiple asymptomatic punctate hyperkeratotic papules involving whole or part of palms and soles. Hyperhidrosis is not a feature. Nails may show longitudinal ridging, notching, trachyonychia, onychoschizia, and onychorrhexis. Ankylosing sponylitis, spastic paralysis, sebaceous hyperplasia, and association with gastrointestinal or pulmonary malignancy can be seen. Two mutations in PPK loci have been mapped to chromosome 15q22-24 and 8q24.13-8q24.21.[43],[44] Histologically, presence of compact hyperkeratosis, hypergranulosis, cornoid lamella absence of epidermal dykeratosis, or hydropic changes differentiates it from porokeratosis.

Dermatoses and syndromes with diffuse or punctate PPK as an associated feature

The diffuse or punctate keratoderma, small rounded papular keratosis on the palms and soles with tendency to coalesce over pressure points, can be a presenting feature of many dermatoses [Table 2] and [Table 3].[4],[16],[17],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64] Flow chart in [Figure 8] depicts proposed approach for the clinical diagnosis of PPK as a feature of common dermatological conditions of diagnostic significance.
Table 2: Syndromes and dermatoses with diffuse or punctate palmoplantar keratoderma (PPK) as an associated feature

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Table 3: Syndromes of ectodermal dysplasia associated with PPK

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Figure 8: Flow chart showing a practical approach to cases with PPK as a feature of other dermatological conditions. (ALOXE, arachidonate lipoxygenase; C 30; connexin 30; CERS3, ceramide synthase-3; EBS-DM, Epidermolysis Bullosa Simplex-Dowling Meara type; EI, epidermolytic ichthyosis; IV, ichthyosis vulgaris; KP, keratosis pilaris)

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PPK associated with systemic abnormalities

[Table 4] lists the PPK with associated major systemic diseases.
Table 4: Congenital diffuse PPK associated with systemic abnormalities

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Treatment of PPK

Hereditary PPK persists lifelong and significantly affecting quality of life. There is no presently available therapy that is specific and curative. Apart from genetic counseling, patient needs to be educated for taking care of hyperkeratotic hands and feet. Mechanical debridement with blade or dental drill and liberal use of topical keratolytic agents as first-line treatment will provide temporary relief. Secondary infection needs require appropriate treatment. Systemic treatment with retinoids improves symptoms of hyperkeratosis in most patients [Figure 3]c and [Figure 3]d. A significant improvement in PPK and gingivitis with oral retinoids in PLS has been reported.[65] However, only low-dose retinoids therapy is preferred in epidermolytic palmoplantar keratoderma (EPPK) as it might trigger epidermolysis, while adverse effects associated with prolonged retinoid therapy remain a concern. Vitamin D therapy reportedly had improved hereditary PPK.[66] Erlotinib, an epidermal growth factor inhibitor, in a dose of 100 mg/day escalated to 150 mg/day improved palmoplantar and perioral keratoderma that could be maintained for over 2 years without significant adverse effects.[67] Topical gentamicin for the treatment of Nagashima-type palmoplantar keratosis appears promising but needs clinical evaluation.[68],[69]

   Conclusion Top

Hereditary PPK develops as a result of compensatory hyperproliferation of the skin due to mutations in the genes involved in palmoplantar keratinization and has a significant genetic and phenotypic variability. It can manifest in diffuse, focal, striate, or punctate forms. The diffuse forms may be associated with transgrediens and/or progrediens. PPK can occur in isolation or in association with other cutaneous and extracutaneous features. The choice of treatment needs to be individualized combined with prophylactic topical antibacterial and antifungal therapies. Regular hydration and skin care remains primary therapy. Molecular studies, despite high cost, are imperative for accurate classification. However, recognizing clinical patterns especially in resource poor settings is important for appropriate diagnosis, genetic counseling, and management.

For patient information

Patients can check with various organizations and self-help groups, such as pachyonychia.org, ichthyosis.org.uk, rarediseases.info.nih.gov (Genetic and Rare Diseases Information Center) for available genetic testing and management guidelines.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2], [Table 3], [Table 4]


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