DISEASE CARD

Definition

Palmoplantar Keratoderma (PPK) describes a group of keratinization disorders with thickening (hyperkeratosis) of the skin on palms and soles. A broad spectrum of genetic heterogeneity has been reported, and many keratinization disorders as well as epithelial adhesion disorders share PPK as a clinical characteristic.¹ Furthermore, acquired forms of PPK do exist (e.g. psoriasis and pityrisis rubra pilaris). This heterogeneity inevitably results in a variety of clinical subtypes, which include epidermolytic (EPPK) and non-epidermolytic (NEPPK) forms^{.2, 3}

Clinical Description

Three distinct clinical phenotypes were identified in PPK: diffuse, focal and punctate:

Diffuse PPK shows a uniform involvement of the palmoplantar skin. Focal PPK presents with localized areas of hyperkeratosis at pressure points and sites of recurrent friction. Punctate PPK consists of tiny hyperkeratotic papules, spicules or nodules, which can either be localized or cover the entire palmoplantar surface.

Hyperkeratosis can be restricted to the palmoplantar region (nontransgradient) or spread dorsally up to the wrist (transgradient). Onset of monogenetic PPK occurs usually in the first few months after birth and is fully developed at age of 3-4 years. In some cases the symptoms may become manifest later in childhood. ^{3, 4}

Table: Summary of PPK subtypes⁵

^{PPK palmoplantar keratoderma; HPPK: hereditary PPK; AD: autosomal dominant; AR: autosomal recessive; XLR: X-linked recessive; SCC: squamous cell carcinoma}

In EPPK (Vörner PPK), the most common type of PPK, a well-demarcated, thick, yellow diffuse hyperkeratosis covers the palms and soles. Occasionally an erythematous rim is seen at the sharp margin of the keratosis and the surface often appears uneven and verrucous. EPPK is usually nontransgradient. Forms with KRT1 mutations may show transgredience. Pitted keratolysis, particularly on the feet as well as knuckle pads may occur.⁷  It has been shown that epidermolytic PPK due to keratin 9 mutation can lead to digital mutilation.⁸

Acquired PPKs show no positive family history, later onset of disease and relative treatment resistance.⁵

Pathogenesis

Mutations in the central regions of KRT9 and sometimes KRT1 were found in EPPK.⁹ KRT1 mutations appear to result in less severe phenotypes.^{10, 11} The inheritance is autosomal dominant. KRT9 expression is restricted to the suprabasal layers of palms and soles, where it dimerizes with KRT1. Keratin 1 is found in the epidermis throughout the skin including the palms and soles. The central rod domains of Keratins are structurally essential for heterodimer formation, filament assembly and stability. Impairment of intermediate filament stability then leads to cytolysis. Mutations in the N-terminal variable end region V1 of KRT1 were associated with non-epidermolytic PPK.¹²

Diagnosis

Differential diagnosis, solely on the phenotypical representation of a patient, is complicated by the genetic heterogeneity of PPK. Differentiations have to be made between hereditary and acquired forms of PPK, epidermolytic and non-epidermolytic forms, diffuse, focal and punctate forms. Clinically identical forms can be distinguished histologically and ultrastructurally. EPPK shows epidermolytic hyperkeratosis in histopathological investigations as well as perinuclear vacuolization, large keratohyaline granules, clumping of tonofilaments and cellular degeneration in spinous and granular cells.¹³ Unequivocal diagnosis can be achieved by DNA sequencing of candidate genes.⁴

Treatment

Application of keratinolytics such as salicylic acid (contraindicated in very young children), urea, lactic acid and propylene glycol in an indifferent ointment under occlusion (e.g. plastic) several nights per week. Mechanical debridement may also be helpful. Use of topical retinoids is frequently limited due to irritation. Systemic retinoids are helpful in severe cases, although they might cause pain, erosions and are limited by side effects and teratogenicity. Topical calcipotriol has been reported to be effective.¹⁴ Treatment with antifungal / antibacterial drugs is necessary in case of infections^.5

References

^{1. Chamcheu JC, Siddiqui IA, Syed DN, Adhami VM, Liovic M, Mukhtar H. Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys. 2011;508(2):123-137.}

^{2. Hamada T, Tsuruta D, Fukuda S, et al. How do keratinizing disorders and blistering disorders overlap? Exp Dermatol. 2013;22(2):83-87.}

^{3. Guerra L, Castori M, Didona B, Castiglia D, Zambruno G. Hereditary palmoplantar keratodermas. Part I. Non‐syndromic palmoplantar keratodermas: classification, clinical and genetic features. Journal of the European Academy of Dermatology and Venereology. 2018;32(5):704-719.}

^{4. Oji V, Metze D, Traupe H. Inherited disorders of cornification. Rook's Textbook of Dermatology, Ninth Edition. 2016:1-97.}

^{5. Thomas BR, O'Toole EA. Diagnosis and Management of Inherited Palmoplantar Keratodermas. Acta Derm Venereol. 2020;100(7):adv00094.}

^{6. Moll R, Divo M, Langbein L. The human keratins: biology and pathology. Histochem Cell Biol. 2008;129(6):705-733.}

^{7. Kuster W, Reis A, Hennies HC. Epidermolytic palmoplantar keratoderma of Vorner: re-evaluation of Vorner's original family and identification of a novel keratin 9 mutation. Archives of Dermatological Research. 2002;294(6):268-272.}

^{8. Umegaki N, Nakano H, Tamai K, et al. Vörner type palmoplantar keratoderma: Novel KRT9 mutation associated with knuckle pad‐like lesions and recurrent mutation causing digital mutilation. British Journal of Dermatology. 2011;165(1):199-201.}

^{9. Reis A, Hennies H-C, Langbein L, et al. Keratin 9 gene mutations in epidermolytic palmoplantar keratoderma. Nat Genet. 1994;6(2):174-179.} 

^{10. Yang JM, Lee S, Kang HJ, et al. Mutations in the 1A rod domain segment of the keratin 9 gene in epidermolytic palmoplantar keratoderma. Acta Derm Venereol. 1998;78(6):412-416.}

^{11. Gach JE, Munro CS, Lane EB, Wilson NJ, Moss C. Two families with Greither's syndrome caused by a keratin 1 mutation. J Am Acad Dermatol. 2005;53(5 Suppl 1):S225-230.}

^{12. Kimonis V, DiGiovanna JJ, Yang JM, Doyle SZ, Bale SJ, Compton JG. A mutation in the V1 end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma. J Invest Dermatol. 1994;103(6):764-769.}

^{13. Navsaria HA, Swensson O, Ratnavel RC, et al. Ultrastructural changes resulting from keratin-9 gene mutations in two families with epidermolytic palmoplantar keratoderma. J Invest Dermatol. 1995;104(3):425-429.}

^{14. Lucker G, Van De Kerkhof P, Steijlen P. Topical calcipotriol in the treatment of epidermolytic palmoplantar keratoderma of Vomer. Ichthyosis, Darier's disease and Palmoplantar Keratoderma. 1994;130:143.}