Slideshow
-
Slide
A 56-year-old woman presents with thickened, yellow skin on the soles of her feet that has been present since she was a child. On examination, the affected areas appear localized to the weight-bearing pressure areas of her feet, with hypertrophy of her fifth toenail. She has a history of hyperhidrosis, and her mother and grandfather had similar symptoms on their soles. Histologic examination of a skin sample shows a nonepidermolytic pattern, with increased thickness of the stratum corneum (hyperkeratosis) and acanthosis. Molecular testing reveals a mutation in the KRT6C gene, which codes for an isoform of keratin 6.
Submit your diagnosis to see full explanation.
Keratoderma refers to a diverse group of disorders presenting with abnormal thickening of the epidermal layer of skin that most commonly affect the palms and soles (palmoplantar keratoderma [PPK]).1 PPKs are divided into 2 categories: hereditary or acquired. The exact prevalence and incidence of PPK are unknown, but they vary geographically. For example, the estimated prevalence of epidermolytic PPK in Northern Ireland is 4.4 per 100,000,2 whereas the estimated prevalence of the most common type of PPK in Asia, PPK type Nagashima, is 1.2 per 10,000 in Japan and 3.1 per 10,000 in China.3
Hereditary PPK usually is caused by mutations in genes coding for structural proteins of the intracellular cytoskeleton, most commonly keratins, leading to hyperkeratosis. Mutations also may occur in genes coding for desmosomal proteins and proteins involved in cell signaling. Acquired PPK can be caused by medications, malnutrition, toxins, systemic disease, infectious etiologies, and malignancy.4
Autosomal dominance is the most common inheritance pattern of PPK, although autosomal-recessive, X-linked, and mitochondrial transmission also have been found.1 Hereditary PPK tends to present at birth, early childhood, or young adulthood, and in the majority of cases the disorder continues throughout a patient’s life.
Hereditary PPK, which exists either in isolation or as syndromic PPK with extracutaneous manifestations, is categorized into subgroups with distinct clinical phenotypes: diffuse, focal, and punctate.
Diffuse PPKs are characterized by symmetric epidermal thickening over the entire surface of the palms and soles.1 There may be a sharp demarcation at the edge of the palms and soles or continuation of patches up to the elbows and/or knees, termed transgrediens hyperkeratosis. Associated hyperhidrosis in the feet can increase the risk for fungal and bacterial infections.1 Diffuse PPKs include Vörner type, Thost-Unna type, DSG1 gene mutation, Mal de Meleda, Gamborg Nielsen type (Norrbotten, Sweden), Nagashima type, Bothnia type, and Greither disease.5
Focal PPKs are characterized by large compact areas of hyperkeratosis that develop at palmoplantar sites exposed to frequent friction or pressure.1 The lesions resemble calluses and may be painful. Focal PPKs include pachyonychia congenita and focal nonepidermolytic PPK.5
Punctate PPKs are characterized by multiple small areas of round lesions scattered around the palmoplantar areas.1 The lesions may grow larger and increase in number with age or develop on the dorsal aspects of the hands and feet. Punctate PPKs include Buschke-Fischer-Brauer syndrome, punctate porokeratosis palmaris et plantaris, and acrokeratoelastoidosis.5
Syndromic PPKs manifest beyond the palms and soles. Extracutaneous manifestations in patients with syndromic PPK tend to appear later in life. Symptoms include deafness, periodontitis, cardiomyopathy, woolly hair, alopecia, mucosal abnormalities, nail abnormalities, esophageal cancer, and corneal dystrophies.5 Certain syndromic PPKs, such as Vohwinkel syndrome and Olmsted syndrome, may present as mutilating PPK characterized by bands that constrict around fingers and toes, leading to autoamputation.6
The differential diagnosis for PPK includes similar diseases that present with thick or hardened patches of skin, including inflammatory conditions such as psoriasis, lichen planus, and chronic dermatitis.1 The color, scaling quality, and location of patches beyond the palms and soles can help distinguish these conditions. Clinical appearance and laboratory testing can help differentiate PPK from infectious etiologies such as warts, tinea corporis, and scabies.
The diagnosis of PPK is made through comprehensive history, skin examination, histologic analysis, and genetic testing. To determine treatment options, it is important to categorize PPK. Diffuse, focal, and punctate PPK are differentiated primarily through skin examination. Epidermolytic and nonepidermolytic PPK are differentiated through histologic analysis. Histopathology findings may show acanthosis and epidermolysis, but the main histologic feature of PPK is hyperkeratosis.7
A patient history supporting a diagnosis of hereditary PPK includes childhood onset of symptoms, positive family history, consanguinity of parents, and extracutaneous manifestations.7 A history supporting acquired PPK includes later onset, occupational hazards, infections, malignancy, medications, and alleviation of symptoms during medication vacation.7 It is important to investigate PPK in patients as a potential first symptom of malignancy. Paraneoplastic PPK often is associated with Sezary syndrome, Bazex syndrome, and Howel-Evans syndrome.7
There are no curative treatments for PPK. Therapies are aimed at cosmetic and symptomatic relief. Keratolysis and mechanical reduction of hyperkeratosis may be achieved through home therapies including regular bathing and foot and hand care.7 Hydration of the skin can be maintained through moisturization, use of emollients such as petroleum jelly, and topical therapy with keratolytic effects, such as urea and salicylic acid. Antifungals and antibiotics should be started as prophylaxis or to treat local infections.7
Systemic treatments including retinoids, specifically acitretin, may improve PPK manifestations. However, retinoids are discouraged for epidermolytic PPK because they can lead to erosions and skin detachment.7 Systemic retinoids also should be avoided in pregnant women because they carry a risk for birth defects; patients of childbearing age must receive contraception before initiating systemic retinoids.8
Hyperhidrosis associated with PPK can be controlled by products containing aluminum chloride. Inflammation from PPK should be targeted with topical corticosteroids. Customized footwear, analgesics, and topical anesthetics can relieve pain from walking and daily activities. Symptoms of acquired PPK may be improved by treatment of the underlying cause, such as in the case of paraneoplastic PPK.4
Genetic counseling and gene therapy would benefit patients with PPK identified through molecular testing.6 Potential curative therapies in the form of RNA interference are being explored for PPK caused by dominant mutations.9 This therapy involves the introduction of site-specific small interfering RNA into cells to turn off dominant negative alleles; wild-type alleles are spared to allow the creation of functioning keratin intermediate filaments.
The patient in our case was treated with emollients and topical salicylic acid. She had symptomatic improvement after several weeks.
Angela Huang, BA, and Yelena Dokic, BSA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist affiliated with Elite Dermatology in Houston, Texas.
References
1. Has C, Technau-Hafsi K. Palmoplantar keratodermas: clinical and genetic aspects. J Dtsch Dermatol Ges. 2016;14(2):123-140.
2. Covello SP, Irvine AD, McKenna KE, et al. Mutations in keratin K9 in kindreds with epidermolytic palmoplantar keratoderma and epidemiology in Northern Ireland. J Invest Dermatol. 1998;111(6):1207-1209.
3. Kubo A, Shiohama A, Sasaki T, et al. Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis. Am J Hum Genet. 2013;93(5):945-956.
4. Patel S, Zirwas M, English JC 3rd. Acquired palmoplantar keratoderma. Am J Clin Dermatol. 2007;8(1):1-11.
5. Guerra L, Castori M, Didona B, Castiglia D, Zambruno G. Hereditary palmoplantar keratodermas. Part I. Non-syndromic palmoplantar keratodermas: classification, clinical and genetic features. J Eur Acad Dermatol Venereol. 2018;32(5):704-719.
6. Kelsell DP, Stevens HP. The palmoplantar keratodermas: much more than palms and soles. Mol Med Today. 1999;5(3):107-113.
7. Schiller S, Seebode C, Hennies HC, Giehl K, Emmert S. Palmoplantar keratoderma (PPK): acquired and genetic causes of a not so rare disease. J Dtsch Dermatol Ges. 2014;12(9):781-788.
8. Guerra L, Castori M, Didona B, Castiglia D, Zambruno G. Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – diagnostic algorithm and principles of therapy. J Eur Acad Dermatol Venereol. 2018;32(6):899-925.
9. Hickerson RP, Flores MA, Leake D, et al. Use of self-delivery siRNAs to inhibit gene expression in an organotypic pachyonychia congenita model. J Invest Dermatol. 2011;131(5):1037-1044.
QUESTION
