Palmoplantar keratoderma
Palmoplantar keratoderma (PPK) refers to a diverse group of skin disorders characterized by abnormal thickening of the skin on the palms of the hands and soles of the feet, primarily due to excessive keratin production. These conditions can be hereditary or acquired, with hereditary forms often resulting from specific genetic mutations. Inherited PPKs display various patterns, including diffuse, focal, and punctate hyperkeratosis, and may also be associated with other health issues, such as deafness or internal malignancies.
Diagnosis of PPK is complex due to its phenotypic and genotypic diversity, typically relying on clinical examination and increasingly on molecular genetic testing to identify specific mutations. There is currently no effective treatment that offers a permanent solution, and management usually focuses on alleviating symptoms and improving the patient's quality of life through various topical therapies and lifestyle adjustments.
Genetic counseling is recommended, especially for families with a history of hereditary PPK, as understanding the genetic basis can provide insights into risks for future generations. Prevalence rates are low, and early diagnosis is crucial for managing symptoms and potential complications associated with this condition.
Palmoplantar keratoderma
ALSO KNOWN AS: PPK; keratosis palmaris et plantaris; Palmoplantar keratosis; Hyperkeratosis of palms and soles; palmar plantar keratodermas
DEFINITION Palmoplantar keratoderma (PPK) is a generic term for an heterogenous group of mostly hereditary disorders characterized by unusual thickening of the skin in soles of the feet and palms of the hands. Excessive or abnormal keratin production leads to hypertrophy of the stratum corneum (hyperkeratosis of the top layer of the skin). Their initial classification is based on whether they are inherited (congenital) or acquired. Hereditary variants result from several gene abnormalities that cause abnormal skin protein.
Risk Factors
Hereditary predisposition is associated with the genetic PPK forms. Therefore, familial association is a common risk factor for patients. Mutations in up to sixteen different chromosomes have been identified as responsible for the inherited variants of PPK in an autosomal dominant or recessive manner. In certain populations, it is common to see a higher frequency of a particular inherited skin disorder, as seen with Naxos disease (the Greek island of Naxos), diffuse PPK (Norrbotten, Sweden), or Mal de Meleda (the island of Meleda, Yugoslavia).
Etiology and Genetics
Keratin is a tough fibrous structural protein and a component of the top layer of the skin, the epidermis. The keratinocyte is the epidermal cell that produces keratin. The normal keratinized skin provides waterproofing and works as a natural barrier to infection or harmful chemicals. Keratoderma is a disease of the skin marked by overgrowth of horny tissue or keratosis. In hyperkeratosis, there is an excess of keratin production in the skin.
Although PPK can manifest itself as an acquired condition, in the inherited form it is frequently present as the result of various genetic mutations. In the acquired type, the condition is not the result of genetic abnormalities and appears because of a shift in the patient’s health or environmental factors. The most evident causes in the acquired variants are mechanical, vascular, endocrine, infective, or drug-induced.
The genetic PPK disorders are inherited from one or both parent(s) by their children. Generally, PPKs result from genetic abnormalities that affect the keratin protein expression, causing atypical thickening of the skin. Inheritance may occur either by an autosomal dominant or autosomal recessive pattern. In autosomal dominant keratodermas, each affected patient has at least one parent phenotypically affected and there is a transmission of the gene defect from generation to generation. There is a 50 percent chance that each offspring will be affected. For the autosomal recessive form, the affected patient has phenotypical unaffected parents and there is no transmission of the abnormal gene from generation to generation. People that carry the abnormal gene are referred to as carriers of the disease. Therefore, the carriers pass on the genetic defect to the next generation, but the children can only exhibit the disease if their other parent also is a carrier of the same abnormal gene and successfully passes it forward. There is a 25 percent chance that each offspring will be affected by the autosomal recessive disorder. Recessive disorders are frequently found in families with increased consanguinity (descendent from a common ancestor).
More than eighty PPK disorders are indexed in the Online Mendelian Inheritance in Man (OMIM) catalog. These mutated genes code for structural skin proteins such as keratins or subcellular structures such as desmosomes. Additional mutations affect protein products related to keratinocyte structure, cell-to-cell adhesion, connexins, and gap junctions. The physiologic role of other molecules related to PPK pathogenesis is not well understood. What is known is that all these affected protein structures interact in a highly regulated and integrated manner to keep epithelia and skin integrity. Keratin gene mutations are responsible for several types of hereditary PPK. Some of the main PPKs, with their corresponding protein product of its mutated gene in parenthesis, are Mal de Meleda (SLURP-1), Thost-Unna keratoderma (keratin-1), Vörner keratoderma (keratin-1 and 9), Vohwinkel mutilating keratoderma (Loricrin and Connexin-26), Papillon-Lefévre syndrome (Cathepsin C), Carrajo syndrome (Desmoplakin), Naxos disease (Plakoglobin), and Richner-Hanhart syndrome (tyrosine amino transferase).
When these PPK mutations alter the normal skin surface functions, the epidermal protective properties are compromised, giving the chance for bacterial and fungal infections, inflammatory skin reactions (eczema or psoriasis), or other severe conditions to arise that have an impact on quality of life or might worsen morbidity and mortality for the affected patient.
Only one pertinent PPK clinical study is listed and completed in ClinicalTrials.gov, and none are ongoing.
Symptoms
In this cutaneous hereditary disorder, there is marked hyperkeratosis present over the palms and the soles of the patient. The three main clinical patterns of epidermal involvement are diffuse, focal, and punctate. In the diffuse form there is uniform hyperkeratosis of the palmoplantar surface. The focal pattern mainly affects pressure points or sites of constant friction. The punctate pattern consists of multiple, hyperkeratotic nodules or tiny bumps on the palms and soles. Generally, the abnormal thickening of the skin is seen only on the surface of the palms and soles (nontransgradient), but sometimes there is transmigration to close areas outside the palmoplantar surface (transgradient). The understanding of the pathogenesis is critical in narrowing down the target genes for each individual case. More apparent symptoms could be present such as knuckle pads, oral lesions, atrophy, blisters, deafness, mental retardation, starfish keratoses, nail changes, constricting bands, redness, malignancies, cardiomyopathies, or sclerodactyly. For some rare PPK types, organs in the body may be implicated so the keratoderma could be a marker of some internal abnormality.
Screening and Diagnosis
The rare and large group of hyperkeratotic disorders that inherited PPKs comprise are phenotypically characterized as extensively heterogeneous. Overcoming the diagnostic challenges posed by phenotypic and genotypic heterogeneity, several classification strategies have been designed using morphology, associated symptoms, distribution, and inheritance mode to improve screening between different genetic variants. Traditionally, diagnosis has been clinically based, but in recent years the molecular genetic classification is slowly being adopted and replacing the historical descriptive system. Clinical reference laboratories for genetic diagnostics are available, and information can be found through OMIM. Screening includes evaluation of the main genetic mutations that affect protein products associated to keratinocyte cytoskeleton structure, gap junctions, connexins, keratins, and subcellular structures such as desmosomes. Differential diagnosis might include blood tests, skin biopsy, histology, PCR, and mutation, microsatellite, and analysis. Knowledge of genetic mutations associated with distinct clinical findings together with a systematic and comprehensive analysis makes the exact diagnosis possible by their molecular pathology. This integrative approach leads to the discovery of the real underlying genetic defect. A full personal and family history, regular medical examinations, and appropriate cancer screenings are crucial for early detection of any associated internal malignancies or cardiomyophathies for some of these patients or whether other skin findings are evident and/or other organs are affected. Dermatopathology plays in increasing role in the diagnosis.
Treatment and Therapy
Currently, there is no effective treatment for any PPK types. Common therapy alternatives mainly cause short-term improvements that are often aggravated by unacceptable adverse side effects. Treatment is tailored to the severity of the symptoms, the age of the patient, the affected areas, and the degree of hyperkeratosis. Generally, treatment will either focus on softening the thickened skin or making it less noticeable. Therapies may range from saltwater soaks and paring to emollients, topical keratolytics, topical or systemic retinoids, topical vitamin D ointment, potent topical steroids, careful footwear selection, or even reconstructive surgery in severe cases to excise the hyperkeratotoic skin, followed by grafting. When the PPK syndrome is also showcased as an associated feature with other diseases (such as deafness, corneal dystrophy, internal malignancy, cardiomyopathy, alopecia, and severe periodontitis), treatment and therapy are particularly adapted to the special needs of each case. Future studies on genotype/phenotype correlations in PPK and their treatment response are vital to improve the patient’s quality of life.
Prevention and Outcomes
Since genetic factors play an important role in PPK inherited disorders and there is no effective way of prevention, genetic counseling should be provided. Disease management is difficult considering there is no effective treatment for any PPK variants. According to research from 2023, the prevalence of PPK was 1.17 cases per 100,000 people. Early diagnosis was essential for disease management purposes, to mitigate some symptoms, and to define possible outcomes. The PPK inherited variant and the severity of the condition defined disease outcome. Outcome strategies for PPK with associated diseases, as with cardiomyopathies, internal malignancies, and systemic conditions, added another layer of variability, complexity, and challenge to disease management.
Bibliography
Bergman, Reuven. “Dermatopathology and Molecular Genetics.” Journal of the American Academy of Dermatology 58, no. 3 (2008): 452-457.
Itin, Peter H., and Stephen Lautenschlager. “Palmoplantar Keratoderma and Associated Syndromes.” Seminars in Dermatology 14, no. 2 (1995): 152-161.
Kimyai-Asadi, A., L. B. Kotcher, and M. H. Jih. “The Molecular Basis of Hereditary Palmoplantar Keratodermas.” Journal of the American Academy of Dermatology 47, no. 3 (September, 2002): 327-343.
Knowles, Ariel, Maya Adams, and Donald A Glass. "Punctate Palmoplantar Keratoderma: A Case Report." Cureus, vol. 15, no. 1, 14 Jan. 2023, doi: 10.7759/cureus.33769. Accessed 4 Sept. 2024.
Lucker, G. P., P. C. Van de Kerkhof, and P. M. Steijlen. “The Hereditary Palmoplantar Keratoses: An Updated Review and Classification.” British Journal of Dermatology 131, no. 1 (July, 1994): 1-14.
Torres, Gisela, et al. “’I Forgot to Shave My Hands’: A Case of Spiny Keratoderma.” Journal of the American Academy of Dermatology 58, no. 2 (2008): 344-348.