Overview of Erythrokeratoderma

Erythrokeratoderma is a group of rare genetic skin disorders with the hallmark physical manifestation of symmetric skin plaques with reddish, dry and thick appearances.¹ These skin lesions are typically found in the arms and legs, specifically the elbows, knees, back, abdomen, hands, and feet.⁴ There is a progressive aspect to this family of disorders, as these skin plaques can grow and spread over time. Progressive Symmetrical Erythrokeratoderma (PSEK) and Erythrokeratodermia variabilis et progressiva (EKVP) are some examples of the specific skin disorders that fall within this group. These two disorders are also the most prevalent.¹

Erythrokeratoderma is known to be caused by mutations in the genes involved in normal skin cell and tissue development and maintenance. However, it is unclear which specific genes experience these mutations. Connexin genes, which produce proteins essential for normal cellular functions, have been the most commonly reported source of mutations that result in the development of this group of disorders.^1,4 The specific connexin genes named in variations of this disorder group include the following:

• Gap junction alpha-1 (GJA1)
• Gap junction beta-3 (GJB3)
• Gap junction beta-4 (GJB4)⁴

Other genes known to be associated with the development of Erythrokeratoderma include:

• Keratin 83 (KRT83)
• 3-Ketodihydrosphingosine reductase (KDSR)
• Transient receptor potential cation channel subfamily M member 4 (TRPM4)
• PERP⁴

Meanwhile, mutations in the Loricrin gene have been found to contribute to the development of multiple PSEK cases.²

These skin plaques can appear at any age, but are most prominent and commonly reported and diagnosed at birth and during childhood.¹³

Since the disorders within this group have a genetic component, the signs and symptoms that appear will be different for each person. Aside from the skin plaques, some examples of other manifestations reported in those with such conditions include:

• Impaired hearing ¹⁰

Thus, a comprehensive approach is utilised in reaching an accurate diagnosis. This includes the following:

• Complete personal and medical history
• Patient assessment
• Genetic testing
• Biopsy of the skin plaque tissue
• Dermoscopy of the skin plaque tissue¹

Emerging Therapies and Clinical Trials

While current treatment and management regimens have evidence supporting their effectiveness, significant amounts of attention are also on those that are on the horizon. The current evolution of science, especially in healthcare, is driving clinical professionals, scientists, and other innovators towards creating and finding new and improved treatments and management agents and programs for many diseases, disorders, and conditions. For the rare and incurable ones, such as Erythrokeratoderma, their research and case studies provide healthcare professionals, patients, and their loved ones with evidence and hope that the signs and symptoms of these disorders can be successfully treated and managed in both the short-term and long-term. Emerging therapies and clinical trials are designed with the goals and objectives to produce safe, effective, efficient, and cost-effective treatments and management regimens. They hope that they address signs and symptoms, slow down disease progression, and, hopefully, cure these chronic conditions. The main question now to be answered is this: where are we now in terms of treating and managing Erythrokeratoderma? Continue reading below to find the answer and to learn more about the emerging therapies and clinical trials for Erythrokeratoderma treatments. 

Current Standard Treatments For Erythrokeratoderma

Currently, there are no standard treatments for Erythrokeratoderma.¹ Thus, the treatment and management regimens selected depend largely on patient-specific signs and symptoms, the genetic variant of Erythrokeratoderma a person has, and what works for them. Some ingredients of the agents used in treating and managing this group of skin disorders include:

• Emollients
• Retinoids and retinoic acid (acitretin, etretinate, tazarotene, and isotretinoin)
• Keratolytics
• Alpha hydroxyl acids (AHAs)
• Topical corticosteroids¹

A topical agent named Calcipotriol showed significant results in minimising the skin plaques and healing the skin surrounding them. It is a well-known ointment used in treating Psoriasis, which is another group of chronic skin conditions whose skin plaques share numerous characteristics with those of Erythrokeratoderma.²

However, while these treatments are effective at treating and managing the skin lesion over a short period of time, nearly all of them have not been able to maintain such results for longer than a few months after stopping the treatment and management regimens.⁴ Despite the short-term effectiveness of these products and ingredients, current knowledge and understanding of how they maintain that level of effectiveness long-term is limited.⁸ Numerous reports indicate a variety of responses to these treatment and management programs, ranging from the complete remission of skin lesions to the worsening of these plaques. ^{7, 9} While there have been cases in which people who underwent these therapies maintained significantly healed skin and minimal indications of other signs and symptoms long after, most people experienced either a return of these skin plaques or no changes at all. 

Another aspect of treatment and management regimens that you must remember is that if you or someone you are caring for is using retinoids, such as acitretin and isotretinoin, make sure that you or they only use them over short periods of time and at the smallest possible doses. This is because of their adverse effects on the bones in the body, leading to growth and development problems, especially in children. Still, long-term retinoid therapy may be possible with maintenance doses and periodic imaging tests that monitor for the adverse effects of these medications on the body.^6,8

Emerging Therapies For Erythrokeratoderma

Gene Therapy

Recent innovations in gene therapy show great promise in effectively treating, managing, and even curing a few chronic diseases, disorders, and other conditions that were once deemed incurable. It is the hope of those either diagnosed with or who knows someone who is diagnosed with Erythrokeratoderma that such advances in science and medicine may yield the same for them.⁴

Repurposing Current Therapies

There are medications and agents available that treat and manage other diseases, disorders, and conditions that may be repurposed to address the cellular abnormalities that occur as a result of the genetic mutations in those with Erythrokeratoderma.⁴

Clinical Trials for Erythrokeratoderma

Currently, there is limited information regarding the conduct of clinical trials on treatment and management therapies for Erythrokeratoderma. The rare nature of these disorders and the multitudes of variants makes determining effective treatment and management therapies a challenge.^4,8

Biologic Therapy

Biologic therapy is one area of treatment and management of skin diseases, disorders, and conditions in which there is some data and information available regarding how it is used in treating and managing Erythrokeratoderma. While Erythroekeratoderma is a group of diseases, disorders, and conditions on its own, its hallmark skin plaques are also found in numerous other diseases, disorders, and conditions. In certain cases, these skin lesions and a myriad of other signs and symptoms are treated and managed using biologic agents. However, the adverse effects of these agents also include the development of similar skin plaques unconnected to the presence of Erythrokeratoderma.⁷ It is important to remember, however, that these therapies are expensive and work in complex ways for different people. Therefore, discussions about including such therapies must be had with your healthcare team, caregivers, and family to discuss whether the agents would be appropriate, how they are expected to work on the body, what outcomes they should produce, and how to finance this aspect of treatment and management.

What Role Do Patients and Families Play?

Given the genetic component in the development of Erythrokeratoderma, it is essential that the family of those with this diagnosis also undergo genetic testing to determine how these disorders are passed from one generation to another.^5,9,11 Such procedures may also lead to the discovery of multiple family members having different types of Erythrokeratoderma disorders.⁵

Since current treatment and management plans for Erythrokeratoderma emphasise addressing signs and symptoms, it is critical for people diagnosed with these disorders, their caregivers, and their families to observe how effective, or otherwise, these plans are. This makes follow-up appointments and discussions with healthcare professionals involved regarding prognosis critical in ensuring that the medications and programs are effectively addressing the signs and symptoms.^1,11

It is important to keep in mind that these skin lesions have the potential to return when the treatment and management regimens stop.¹ However, in certain cases, such as the one where the skin plaques were treated with Calcipotriol, the skin managed to remain free of these lesions a few months after completing and stopping the treatment plan. This indicates that it is possible for people who undergo certain treatment and management programs for Erythrokeratoderma to experience and maintain clear skin, free of these lesions, for months after stopping them.

As stated earlier, the skin plaques typically seen in people diagnosed with Erythrokeratoderma share similarities with those of Psoriasis. These two groups of chronic skin disorders may appear in similar shapes and forms and share treatment and management plans. However, they remain distinct, especially in how genetics plays into their respective development and how the affected skin cells and tissues appear histopathologically under a microscope.³ This necessitates conducting other diagnostic tests, especially those focused on differential diagnostic procedures, to determine whether a person has Erythrokeratoderma or another disease, disorder, or condition that has a similar physical presentation. Such procedures may also help decipher what type of Erythrokeratoderma disorder a person has, since the disorders that fall within this category remain distinct, despite the similarities in how the signature skin lesions appear.⁵

To conclude, Erythrokeratoderma and all diseases, disorders, and conditions that fall within this group are currently incurable. This is why news on emerging therapies and clinical trials regarding treatment and management regimens are considered a source of hope for those diagnosed, their caregivers, and their loved ones.

Summary

• Erythrokeratoderma is a group of rare genetic skin disorders that produces symmetric, reddish, dry, and thick skin plaques on various parts of the body
• Research and case studies have led to the discovery of emerging therapies and the conduct of clinical trials to determine the effectiveness of new and upcoming medications and regimens
• Currently, there are no standard treatment regimens for Erythrokeratoderma
• Emerging therapies for Erythrokeratoderma include gene therapy and repurposing treatments for other similar skin conditions
• Besides biologic therapies, there are no other clinical trials being conducted for medications and other therapies to treat and manage Erythrokeratoderma
• Since the skin lesions seen in Erythrokeratoderma have similar presentations to other skin conditions, it is important to use a comprehensive approach in determining differential diagnoses that would lead to making an accurate diagnosis