Introduction

One of the many challenging and rare keratinisation disorders, a group of conditions that affect how the skin outer layer is formed, that this article will focus on is erythrokeratoderma (EK). Discoloured, red, scaly, patterned skin is a common sign of EK, but the symptoms also mimic common dermatological conditions like psoriasis or ichthyosis. This overlap makes it difficult to diagnose EK correctly, because the approach to each condition is different. This can delay appropriate management, or patients can be given ineffective treatment. There are subtle clinical clues to differentiate EK from other disorders to accurately find the diagnosis. We will explore the defining features of EK and highlight strategies to differentiate this skin disorder from others that are similar in appearance.

Clinical features of erythrokeratoderma

The main features of EK are presented as red, scaly patches on the skin that feel thick due to the extra keratin production. This can appear across the body, usually looking like multiple, patterned plaques that can migrate and change to a more symmetric shape. This could be a sign pointing towards EK.

Two subtypes of EK have been found:

Progressive symmetric erythrokeratoderma (PSEK)¹

• Well-defined, dry, and red marks
• Appears on both sides of the body, mostly symmetrical, e.g. both knees, both arms
• They appear in the same areas for long periods of time
• Position rarely changes as the patient ages and can form new patterns gradually
• It is not painful or itchy, just unsettling

Erythrokeratoderma variabilis (EKV)

• Less predictable in terms of shape and size compared to PSEK
• They can shift and move to different areas of the body, mainly near the limbs
• These patterns can fade and appear within hours or days
• The patches can remain longer, but usually fluctuate and migrate
• Any change in the environment that can cause temperature shifts, stress, or illness can cause a flare-up on the skin or shifts in lesions
• It is not painful, but difficult to predict where it will appear next

Both these conditions appear in childhood and gradually becomes more visible as the child grows. This makes it difficult to diagnose. A way to spot EK a bit more clearly is the way that the patterns disappear and appear over time. This can separate it from the diagnosis of psoriasis and ichthyosis.

Psoriasis vs. erythrokeratoderma

Psoriasis is a chronic skin disorder that is triggered by the immune system. The immune system usually protects you from infections, but when it malfunctions, it can send the wrong signals around the body. In the case of psoriasis,  the immune system mistakenly perceives the skin is under attack, even when nothing harms the skin. The skin will try to renew itself, but it does not give time for the old skin to fall off. There will be a buildup of skin, which causes an appearance of silvery, thick scales with red patches. 

This disease appears on the skin of the joint areas, like the knees and elbows. In some patients, psoriasis is accompanied by nail changes and arthritis. In summary, psoriasis is an immune dysfunction, while EK is a keratinisation disorder. Both conditions begin in early childhood and are characterised by dry, red patches. In EK, the lesions shift to different locations over time, which is the unique feature to tell apart psoriasis from EK. There is no nail involvement in EK either.

There are clinical clues to distinguish the two disorders. In psoriatic tissue, you will often see: 

• Parakeratosis is when the skin sheds too fast, and the cells at the surface haven’t had time to fully mature, so they keep their nuclei
• Munro’s microabscesses are tiny clusters of immune cells only seen under a microscope²

In EK, there is:

• Epidermal thickening, when the outer layer of skin is thicker than usual
• Abnormal keratinisation, when the cells do not mature correctly, and the skin behaves differently
• Orthohyperkeratosis, when too much keratin is made, the cells lose their nuclei, and there is excessive thickening

Ichthyosis vs. erythrokeratoderma

Ichthyosis is a common condition characterised by persistent, dry skin that affects the entire body. These so-called ‘fish scales’ stem from early infancy. The pattern is spread evenly across the entire body surface and diffuses outwards. This is a chronic condition, as opposed to EK, which is more spontaneous.

Hyperkeratosis and erythema are common signs of EK, as well as its more common forms, PSEK and EKV. The behaviour of the skin is unpredictable and is very patchy. This is the key feature of EK, due to its stability, which differs from that of ichthyosis.

The differences between them are more notable. Ichthyosis can show hyperkeratosis like EK, which explains the dry, scaly skin. The absent granular layer is typical because this layer of the skin is very thin or missing. This part is normally protected by the barrier proteins, like filaggrin, which help the skin stay hydrated and keep the cells together, and are contained. However, ichthyosis can break the barrier that causes it to be dry and scaly.

EK has focal acanthosis that provides thicker skin, and hypergranulosis that has the thick granular layer.³ Comparing both of them, the difference between them is the skin barrier, thus, microscopic examinations can help make an accurate diagnosis. Ichthyosis is linked to the filaggrin mutation and other barrier defects. The genetic factor of EK is the cell communication in the skin. While both share hyperkeratosis, EK affects different parts of the body, while ichthyosis scales most of the body and spreads widely.

Other conditions in the differential

There are other conditions that clinicians think of beyond psoriasis and ichthyosis. Some examples are:

Atopic Dermatitis

Atopic dermatitis is a chronic inflammatory condition that starts in childhood and presents itself in areas that can flex, like your elbows and knees. They can flare up and persist over time. It is usually associated with patients who have allergies or asthma.

Pityriasis rubra pilaris (PRP)

PRP results patches with orange/red colour and can clog the follicles with dead skin cells, similar to keratosis pilaris, which appears red and bumpy. It occurs spontaneously, but in rare cases can be inherited. PRP can cover the entire body, but the most common areas are the elbows, knees, palms, and soles.

Seborrheic dermatitis

Seborrheic dermatitis is an inflammatory condition that appears on the face, scalp and chest as oily, yellowish scales. It does look unsettingly greasy at times and can flare up. It is not contagious and may cause irritability.

Keratoderma

Keratoderma is the thickening of the skin, but the difference between this and EK is that keratoderma does not migrate in any way. Palmoplantar keratoderma can only appear on the soles of the feet and the palms. There is no symmetry involved or any migration.

These conditions all have different features, including different therapies and treatments. The careful examination of the patient’s history and the histology of the condition will help drastically to create an accurate diagnosis.

Clinical, histological, and genetic diagnostic tools

Diagnosing EK requires laboratory help and genetic investigations. In a clinical examination, a patient’s history of EK occurring in early childhood is a key clue, along with the plaques shifting in size and location, or its symmetrical plaques. To help narrow the diagnosis, a noticeable pattern of symmetry across the body is evident. Family history is important because EK is inherited in an autosomal dominant pattern.

The clinical presentation of EK typically consists of epidermal thickening and an abnormal keratinisation process to show the altered maturation, which leads to dead skin cells building up on the outer layer.

Genetic testing is used to determine the diagnosis. In the case of EK, it is linked to the connexin mutation, which affects the proteins responsible for cell communications. The proteins form channels to neighbouring skin cells. These cells send signals to coordinate skin growth and shedding chronologically. When a mutation occurs, the connexin gene channels do not function properly, which results in keratinisation and disorganised cell growth. This faulty communication is the reason why genetic testing is essential.⁴

In laboratory testing, it can help exclude other disorders by searching for inflammatory or autoimmune markers. They can also examine the tissues under the microscope to distinguish differences that are not normally visible. These tools allow clinicians to avoid confusion with other disorders and provide precise diagnosis.

Summary 

Erythrokeratoderma is a rare disorder that can mimic other common skin conditions, like psoriasis and ichthyosis. Careful comparisons can be made to distinguish it from other similar skin disorders, providing an accurate diagnosis. This can be done by relying on clinical patterns, histology of each condition, and genetic confirmation. There are some similarities, but with the right information and tools, the correct classifications will ensure appropriate management and treatment to extend the future knowledge of erythrokeratoderma.