Erythrokeratoderma, a term derived from the Greek words "erythros" (red), "keratos" (horn), and "derma" (skin), refers to a rare group of genetic skin disorders. These disorders are characterised by distinct symptoms that frequently pose diagnostic and management challenges. Erythrokeratoderma encompasses a spectrum of disorders, each with its unique clinical presentation, genetic basis, and impact on affected individuals.

At its core, erythrokeratoderma is a group of hereditary dermatological conditions characterised by a combination of erythema (redness) and keratoderma (abnormal skin thickening). These conditions manifest primarily as skin abnormalities, but they can also involve the nails and, in some cases, other organ systems.

In this article, we will delve into the intricacies of erythrokeratoderma, exploring its diverse forms, underlying genetic causes, clinical manifestations, and the current state of research and treatment options. By gaining a comprehensive understanding of this intriguing skin disorder, we aim to shed light on its complexities and the potential for advancements in its diagnosis and management.

Introduction

Definition of Erythrokeratoderma

Erythrokeratoderma, or erythrokeratodermia, is a group of dermatological skin conditions that present disordered keratinisation. The process of keratinisation involves the formation of the different layers of the outermost part of the skin, which is called the epidermis. The different types of erythrokeratodermas are characterised by distinguishable  redness and plaques (erythema) and scaling of the skin (hyperkeratosis).. Plaques can be visibly elevated above the surface of the skin, or present as lesions.¹

Importance of Understanding Erythrokeratoderma

Erythrokeratoderma is a rare genetic skin disorder and, as such, not much is known about it. However, a better understanding of this disease and its underlying causes will inevitably lead to a more accurate diagnosis of the condition. This can reduce misdiagnosis, prevent unnecessary treatments, and lead to faster, more effective management of the disease. Understanding this condition also allows healthcare professionals to better manage not only its physical symptoms, but also provide psychological support for those experiencing low self-esteem and anxiety. For example, as understanding and awareness of these conditions grows from research, patient advocacy groups and support networks can emerge and provide  resources and emotional support for patients and their families. 

Types of Erythrokeratoderma

Erythrokeratoderma Variabilis

Erythrokeratoderma Variabilis (EV)  is the most common subtype out of the erythrokeratodermas. It can be autosomal dominantly inherited, meaning that a single non-sex chromosome expressing EV in either parent can cause a child to have EV; or sporadic, meaning that it arises due to a random mutation in an individual’s DNA.   Most individuals with EV show skin lesions at birth or within their first year of life. 

EV shows as distinct reddish patches that are scaly. They can either be fixed plaques (usually on the arms or legs) or migratory lesions, meaning they appear,fade, and reappear elsewhere on the body. In severe cases, EV can be widespread, and some patients can experience itching or burning sensations on the patches. The formation of these skin lesions can be provoked by sudden temperature changes, emotional stress, or mechanical friction.¹

Progressive Symmetrical Erythrokeratoderma

Progressive Symmetrical Erythrokeratoderma (PSEK) is a rare form of erythrokeratoderma, which also develops shortly after birth or during the first year of life. Patients with PSEK develop thickened plaques of red, scaly skin, usually on the face, arms or legs. These lesions can be fixed or slowly progressive, covering large areas of the body during early childhood. These may get progressively worse, stabilise, or even regress later on in life. The distribution of these lesions is almost perfectly symmetrical, which is a hallmark symptom of this rare condition. Rarely, waxing and waning of these lesions could occur. However, abnormally calloused and thickened skin on palms an soles of feet is common and quite often disabling.²

Porokeratotic Eccrine Ostial and Dermal Duct Nevus 

Porokeratotic Eccrine Ostial and Dermal Duct Nevus (PEODDN) is a very rare congenital disorder under the erythrokeratoderma umbrella. In PEODDN, small, scaly pupules (solid or cystic spots) and plaques develop in a linear patterns along the extremities, such as the palm of a hand and soles of the feet. PEODDN may become more wart-like and persist despite treatments.³

Other Less Common Subtypes

Other atypical forms of erythrokeratoderma can include:

• Progressive partially symmetrical erythrokeratoderma - causes  deafness, muscle weakness, peripheral nerve damage, physical and intellectual disability, and unusual erythrokeratoderma in the extremities (hands, feet) 
• Erythrokeratoderma en cocardes (Degos syndrome)
• Erythrokeratoderma with ataxia (problems with co-ordination, balance, and speech)
• Annular migrating erythrokeratoderma.¹

Genetic Basis of Erythrokeratoderma

Typically, pathogenic variants (mutations) in any of the known erythokeratoderma genes (or a gene that has not yet been identified) cause erythrokeratoderma. These mutations can be inherited in an autosomal dominant or autosomal recessive pattern, or can apper randomly (i.e., spontaneous mutation). Erythrokeratoderma may have a number of different causes, according to recent research, and may also be a feature of other genetic skin disorders. 

Clinical Manifestations

Skin Abnormalities 

Erythema and Hyperkeratosis

Erythema (redness or inflammation of the skin) is essentially due to hypersensitivity in the cutaneous and mucosal layers of the skin and manifests as papular, bullous lesions.⁵ As such, these lesions may vary in colour or be cyst or blister-like. Hyperkeratosis is another common symptom of erythrokeratoderma, and is the increased thickness of the outermost layer of the skin, known as the stratum corneum.⁶

Variability and Progression of Symptoms

Impact on Quality of Life

Erythrokeratoderma can have a significant impact  on the quality of life of  affected individuals. The characteristic skin abnormalities can be not only physically uncomfortable but also emotionally distressing. Visible skin changes may lead to self-consciousness and social anxiety, affecting patients’ interpersonal relationships and self-esteem. This emotional and psychological burden may be further exacerbated by the  condition's chronic nature and variable symptoms. 

Diagnosis and Differential Diagnosis

Clinical Evaluation

A diagnosis of erythrokeratoderma is made based on the presence of distinctive symptoms, a thorough review of the patient's medical history, a comprehensive clinical examination, and specialised tests, such as genetic testing, surgical removal (biopsy), and microscopic examination of the affected tissue.

Differential Diagnosis with Similar Skin Disorders

The following conditions can have symptoms that are similar to erythrokeratoderma. Comparisons may be helpful for a differential diagnosis. 

• Ichthyosis - a group of generalised skin scaling disorders that may present with or without erythema. Ichtyhosis can affect the hair, nails, eyes, and hearing and additional abnormalities.
• Psoriasis - a chronic, inflammatory skin disease that manifests as dry, erythematous (reddish), thickened patches of skin covered with gray-ish scales. These patches may be referred to as papules or plaques and most often affect the scalp, elbows, knees, hands, feet and r lower back. The plaques may be severely itchy (pruritis) or sore. Psoriasis patients sometimes have abnormalities in their fingernails, toenails, and soft tissues inside their mouths. The severity of psoriasis varies from person to person. A family history of psoriasis is found in about one-third of cases.²

Genetic Mechanisms of Erythrokeratoderma

Role of Gap Junction Proteins (Connexins)

Connexin genes encode proteins that form the  components of gap junction channels. Gap junction channels are specialised protein channels that allow direct communication and exchange of ions and small molecules between neighboring cells in various tissues. These channels play a crucial role in coordinating cell activities, such as signaling, synchronisation, and maintaining a healthy internal environment. Mutations in the connexin genes can disrupt the normal functioning of these gap junction channels, impairing the communication between skin cells. This disruption leads to the accumulation of ions and molecules in the skin, resulting in the characteristic symptoms of erythrokeratoderma, including skin redness and abnormal thickening.²

Treatment and Management

Symptomatic Relief

Treatment for erythokeratoderma is mainly  directed toward specific symptom management, such as reducing the thickening and reddening of skin. Treatment normally involves prescribing skin-softening emollients or keratolytics, that cause the hardened outer layer of skin to come off (such as urea, salicylic acid or alpha hydroxy acids). Topical steroids or topical/oral retinoids may also be prescribed.¹

Lifestyle Modifications

Some lifestyle changes for individuals with this condition include:

• Skincare:
  • Use mild, fragrance-free cleansers and moisturisers to keep the skin hydrated and prevent excessive dryness.
  • Avoid harsh skincare products or abrasive exfoliants that can irritate the skin.
  • Apply sunscreen regularly to protect the skin from UV damage, which can exacerbate symptoms.

• Temperature regulation:
  • Avoid extreme temperatures, as both heat and cold can worsen erythrokeratoderma symptoms.
  • Use humidifiers in dry indoor environments to prevent skin dryness.

• Regular dermatologist visits:
  • Maintain regular follow-up appointments with a dermatologist for ongoing skin care and treatment adjustments.⁵

Lifestyle modifications can vary from person to person, as the severity and specific symptoms of erythrokeratoderma can differ among individuals. It's essential for individuals with the condition to work closely with their healthcare providers to tailor their lifestyle strategies and treatment plans to their unique needs.

Potential for Gene Therapy

Genetic counselling is advised for affected people and their families to discuss potential causes of erythrokeratoderma, the risk of having children with this disorder, and the potential for genetic testing.

Psychosocial Support for Patients and Families

Coping with a visible and chronic skin condition can lead to emotional stress, social isolation, and reduced self-esteem. Support networks, including family and friends, play a vital role in providing empathy and understanding. Additionally, connecting with patient advocacy groups and seeking professional psychological counseling can help individuals affected by erythrokeratoderma better navigate the emotional challenges they may face. These resources not only offer emotional support but also empower patients and families with information, coping strategies, and a sense of community, ultimately contributing to improved mental well-being and a better overall quality of life.

Summary

Erythrokeratoderma is a rare genetic skin disorder characterised by redness and thickening of the skin, impacting the quality of life of affected individuals. This condition's complexity lies in its various subtypes, genetic underpinnings, and the challenges it poses in diagnosis and management. Given its rarity, there is a crucial need for increased awareness, research, and support networks to assist those living with Erythrokeratoderma and their families. Continued research efforts are essential to unravel the intricacies of this condition, leading to better diagnostic tools, more effective treatments, and improved psychosocial support. By recognising the complexity of this disease and advocating for ongoing research and support, we can make significant strides in enhancing the lives of those affected by this condition and advancing our understanding of rare genetic skin disorders as a whole.