Introduction

Epidermolytic ichthyosis (EI), previously referred to as epidermolytic hyperkeratosis, is a rare genetic skin disorder with an estimated incidence of approximately one in 200,000 to 300,000 live births. It follows an autosomal dominant pattern of inheritance and results from dominant-negative mutations in keratin 1 (KRT1) or keratin 10 (KRT10).¹ These mutations undermine the structural stability of suprabasal keratinocytes, disrupting epidermal differentiation and compromising barrier function. Although no curative treatment currently exists, topical therapies remain central to care. They are primarily aimed at addressing the key clinical manifestations of EI: abnormal cornification, marked hyperkeratosis, persistent scaling, epidermal fragility, and the heightened risk of secondary infection. Effective treatment requires a nuanced and personalised approach, often combining several agents to maximise benefits while limiting harm.²

Pathophysiology and clinical features

The clinical picture of EI evolves with age. Affected neonates usually present with diffuse erythroderma and widespread blistering. As patients grow older, blistering tends to diminish, while hyperkeratosis gradually becomes the dominant feature. This hyperkeratosis often produces thickened, sometimes malodorous scales, which are particularly pronounced in flexural areas such as the neck, axillae, and groin. These changes can cause physical discomfort and, in some cases, functional limitations.³ The associated odour and visible skin changes may also result in a significant psychosocial burden.

The pathogenesis of EI lies in the cytoskeletal fragility of keratinocytes caused by abnormal keratin filament formation. This structural weakness renders cells highly susceptible to mechanical stress and microtrauma, producing erosions and impairing barrier integrity.⁴ The impaired barrier stimulates a cycle of hyperproliferation and compensatory hyperkeratosis. This thickened stratum corneum not only accentuates scaling but also creates an environment that favours microbial colonisation and recurrent infection. Effective topical therapy must therefore strike a delicate balance between reducing scale and thickening on the one hand, and avoiding excessive fragility, erosions, or secondary infection on the other.⁵

General principles of topical therapy

Topical therapy in EI serves three principal purposes: to hydrate and support the barrier, to reduce hyperkeratosis and scaling through keratolysis, and to limit complications such as fissuring, infection, or malodour. Treatments must be tailored carefully according to the age of the patient, the anatomical location of the disease, its severity, and the individual’s tolerance of specific agents.6 Younger children and neonates require gentler approaches, since both their skin and systemic capacity to metabolise absorbed agents are less mature. Areas such as the face, flexures, and genitalia require greater caution because they are inherently more vulnerable to irritation. More severe cases may necessitate systemic therapy, but even then, topical regimens remain indispensable in order to improve comfort and to reduce the burden of systemic medication. Equally important is consideration of the patient’s lifestyle and adherence; daily, intensive skin care routines can be burdensome, and treatment plans must therefore be realistic, tolerable, and adapted to evolving needs.⁷

Combination therapy is often most effective. Emollients provide the foundation, while keratolytics or topical retinoids may be added according to severity and tolerability. Alternating or layering products can enhance efficacy while minimising side effects.

Emollients and barrier repair agents

Emollients form the cornerstone of therapy for all individuals with EI. They work by restoring hydration of the stratum corneum, reducing fissuring, and softening thickened skin. Traditional preparations such as petrolatum, lanolin, glycerol, and paraffin-based ointments provide effective occlusion, thereby limiting transepidermal water loss. They are non-irritating and safe for all ages, including neonates.⁸

In recent years, more advanced formulations have emerged that contain ceramides, cholesterol, and free fatty acids in physiologically balanced ratios. These products mimic the natural lipid barrier of healthy stratum corneum, thereby strengthening barrier repair in addition to providing hydration. Evidence from studies in other skin disorders, such as ichthyosis vulgaris and atopic dermatitis, suggests that such formulations can significantly improve barrier function. Case reports also describe benefits in EI, particularly when applied liberally and frequently. Application immediately after bathing is especially valuable, as it helps retain moisture absorbed during immersion. Bath additives, such as oil dispersions or colloidal oatmeal, can also soothe the skin and prepare it for subsequent emollient application.⁹

Urea and lactic acid

Keratolytic agents are frequently used to complement emollients. Urea, in concentrations between 10 and 30 per cent, has both humectant and keratolytic properties. It attracts water into the stratum corneum and simultaneously disrupts hydrogen bonding within keratin, resulting in loosening and detachment of scale. Clinical reports consistently demonstrate reduced scaling, improved skin pliability, and high patient satisfaction with urea creams.¹⁰

Lactic acid, typically used in concentrations of 5 to 12 percent, works by weakening corneocyte cohesion. It is effective in reducing scaling but has a greater tendency to sting or irritate fissured or inflamed skin, limiting its use in sensitive areas and in young children. The choice of concentration must be individualised: mild cases or sensitive anatomical sites are generally treated with lower strengths, whereas more recalcitrant plaques or palmoplantar disease may benefit from higher strengths of urea.¹¹ Combination formulations that blend urea or lactic acid with emollients can provide enhanced efficacy and tolerability.

Topical retinoids

Topical retinoids, including tretinoin, tazarotene, and adapalene, normalise keratinocyte proliferation and differentiation. This mechanistic effect translates clinically into reduced hyperkeratosis and smoother skin texture. Their role in EI is supported by case series and histological studies demonstrating suppression of abnormal keratinocyte activity.¹²

Tretinoin is effective but often irritates the skin, which restricts long-term or extensive use. Tazarotene, a third-generation retinoid, is more potent and can be helpful for localised thick plaques, although tolerability remains a limiting factor. Adapalene is generally better tolerated, with greater stability and reduced irritation compared with older retinoids. Reports of its use in children suggest meaningful improvements in facial and flexural involvement, areas where other retinoids may be too harsh.¹³

The main drawbacks of retinoids are erythema, irritation, and photosensitivity. Their use is usually restricted to localised hyperkeratotic lesions, with careful adjustment of frequency and concentration depending on skin tolerance. Extensive application, especially over erosive areas, is avoided to reduce irritation and prevent significant systemic absorption.¹⁴

Salicylic acid and propylene glycol

Salicylic acid is a potent keratolytic agent that acts by dissolving intercellular cement. Concentrations between 3 and 6 per cent are sometimes used to treat resistant plaques of hyperkeratosis in EI. Its use, however, is limited by the risk of systemic absorption, particularly in children or when applied to large areas. Toxicity can manifest as salicylism, which makes cautious, localised application essential.

Propylene glycol, often used in concentrations of 20 to 40 per cent, enhances penetration of other agents and has mild keratolytic activity of its own. When combined with urea or lactic acid, it can be effective for moderate hyperkeratosis. Nevertheless, it may provoke irritant dermatitis or, rarely, allergic contact dermatitis.¹⁵

Tailored and combination approaches

In practice, the most effective management strategies combine emollients with keratolytics or retinoids, carefully tailored to the individual’s disease pattern and tolerance. For example, a patient may apply emollients daily as a base, introduce urea cream on alternate evenings to soften hyperkeratosis, and use adapalene for localised resistant plaques. Alternating products not only enhances efficacy but also reduces irritation and improves adherence. Adjustments may be needed seasonally, as colder weather often worsens xerosis and scaling.

For patients with severe or extensive disease, systemic retinoids such as acitretin may be required. Nevertheless, topical therapy remains important alongside systemic treatment, as it permits lower systemic doses and thereby reduces systemic side effects.¹⁶

Limitations of current therapies

Despite their value, topical therapies for EI have limitations. Daily treatment routines are labour-intensive and can significantly affect quality of life. Irritation, stinging, erythema, or allergic contact reactions occur with certain agents, particularly keratolytics and retinoids, and these adverse effects can limit compliance. Even with optimal regimens, complete control is rarely achieved, and patients often continue to experience substantial scaling and skin fragility. For adolescents in particular, the burden of daily application and the social implications of visible skin disease present additional challenges. Multidisciplinary support that includes dermatologists, nurses, and psychological services can be invaluable in helping patients sustain long-term adherence and maintain well-being.

Future directions

Research into new topical strategies continues to advance. Delivery systems using liposomes or nanoparticles may allow deeper penetration of active agents with reduced irritation. Barrier-targeted therapies, including protein replacement and topical gene correction, are being explored in preclinical studies. Immunologically targeted biologics, particularly those directed against IL-17 and IL-23 pathways, have shown encouraging results in some forms of ichthyosis, although their role in EI remains experimental. The skin microbiome is another emerging area of research, with efforts underway to develop probiotic or bacteriophage-based therapies to reduce bacterial colonisation and malodour.

As understanding of the genetic and immunological landscape of EI deepens, it is hoped that topical treatments can evolve beyond symptomatic management to address underlying disease mechanisms.

Conclusion

Topical therapy remains fundamental to the management of epidermolytic ichthyosis. A patient-centred approach that combines emollients, keratolytics, and, in selected cases, topical retinoids is essential for reducing hyperkeratosis and improving quality of life. Antimicrobial strategies may be required to manage secondary complications, while tailored and flexible regimens help maintain efficacy and tolerability over time. Although systemic treatments and novel biologics may gain greater prominence in the future, topical therapies will remain indispensable in daily management. Beyond improving skin physiology, these strategies also play a vital role in alleviating discomfort, reducing infection risk, and supporting psychosocial wellbeing for individuals living with this lifelong condition.

FAQs

What is the main goal of topical therapy in epidermolytic ichthyosis?

The primary goal is to reduce hyperkeratosis and scaling while supporting barrier function, alleviating discomfort, and minimising infection risk. Since there is no curative therapy, treatment focuses on symptomatic control and improving quality of life.

Are emollients alone sufficient for managing epidermolytic ichthyosis?

For milder cases, regular use of emollients can provide substantial relief by hydrating the skin and reducing fissuring. However, most patients require additional keratolytic agents or retinoids to adequately control hyperkeratosis.

Which keratolytic agents are most commonly used?

Urea and lactic acid are most frequently applied. Urea acts as both a humectant and a keratolytic, while lactic acid weakens corneocyte cohesion. Salicylic acid may be used for stubborn plaques, but requires caution due to systemic absorption risks.

Can topical retinoids be used in children?

Yes, but with care. Adapalene is generally better tolerated in paediatric patients compared to tretinoin or tazarotene. Treatment should be localised and closely monitored to avoid irritation.

How is malodor managed in patients with EI?

Malodour is usually linked to bacterial colonisation. Antiseptic washes, dilute bleach baths, and sodium bicarbonate soaks can reduce bacterial burden and odour. Topical antibiotics should be reserved for active infection to prevent resistance.

Are topical treatments enough for severe cases?

Not always, severe EI often requires systemic retinoids such as acitretin. Nonetheless, topical therapy remains essential for comfort and to help reduce systemic dosage.

What are the main side effects of topical therapies?

Common issues include stinging, burning, erythema, or irritation, especially with keratolytics and retinoids. Salicylic acid carries a risk of systemic toxicity in young children. Emollients are generally safe but can occasionally cause contact dermatitis.

What future directions are being explored for EI management?

Emerging strategies include nanoparticle delivery systems, topical protein replacement, gene-corrective approaches, immune-targeted biologics, and microbiome modulation. These remain experimental but highlight the potential for therapies that go beyond symptom control.