Introduction

Epidermolytic ichthyosis, also known as epidermolytic hyperkeratosis (EHK), is a rare genetic skin disorder characterised by blistering, hyperkeratosis (thickening of the skin), inflammation, and scaling. Symptoms typically appear at birth, with varying degrees of severity that may change over time.

 Infants born with epidermolytic ichthyosis have a disrupted skin barrier and may develop severe fluid-filled blisters, which can progress to widespread scaly skin later in life. In healthy individuals, the outer layer of the skin acts as a barrier to maintain body temperature and moisture levels of the body and protects against skin infections. A disrupted skin barrier, particularly in infants, interferes with body temperature regulation and reduces sweating, making it difficult to maintain adequate hydration and fluid balance. Fluid imbalance can further disrupt the regulation of electrolyte levels in the body, such as sodium and can lead to abnormally dry skin. 

Persistent inflammation of the outer skin layer triggers the production of additional skin cells faster than the natural shedding process of the skin, causing the cells to build up, resulting in thick layers or scales on the surface of the skin. The scales typically develop along the rows of spines or ridges. Damaged or cracked skin creates entry points for pathogens, increasing the risk of skin infections. Symptoms such as skin redness (erythroderma), severe itchiness (pruritus), dry skin and heat intolerance can significantly affect the quality of life of affected individuals and increase daily stress due to the high burden of the disease. Diagnosis is based on the presenting clinical symptoms, supported by microscopic evaluation of a skin biopsy. Genetic testing may also be recommended for confirmation.^1,2 

Treatment focuses on the management of the symptoms and may require a combination of long-term therapies. Topical skin medications containing keratolytics such as urea or sodium bicarbonate, or antiseptic baths, can be beneficial in reducing the symptoms; however, they remain insufficient for severe cases.⁵ Persistent and long-lasting symptoms of the condition, such as severe pruritus and skin fragility, significantly reduce the quality of life for individuals living with this condition, sparking scientific interest in developing new therapies and improving current recommended treatments. For severe epidermolytic ichthyosis, systemic retinoid therapy remains the most effective treatment option, providing significant symptomatic relief and improvement of the quality of life. However, limitations and risk factors must always be considered before initiating systemic treatment.³

Pathophysiology of epidermolytic ichthyosis

Epidermolytic ichthyosis is caused by mutations in the KRT1 or KRT10 genes. In the majority of cases, mutations are inherited from a parent; however, up to 50% of patients acquire them spontaneously without a family history of the condition.⁴ These genes give instructions to produce structural proteins, particularly found in epithelial and epidermal cells, called keratin 1 and keratin 10. Improper expression of these proteins impairs the formation of keratin filaments and disrupts the skin barrier, which can lead to epidermal inflammation, easy blistering, hyperproliferation and hyperkeratosis.⁵ Epidermolytic ichthyosis is an autosomal dominant genetic disorder, which means inheriting only a single copy of the gene variant is sufficient to cause the disease.² Mutations in KRT1 are associated with palmoplantar keratoderma, a condition in which skin becomes thicker on the soles of the feet and palms.⁵

Systemic retinoids: mechanism of action

Retinoids are naturally occurring and synthetic derivatives of vitamin A that regulate cellular activities, particularly cell growth and differentiation. They are widely used in the treatment of skin disorders. Retinoids regulate keratinocyte differentiation and proliferation by selectively binding to retinoic acid and retinoid X receptors in skin cells, affecting gene transcription. This binding reduces excessive keratinocyte proliferation, slows hyperkeratosis and restores balance between skin cell production and natural shedding. Normalisation of keratinocyte differentiation and proliferation prevents thickening of the skin and reduces abnormal keratinisation and fissure formation (deep cracks in the skin). It also improves skin barrier functioning, reducing the frequency of secondary infections and scaling. In addition to their effect on regulating keratinocyte proliferation, retinoids have anti-inflammatory effects by modulating inflammatory pathways and can reduce erythema and skin irritation.^6,7

Clinical benefits of systemic retinoids in EI

Both topical and systemic retinoids have been used in the treatment of ichthyoses and other similar cornification skin disorders for decades. The use of systemic retinoids has been proven to be the most effective management strategy and is included in the European guidelines on the management of congenital ichthyosis, published in 2018. Retinoids improve the skin condition and flexibility by normalising the differentiation and proliferation of keratinocytes. Reduced thickening, tenderness and fissuring of the skin, relieve the pain, itchiness and discomfort associated with this disorder. Systemic retinoids enhance the skin barrier and reduce the risk of secondary infection and inflammation. Improved skin texture and condition enhance joint mobility and reduce restriction in daily activities. By reducing the skin abnormalities associated with this disorder and alleviating key symptoms, retinoids improve the individuals` comfort and quality of life.⁶

Limitations and risks of systemic retinoid therapy

Systemic retinoids are highly teratogenic; they interfere with fetal development,, leading to central nervous system malformations, birth defects and functional impairments. Strict pregnancy prevention programs should be followed during treatment with systemic retinoids, and patients must be informed about the consequences. Before initiating treatment, the possibility of being pregnant should be excluded. Retinoids may also reduce the efficacy of oral contraceptives, particularly progesterone-only formulations; therefore combination of contraception methods, such as additional barrier use, should be considered. As retinoids are stored in adipose tissue and have a long half-life, contraceptive protection is recommended to be continued for up to two years after completing treatment.⁷

Systemic use of retinoids can lead to elevation of liver enzymes and triglyceride levels; thus, monitoring is necessary throughout treatment. Mucocutaneous xerosis, abnormal dryness of skin, lips and eyes, and skin irritation and fragility are common side effects of systemic retinoid treatment. Hair loss, myalgia and arthralgia are also included in the reported side effects. With long-term treatment, complications such as premature epiphyseal closure, tendon calcification, spinal hyperostosis and osteoporosis may develop; hence, annual assessments should be done. 

Retinoids increase photosensitivity, so patients receiving systemic retinoid treatment should be informed about the importance of UV-protection. Discontinuation or dose adjustments should be considered if any of these side effects occur, causing significant harm to the patient receiving the treatment. Although the side effects of various retinoids are similar, their incidence can differ depending on the specific type and dose used. Patient response can vary due to differences in drug tolerance, and upon discontinuation, exacerbations may be observed.^{6 7}

Monitoring and safety considerations

Patient counselling regarding side effects and teratogenic risks is essential before initiating and throughout systemic retinoid treatment. Regular monitoring of liver enzyme levels and function, lipid profile and bone health is recommended, and individuals should be informed about the importance of these routine checks. Dose adjustments are based on patients' medical condition, clinical response and tolerance.

Summary

Epidermolytic ichthyosis is a rare genetic skin disorder seen in 1 in 100,000-300,000 infants. Prevalence is equal between genders and caused by spontaneous or inherited mutations occurring in the keratin-expressing genes called KRT1 or KRT10.⁴

Symptoms of epidermolytic ichthyosis include redness, itchiness, scaling, blisters, hyperkeratosis and inflammation. In infants, severe blistering and inflammation are commonly observed, whereas scaling becomes more prominent as they grow up. Epidermolytic ichthyosis significantly reduces the quality of life of the affected individuals; thus, early intervention and effective management of symptoms play an important role. As a lifelong condition, it requires consistent, effective combination therapies and long-term management. 

Systemic retinoids are considered the most effective treatment option for severe cases, offering significant relief of symptoms and improvements in hyperkeratosis, scaling and quality of life.³ However, their use is limited due to their high-risk side effect profile, teratogenic potential and strict monitoring requirements. Careful patient selection, dose adjustment and regular monitoring are crucial to maximise therapeutic effects and reduce harm.^6,7 While systemic retinoids remain the most effective therapy, future research should aim to develop safer long-term alternatives