Introduction

Most people are not familiar with Epidermal Nevus Syndrome (ENS), although it was first described in 1957 due to one of its numerous features, Schimmelpenning syndrome. However, the condition, which is a combination of several birth disorders, remains uncommon because it is not frequently reported.1 ENS is the presence of harmless spots or moles as a result of an unusual growth of the skin together with an abnormal development in other systems such as the brain, heart, eyes, bones, urinary and genital organs.

Given the nature of ENS, it is essential to understand the long-term outcomes associated with it. For instance, its underlying brain complications can affect intelligence and development, while bone and eye problems can reduce physical and visual function. Lastly, the visible skin growths can trigger psychological and social well-being issues. Hence, an understanding of the long-term outcomes will provide insights about ENS progression, its management, and the best way to improve the quality of life in individuals living with ENS.

Medical background

Definition

Epidermal nevus syndrome (ENS) is a rare disorder from birth that is seen on the skin due to mild overgrowth of the skin cells, that is the epidermis, it is also referred to as the epidermal nevi, most often, it also present with abnormal development in multiple organs of the body, that is the skin, eyes, nervous and skeletal systems.² 

ENS is considered a neurocutaneous syndrome because it affects both the skin and nervous system.³

Etiology

The aetiology of ENS implies the causes of ENS, which are mostly attributed to the formation of a fertilised egg (a baby) having multiple gene types referred to as genetic mosaicism caused by postzygotic somatic mutations, that is, genetic changes that occur after the egg has been fertilised.⁴

These mutations affect the non-reproductive areas of the body and just a subset of cells, which explains the appearance and distribution of overgrown epidermal cells on the lines of normal cell development in the skin (Blaschko lines). The major changes happen in genes coding for keratins, that is, the K1 and K10 and a triggered mutation in FGFR3, which contributes to the growth of skin cells and the mosaic pattern of lesions.^5,6

Types of epidermal nevi

Epidermal nevi vary and can be classified based on their cellular and structural makeup:

1. Keratinocytic (non-organoid) epidermal nevi: it is the most common type and involves only keratinocytes. They appear as linear or verrucous tan or brown patches^4,7
2. Sebaceous (organoid) nevi: It involves the sebaceous glands and manifests as yellow-orange waxy patches often on the scalp or face, and sometimes it may lead to loss of hair. It has a higher risk of tumour development^4,7
3. Other organoid nevi include follicular, apocrine, and eccrine types, involving hair follicles and sweat glands⁷

Symptoms linked to ENS

• Neurological symptoms: This is common and affects close to half of all ENS cases. These include: seizures, developmental delay and intellectual disabilities, hemimegalencephaly, gyral malformations, cerebral vascular anomalies, cortical atrophy, ipsilateral to the affected skin, hemiparesis and infantile spasms^2,3,4
• Symptoms related to the skeletal system It is frequent in many ENS cases. These symptoms may include: scoliosis, bone deformities, hypophosphatemic rickets and osteopenia^4,8
• Eye-related symptoms: It is seen in one-third of people experiencing ENS. It includes: colobomas of the eyelid, iris, and retina; epibulbar choristomas or lipodermoids; corneal opacities, cataracts; microphthalmia, macroophthalmia, or anophthalmia^4,8

Risk of secondary tumours in nevus lesions

Though epidermal nevi are benign, they carry a risk of developing secondary tumours. Secondary malignancies, while rare, may include:

• Squamous cell carcinoma
• Basal cell carcinoma
• Bowen’s disease
• Keratoacanthoma and other adnexal tumours

The rate of secondary malignancy is relatively low but higher in sebaceous nevi. There are no established clinical guidelines for prophylactic removal, but suspicious changes in lesions warrant medical removal.^7,9

Long-term outcomes of ENS

The long-term outcomes in people living with epidermal nevus syndrome (ENS) affect a variety of organs in the body due to its multisystem involvement. Below are different expected outcomes based on the body organ.

Skin outcomes

1. Epidermal nevi generally persist throughout life. It stabilises after adolescence, although it is rare for it to spontaneously disappear. The lesions often remain stable in size and appearance during adulthood, but may cause cosmetic concerns due to their visibility and extent¹⁰ 
2. There is potential for the epidermal nevi to gradually develop into a malignant tumour; although rare, it is mostly common with the basal cell carcinoma, squamous cell carcinoma, and Bowen's disease.¹¹ However,  Sebaceous nevi, a subtype of epidermal nevus, have a higher risk of leading to malignancy; it is estimated to be around 0.8-3.5%^11,12
3. Visible epidermal nevi have an impact on quality of life and psychosocial well-being. People experiencing this condition may have low self-esteem, social withdrawal, anxiety, depression, and mood disorders resulting from stigma and physical unappealingness¹³

Neurological outcomes

1. One of the symptoms people living with ENS encounter is seizures; most of the time, it is challenging to manage. Some people achieve good control with antiepileptic drugs, while others suffer from uncontrollable epilepsy requiring the need for surgical interventions such as hemispherectomy to be used. Neurological outcomes may vary depending on the seriousness and amount of the central nervous system involved¹⁴
2. Cognitive impairment, such as intellectual disability and developmental delay, is frequently seen in people with ENS whose central nervous system is affected. This may remain stable or worsen with time¹⁵

Skeletal outcomes

1. ENS often leads to skeletal deformities like scoliosis, bone asymmetry, hypophosphatemic rickets and osteopenia. Chronic deformities can cause persistent pain and affect physical function. These problems eventually get worse and may need management by an orthopaedic doctor.¹⁶ 
2. When their bones and skeletal system are severely impacted, it may hamper their ability to move, leading to dependence.

Ophthalmological outcomes

There are eye-related problems linked to ENS, which may lead to loss of sight. Examples include: colobomas, cataracts, and retinal anomalies. Over time, it may result in glaucoma and progressive retinal changes, further worsening the vision. 

Oncological outcomes

The lifetime risk of ENS leading to skin cancer is low but unavoidable, especially for the sebaceous nevi type. Hence, it is necessary to monitor for malignant changes. There are also reports of cancer developing within the nevus tissue, e.g basal cell cancer and squamous cell cancer.

Quality of life in ENS

Physical health

1. People with ENS often need continuous medical management, including surgeries to remove overgrowths, antiepileptic drugs for seizures, physical and occupational therapies for functional impairments, and eye care²
2. Neurological and skeletal challenges due to ENS can lead to different kinds of disability, such as intellectual disability, motor deficits, scoliosis, and reduced physical function. Functional impairments can lead to dependence in carrying out daily activities, thereby requiring long-term supportive therapies^16,17

Psychological and emotional well-being

1. Due to visible skin lesions on individuals living with ENS, they may experience low self-esteem and have concerns about their bodies. They may feel embarrassed, ashamed, and socially withdrawn because of their appearance. These feelings may be severe in adolescents, as they are more vulnerable to emotional distress.18
2. There is an increased risk of depression and anxiety with ENS because of the associated brain disorders and psychosocial burden of visible lesions.¹⁸

Social and educational impact

1. Neurological conditions like intellectual disability and seizures can cause barriers to school attendance, learning, and cognitive development. These challenges may need specific educational plans and support to be designed^17,19
2. Social stigma and bullying due to visible growth can lead to social isolation and difficulties in peer relationships. Individuals often experience discrimination or misunderstanding, which worsens psychosocial challenges¹⁸
3. Caregivers and families get burdened by the stress and demands of caring for individuals living with ENS. The challenges include: emotional distress, role strain, and financial challenges, calling for supportive interventions and resources²⁰

Economic burden

Economic burden of ENS may involve costs that arise from surgeries, medications, ongoing therapies, monitoring for malignancy, and specialised educational and social services. Direct medical costs include hospital stays, medications, and outpatient care, while indirect costs relate to lost productivity and caregiver time.

Conclusion

In summary, epidermal nevus syndrome is a complicated yet rare disorder that affects both the long-term outcomes and quality of life of people living with it. Hence, for proper management, individuals and their caregivers need to understand how this affects them generally and seek proper management from health professionals who can tailor interventions based on their specific needs.