What are epidermal nevus syndromes (ENSs)?
Epidermal Nevus Syndromes (ENSs) are rare genetic disorders characterised by the presence of epidermal nevi, unusual, raised skin growths that vary in size, shape, and colour from the surrounding skin.¹,² These lesions are often found on the head, neck, and upper back but can extend to other parts of the body. They frequently follow Blaschko’s lines, forming S- or V-shaped patterns.1,2,3,4,5
While some epidermal nevi appear in isolation and cause no health concerns, their presence alongside developmental abnormalities or other systemic signs may indicate an underlying ENS.¹,² ENSs affect multiple organ systems, including the brain, spinal cord, nerves, endocrine glands, and skeletal system.²,³ Clinical manifestations can include seizures, developmental delays, vision problems, and abnormal growths in the central nervous system.¹–³
Genetic mutations play a key role in ENSs. Mutations in FGFR3 are associated with epidermal nevi affecting the nervous system.¹,² Mutations in HRAS and KRAS genes are linked to nevi involving sebaceous (oil) glands.³ These genes regulate proteins essential for cell growth, division, and development, explaining the multisystem nature of ENSs.
Why skeletal anomalies are important in ENSs
ENSs can impact the skeletal system, which includes bones, cartilage, and joints. Mutations affecting FGF23, a protein that regulates phosphate, calcium, and vitamin D, may disrupt bone growth and maintenance.²,⁶ Elevated FGF23 levels combined with low phosphate and vitamin D can lead to skeletal anomalies and weakened bones.²,⁶
Symptoms vary by syndrome. For example, Verrucous ENS may present with notable skeletal abnormalities,² whereas Schimmelpenning syndrome may not⁴. Identifying skeletal involvement is essential for diagnosis, treatment planning, and preventing long-term complications.
Common skeletal anomalies in ENSs
Patients with ENS may experience:
- Scoliosis²,³,⁵
- Bony growths²,³
- Joint dislocations and deformities²,³,⁵
- Rickets in children²,⁶
- Weak or soft bones²,³
- Delayed bone growth²,³,⁵,⁷
In Cutaneous-Skeletal Hypophosphatemia Syndrome (CSHS), these anomalies are often accompanied by low phosphate and vitamin D levels.²,⁵,⁶ Physical consequences may include:
- Impaired mobility
- Postural difficulties
- Muscle weakness
- Abnormally shaped bones
- Delayed bone and joint healing
- Bone and muscle pain
- Increased fracture risk³,⁵,⁷
Diagnosing ENSs and skeletal anomalies
Early signs
The first indicator of ENSs is typically epidermal nevi, either present at birth or developing later.¹,² Clinicians should assess their size, shape, colour, texture, and alignment along Blaschko’s lines.¹,⁵ Neurological signs such as seizures, developmental delays, or abnormal CNS growths may also suggest ENS.²,³,⁵,⁷
Skeletal anomalies can indicate disrupted phosphate and vitamin D regulation, guiding further evaluation.⁴,⁷
Diagnostic steps
- Physical Assessment: A head-to-toe skin and skeletal evaluation identifies the type of nevi, bone deformities, posture issues, and mobility limitations²,⁸
- Laboratory Tests: Serum phosphate, calcium, and vitamin D levels should be measured to monitor skeletal health²,⁵.
- Imaging: X-rays, CT scans, and MRIs detect fractures, abnormal bone growths, scoliosis, and other skeletal anomalies²,³,⁵,⁷,¹⁰
- Histopathology: Biopsy of nevi confirms tissue type and supports diagnosis.¹,⁵,⁷,⁹ Dermoscopy may provide a noninvasive alternative⁸
- Genetic Testing: Confirms mutations in FGFR3, HRAS, or KRAS and supports diagnosis when combined with clinical and imaging findings²,⁷
Treatment and management
Skin lesions
ENS skin lesions can be treated surgically or non-surgically, depending on severity and cosmetic concerns.¹,⁴ Options include:
- Dermabrasion
- Cryosurgery
- Electrosurgery
- Laser therapy¹,⁴
Topical treatments with salicylic acid, retinoids, emollients, or corticosteroids may improve the appearance of lesions.¹,⁴,¹¹
Skeletal anomalies
Management focuses on correcting phosphate, calcium, and vitamin D deficiencies and addressing mobility limitations:
- Nutritional supplementation²,⁵
- Burosumab for FGF23-related phosphate wasting⁶
- Physiotherapy and occupational therapy²,¹²
- Assistive devices for posture and mobility²,¹²
Neurological management
Seizures require antiseizure medications such as carbamazepine, oxcarbazepine, valproic acid, topiramate, levetiracetam, hydantoins, or clonazepam,¹² with regular monitoring.
Individualised care
Every patient with ENS presents differently. Treatment plans should be tailored to the individual’s specific symptoms, functional limitations, and personal goals.
Summary
ENSs are rare multisystem disorders characterised by epidermal nevi and often skeletal anomalies. Mutations in the FGFR3, HRAS, and KRAS genes can disrupt phosphate, calcium, and vitamin D metabolism, leading to bone abnormalities and impaired mobility. Early recognition through skin assessment, imaging, lab tests, and genetic testing allows clinicians to provide targeted treatment, improve skeletal health, and support quality of life. Management should be personalised to each patient’s unique needs.
FAQs
Q1: Are epidermal nevi dangerous?
Most epidermal nevi are harmless. However, when associated with ENSs, they may indicate multisystem involvement, including skeletal anomalies.¹,²
Q2: Can skeletal anomalies in ENS be prevented?
Early diagnosis and management of phosphate, calcium, and vitamin D levels can help reduce bone complications.²,⁵
Q3: Is ENS hereditary?
ENSs are caused by somatic mutations and are usually not inherited, though some syndromes may have a genetic component.²,³
Q4: What is the role of burosumab?
Burosumab is a targeted therapy that treats phosphate wasting caused by excess FGF23, improving bone strength and reducing skeletal complications.⁶
Q5: Can ENS symptoms change over time?
Yes. Skin lesions, skeletal anomalies, and neurological symptoms may progress or emerge later in life.¹,²,⁵
Q6: How often should patients be monitored?
Regular follow-up with physical exams, imaging, lab tests, and genetic assessments is recommended to track skeletal, skin, and neurological health.²,⁵,⁷
References
- Arora B, Singh Khinda VI, Bajaj N, Singh Brar G. Congenital Epidermal Nevus. Int J Clin Pediatr Dent. 2014;7(1):43–6.
- Sharma R, Singal A, Verma P, Rohatgi J, Sharma S. Epidermal nevus syndrome associated with unusual neurological, ocular, and skeletal features. Indian J Dermatol Venereol Leprol. 2012;78(4):480–3.
- De Vito A, Taranath A, Dahmoush H, Ganapathy SS, Sudhakar S, Mankad K. Neuroimaging manifestations of epidermal nevus syndrome. Quant Imaging Med Surg. 2021;11(1):415–22.
- Dwiyana RF, Hazari MN, Diana IA, Gondokaryono SP, Effendi RMRA, Gunawan H. Schimmelpenning Syndrome with Large Nevus Sebaceous and Multiple Epidermal Nevi. Case Rep Dermatol. 2020;12(3):186–91.
- Lim YH, Ovejero D, Derrick KM, Yale Center for Mendelian Genomics, Collins MT, Choate KA. Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy. J Am Acad Dermatol. 2016;75(2):420–7.
- Huynh C, Gillis A, Fazendin J, Abdullatif H. A case report to assess the safety and efficacy of Burosumab, an investigational antibody to FGF23, in a single pediatric patient with Epidermal Nevus Syndrome and associated hypophosphatemic rickets. Bone Rep. 2022;17:101605.
- Ovejero D, Lim YH, Boyce AM, Gafni RI, McCarthy E, Nguyen TA, et al. Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment. Osteoporos Int. 2016;27(12):3615–26.
- Elmas ÖF, Akdeniz N. Dermoscopic aspect of verrucous epidermal nevi: New findings. Turk J Med Sci. 2019;49:1–8.
- Pektas SD, Akoglu G, Metin A, Adiyaman NS, Demirseren ME. Becker nevus syndrome presented with ipsilateral breast hypoplasia. Indian J Dermatol. 2014;59(6):634–4.
- Tadini G, Rossi LC, Faure E, Besagni F, Boneschi V, Esposito S, et al. A Second Case of Gobello Nevus Syndrome. Case Rep Dermatol. 2016;8(1):85–90.
- Guite Z, Pamei D, Gunto H, Das K. Epidermolytic hyperkeratosis in verrucous epidermal nevus. J Med Soc. 2014;28(1):47–7.
- Ruggieri M, Polizzi A, Strano S, Schepis C, Morano M, Belfiore G, et al. Mixed vascular nevus syndrome: a report of four new cases and a literature review. Quant Imaging Med Surg. 2016;6(5):515–24.
