Jieyi REN ,Manmei LONG ,Yuehua LI ,Bin GU ,Zhichao WANG

ABSTRACT Background Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare type of epidermal nevus that occurs in infancy and develops along Blaschko’s lines.Due to its rarity and clinical/histological similarities with other cutaneous disorders,correct diagnosis is sometimes difficult.In the present case,the whole exome sequencing of blood found no germline mutation,but the sequencing of the biopsy specimen revealed a novel potential pathogenic somatic mutation,C >T at rs200881715 (p.R698X) in the cspp1 gene,which may provide new insight into the mechanism of ILVEN.Patient concerns A 10-year-old girl presented with linear,pruritic,erythematous,scaly,and exophytic verrucous skin lesions on her left thigh,buttock,and hand unilaterally along Blaschko’s lines from the third day after birth.Diagnosis Biopsy revealed psoriasiform acanthosis,papillary hyperplasia with orthohyperkeratosis,and parakeratosis of squamous epithelium,which are histological characteristics of ILVEN.Interventions Owing to the large lesion size and significant refractory response to previous treatments,multiple-stage surgical resections with a tissue expander were performed.Outcomes After surgical resection and defect reconstruction with a tissue expander,the outcome was satisfactory for the patient and her family.No recurrence was detected during the follow-up visits.Conclusion ILVEN is a rare type of cutaneous hyperplastic disease,and treatment is extremely challenging.Biopsy should be performed at the diagnostician’s discretion or if refractory to conservative treatments.Timely diagnosis and surgical intervention could result in satisfactory outcomes.

KEY WORDS Inflammatory linear verrucous epidermal nevus;Blaschko’s lines;Psoriasis;Differential diagnosis;Surgical resection

INTRODUCTION

ILVEN is a rare type of epidermal nevus.Its exact etiology and epidemiological characteristics remain unclear due to its rarity[1].Although it shares clinical and pathological similarities with other skin hyperplastic disorders,including linear psoriasis and other types of epidermal nevus,the treatments vary significantly.Mild ILVEN might respond to conservative treatments,such as administration of topical ointment[2]and laser[3].Progressive and refractory ILVEN requires surgical intervention[4],which is not the treatment option for some differential diagnoses.Therefore,the correct diagnosis of ILVEN is vital for treatment planning and corresponding outcomes.

ILVEN usually starts as reddish or linear plaques associated with prominent pruritus[3],which might further proceed to a hyperplastic phase with cobblestone or cerebriform pattern.It is caused by dysregulation of keratinocytes exhibiting genetic mosaicism[5-6].Pathologically,ILVEN is derived from keratinocytes in the skin[7].Therefore,significantly high expression of cytokeratin is a major differential parameter.ILVEN presents along Blaschko’s lines and affects unilaterally with a predilection for leg,buttock,or arms[7].

ILVEN is refractory to treatments,and currently,there is no effective treatment.The response mainly depends on the severity.Conservative therapies include the administration of topical agents such as corticosteroids[8],calcipotriol[9],and 5-fluorouracil[10].Invasive treatments include cryotherapy[11],pulsed and ablative CO2laser[3],and surgical resection[4].

The development of molecular diagnostics provides an avenue for the diagnosis,treatment,and research of diseases.Thus,whole exome sequencing for germline and somatic mutations in this case was performed,and a novel somaticcspp1mutation was detected.

Early diagnosis and treatment are keys to satisfactory outcomes.Therefore,we present a relatively severe ILVEN case treated in our department,with a summary of the current knowledge of differential diagnosis for ILVEN.

CASE PRESENTATION

A 10-year-old girl presented to the plastic and reconstructive clinic with linear,pruritic,erythematous,scaly,and exophytic verrucous skin lesions on her left thigh,buttock,and hand unilaterally along Blaschko’s lines from the third day after birth (Fig.1).Nails of the left hand were also affected (Fig.2).The initial appearance was reddish hyperkeratotic lesions.The lesion size increased in scale along with her growth and showed papillated epidermal hyperplasia with inflammatory exudation.The associated symptoms changed from occasional pruritis to continuous pruritis with pain.During the last 5 years,she has undergone various treatments with topical corticosteroids,antibiotics,and anti-fungus ointments,as well as excimer laser therapy.Standard treatment protocols were followed,but no obvious improvement was observed.No other symptoms were reported,and the overall physical exam was normal.The patient was the first and only onset in her family with no other systemic disease but a history of milk allergy.Resultsof routine laboratory tests,chest radiography,and electrocardiogram were normal.Discharge culture and antibiotic sensitivity tests revealed microorganism infection with non-drug-resistantStaphylococcus aureus,Pseudomonas aeruginosa,andP.mirabilis.A punch biopsy was performed for both the left thigh and hand lesions (Fig.3 and 4).Whole exome sequencing of blood and skin lesions was conducted.Histopathological biopsy of both the left thigh and hand showed psoriasiform acanthosis,papillary hyperplasia with orthohyperkeratosis,and parakeratosis of the squamous epithelium (Fig.3 and 4).Hyperpigmentation of the basement layer and mild perivascular neutrophil infiltration were detected.Significant overexpression of cytokeratin was observed in the biopsied region compared with adjacent normal skin tissue (Fig.5 and 6).All characteristic findings led to the diagnosis of ILVEN.

Fig.1 Linear,pruritic,erythematous,scaly,and exophytic verrucous skin lesions on the left thigh

Fig.2 Skin lesions on the left hand

Fig.3 Histopathological examination of the lesions on the left thigh

Fig.4 Histopathological examination of the lesions on the left hand

Fig.5 Histopathological examination of the lesions on the left thigh

Fig.6 Histopathological examination of adjacent normal skin tissue

DISCUSSION

ILVEN is a rare cutaneous disease that was first described in 1971 by Altman and Mehregan[5]and concluded by Morag and Metzker in 1985[12].ILVEN is classified under the keratinocytic type of epidermal nevus and comprises approximately 6% of all epidermal nevi[7].It has a predilection for the lower extremities and girls[5].Classic manifestations of ILVEN include[13]clinical presentation as typical unilateral linear verrucous morphology along Blaschko’s lines accompanied by intense pruritus;early age of onset,usually infancy or childhood;psoriasiform acanthosis with parakeratosis on pathological examination;resistance to therapy.Both genetic and environmental factors have been implicated in ILVEN pathogenesis.IVLEN is mostly sporadic,and a somatic heterozygous mutation ofGJA1is a potential causative mutation[14].The significance of proinflammatory cytokines,especially the upregulation of interleukin (IL)/ tumor necrosis factor α and IL-36γ/ IL-17A axis,play a vital role in ILVEN pathogenesis[1].

In the present case,whole exome sequencing of blood found no germline mutation;however,sequencing of the biopsy specimen revealed a novel potential pathogenic somatic mutation,C>Tat rs200881715 (p.R698X) in thecspp1gene.Thecspp1gene encodes centrosome and spindle pole-associated protein1,which plays an important role in cell mitosis and spindle organization[15].It has been reported mostly in cancer[15]and Joubert syndrome,an autosomal recessive disorder that mainly affects the nervous system[16].However,the biological impacts and underlying mechanism ofcspp1mutation in ILVEN need further detailed investigation in the future.

Although ILVEN has unique clinical features,it still has a high risk of misdiagnosis due to its rarity,and it is important to differentiate it from other skin disorders.It is not difficult to distinguish ILVEN from congenital giant pigmented nevi (CGPN) by the morphology of the nevi.The ILVEN lesion usually seems to be reddish owing to its inflammatory status,whereas CGPN are dark brown due to hyperactivity of melanocytes.Linear psoriasis share similarities both clinically and pathologically.As ILVEN is refractory to most treatments,it might require invasive surgical resection,which is not applicable to patients with linear psoriasis.Clinical differential diagnosis might be challenging,and some scholars even postulated ILVEN as a mosaic form of cutaneous psoriasis due to great similarity[6].Therefore,a biopsy is usually needed,especially when considering invasive treatments.Another differential diagnosis is lichen striatus.Lichen striatus is a self-limiting inflammatory condition of unknown etiology in which the lesions follow Blaschko’s lines,similar to ILVEN.However,the lesions of lichen striatus seldom cause itching or other discomforts to the affected person and might resolve after a period.Dermoscopy[17]and biopsy could be useful in diagnosis.

The first-line treatment for linear psoriasis and lichen striatus is the usage of topical steroid cream,which only provides temporary symptomatic relief in ILVEN.Laser therapy shows promising results but requires longterm repeated treatments with a high recurrence rate.In addition,complete clearance cannot be achieved.After detailed communication and informed consent,surgical resection and defect reconstruction with a tissue expander was performed.The outcome was satisfactory for the patient and her family.No recurrence was detected during the follow-up visits.

CONCLUSIONS

ILVEN is a rare type of cutaneous hyperplastic disease.The differential diagnosis of the present case based on clinical presentation could be ILVEN or linear striatus or linear psoriasis,which can be misleading in the clinical practice.Biopsy should be performed to determine the exact diagnosis based on the diagnostician’s discretion or if refractory to conservative treatment.Early diagnosis and proper surgical intervention may result in a satisfactory outcome.

FUNDINGS

This work was supported by grants from the Youth Doctor Collaborative Innovation Team Project (QC201803) of Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai Youth Top-Notch Talent Program (201809004),Chenguang Program supported by the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (19CG18),and the Science and Technology Commission of Shanghai Municipality (19JC1413),Shanghai Rising Star Program (20QA1405600),and innovative research team of high-level local universities in Shanghai (SSMU-ZDCX20180700).

ETHICS DECLARATIONS

Ethics Approval and Consent to Participate

The need for ethics approval was waived as it was a case report.The mother of the patient provided written informed consent before study enrollment.

Consent for Publication

All the authors have consented to the publication of this article.

Competing Interests

The authors have no potential conflicts of interest to disclose.The authors state that the views expressed in the article are their own and not the official position of the institution or funder.

AUTHORS’ CONTRIBUTIONS

B G,ZC W,YH L,and JY R were involved in the surgical treatment of the patient.MM L was involved in HE staining and immunohistochemistry for pathological diagnosis.All authors were involved in the manuscript and figure preparation.All authors have read and approved the final manuscript.