CASE REPORT
A 34-year-old female patient (Fig. 1), her 12-year-old daughter and her 66-year-old father (Fig. 2) presented to the Dermatological Outpatient Clinic because of chronic, relapsing skin eruptions of non-specific character. Clinical examination revealed in the 34-year-old woman and her father multiple, diffuse firm papules, plaques and nodules located on the back and extensor surfaces of the extremities. The lesions were very pruritic, and numerous excoriations and scattered scars were observed. The clinical manifestation was consistent with prurigo nodularis. The following conditions were included in differential diagnosis: pemphigoid nodularis, lichen simplex, lichen planus, nodular scabies, dermatillomania, Münchhausen syndrome by proxy, as well as epidermolysis bullosa pruriginosa (EBP). Laboratory tests did not reveal any abnormalities. Evaluation of severe pruritus causes were performed: complete blood cell count, metabolic panel, thyroid studies [free T4 (fT4) and thyroid stimulating hormone (TSH)], urinalysis, stool exam, HIV antibodies, serum IgE and chest X-ray. Laboratory tests did not reveal any abnormalities. The histopathological assessment demonstrated thickening of the epidermis, ortho-hyperkeratosis, irregular epidermal hyperplasia, and pseudoepitheliomatous hyperplasia. Moreover, focal parakeratosis with irregular acanthosis, diminished nerve fibre density and a nonspecific dermal infiltrate containing lymphocytes, macrophages, eosinophils, and neutrophils were observed (Fig. 3). Direct immunofluorescence test was negative. No circulating antibodies indicative of bullous diseases were detected.
Molecular genetic tests were performed — firstly by new generation sequencing (NGS) study that covered 33 mutations related to EB (this included: CAST, CD151, CDSN, COL17A1, COL7A1, CSTA, DSG1, DSP, DST, EXPH5, FERMT1, ITGA3, ITGA6, ITGB4, JUP, KLHL24, KRT1, KRT2, KRT5, KRT10, KRT14, KRT16, KRT17, LAMA3, LAMB3, LAMC2, PKP1, PLEC, PLOD3, SERPINB8, SPINK5, TGM5, VPS33B). A novel missense mutation of p.Val2402Gly/- c.7205T>G in exon 94 of the COL7A1 gene was found in the patient, her daughter and her father (Tab. 1). As of the 2nd of August 2023, this mutation is not yet present in Mondo Global Medical Database (MGMD) and Clinical Variant Database (ClinVar). Based on the Genome Aggregation Database (GnomAD), the incidence of this mutation in the general population is very low — that is 0,00089%. NGS study was later confirmed with Sanger sequencing. Finally, the diagnosis of EBP was made based on the family history, symptoms and results of molecular genetic tests. The patient’s asymptomatic 6-year-old son was also included in the study, but the result of the genetic tests was negative. Treatment was implemented: topical emollients and potent topical steroid creams that resulted in improvement in the patient’s daughter and father. Due to the lack of substantial clinical benefits, the patient was given local corticosteroid injections (triamcinolone acetonide 40 mg/mL), oral antihistamines and phototherapy with ultraviolet B (UVB) 311 nm. After a 3-month treatment period, complete skin lesions and reduction of itch were achieved. The patient and their family remain in constant care and observation.
|
Patient |
1 |
2 |
3 |
|
Age |
34 |
12 |
66 |
|
Sex |
Female |
Female |
Male |
|
Indication |
Prurigo-like skin lesions |
Prurigo-like skin lesions positive result of NGS — Col7A1 in patient 1 |
Prurigo-like skin lesions positive result of NGS — Col7A1 in patient |
|
Material for laboratory testing |
DNA |
DNA |
DNA |
|
Medical procedure |
Analysis of any mutation without DNA isolation (GEN23A) |
Analysis of any mutation without DNA isolation (GEN23A) |
Analysis of any mutation without DNA isolation (GEN23A) |
|
Result |
Col7A1:Val2402Gly/-VUS |
Col7A1:Val2402Gly/-VUS |
Col7A1:Val2402Gly/-VUS |
DISCUSSION
Epidermolysis bullosa pruriginosa (EBP) is an extremely rare form of dystrophic epidermolysis bullosa (DEP). Its cause is the underlying mutation, most often in the COL7A1 gene. Based upon a specific type of mutation in a patient (missense, non-sense, frameshift, splice-site mutations), a distinct, specific phenotype can be observed [1–3]. Clinically, the mean time of symptoms onset is the age of 14. Constant, intense pruritus is present in nearly all patients. The main skin lesions found in EBP are hypertrophic prurigo-like papules and plaques nodules, and violaceous papules, often in a linear or circular configuration, often with secondary lichenification, nodule, plaque and scar tissue formation. Other skin findings are millia, nail dystrophy, albopapuloid lesions, and atrophic scars [4]. The phenotype-genotype correlation of EBP is substantially wide and is based on the mutation type. However, some family members with the same mutation can present significantly different manifestations of the condition. Thus, other environmental factors must be accounted for EBP’s non-negligible heterogeneity, however, no specific factors were found in its pathogenesis. In 2015 Kim et al. [1] analysed this correlation and divided 74 patients into four mutation groups: glycine substitution (GS) — 52.7%, in-frame skipping (IFS) — 33.8%, non-glycine substitution (NGS) — 8.1%, and premature terminal codon (PTC) — 5.4%. Except for IFS carriers, EBP patients were predominantly female (66.2%). IFS patients were more prone to develop blisters and shared a more linear or circular configuration of the lesions, but had lower nail involvement, presence of milia, and atrophic scars and showed no albopapuloid lesions (which were mostly present in the PTC group). GS was also found to be a group with the most clinical features [1].
CONCLUSIONS
Epidermolysis bullosa pruriginosa is usually inherited in an autosomal dominant manner, but an autosomal recessive pattern is also present in the literature [1]. Another study points to a possible skewed T-helper type 2 (Th2)-related immunity in patients with EBP [4].
Treatment in EBP is purely symptomatic and revolves around reducing the itch. Traditionally, topical glucocorticosteroids and emollients are applied to the skin to reduce the itch. Some patients are treated with phototherapy, most commonly (narrowband ultraviolet B) NB-UVB with moderate success.
Recently, some cases of EBP treated with dupilumab were reported with positive clinical outcomes [5–8]. No causal treatment is currently available for EBP.
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Author contributions
Writing: original draft, data curation, conceptualization — KK; supervision — RN; writing-original draft, analysis and description of histopathological examination — EGD; data curation, table and figure preparation — AK; supervision — IB. All authors contributed to the article and approved the submitted version.
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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. All authors had full access to all of the data in this study and took complete responsibility for the integrity of the data and the accuracy of the data analysis. No medical writing or editorial assistance was received in the preparation of this manuscript.
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