Genetic diagnosis of a rare COL7A1 variant causing dystrophic epidermolysis bullosa pruriginosa through whole­exome sequencing.

Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare subtype of inherited DEB. In the present study, whole-exome sequencing was conducted on 12 individuals from the same affected family and a rare heterozygous variation was identified in the collagen type VII, α1 (COL7A1) gene, namely c.6859G>A (p.Gly2287Arg). Subsequently, this heterozygous variant was confirmed using Sanger sequencing of individual plasma cell-free DNA (cfDNA) and it was demonstrated for the first time, to the best of our knowledge, that COL7A1 exons can be amplified from plasma cfDNA. Within the large pedigree examined, 14 out of 18 individuals carried the variant, 3 carried the wild type, and one exceptional case, III-9, showed no disease symptoms despite carrying the disease variant. A general association between genotype and phenotype was established. Of note, the mutation landscape indicated that this G2287R variant is primarily reported in Asian countries. In silico structure prediction suggested that the residue resulting from the mutation may affect collagen protein stability. In conclusion, the present study provides evidence for the involvement of the COL7A1 G2287R gene variant in the development of DEB-Pr and highlights the potential utility of cfDNA in genetic disease diagnosis.

Identification of a novel COL7A1 variant associated with dystrophic epidermolysis bullosa pruriginosa responding effectively to dupilumab.

BACKGROUND: Variants in COL7A1 cause an extremely rare and clinically heterogeneous syndrome known as dystrophic epidermolysis bullosa pruriginosa (DEB-Pr). Duplilumab, a fully humanized anti-IL-4Ra monoclonal antibody, can inhibit IL-4 and IL-13-driven signaling. METHODS: Ethical Compliance: Following our Institutional Review Board, genetic testing has been made available after completing a signed informed consent form. This article presents the case study of a DEB-Pr patient who received dupilumab therapy. Genomic DNA was extracted from the peripheral blood of the patient. RESULTS: The findings showed that a unique COL7A1 mutation was discovered in the patient who underwent genetic testing. As a result of the patient receiving dupilumab treatment, the individual reported experiencing significantly less itching and considerably improved erythema, less severe scales, crusts, and flattening of plaques. CONCLUSION: In conclusion, the current investigation showed that to the best of our knowledge, this is the first DEB-Pr patient with heterozygous COL7A1 (NM_000094.3:c.8110G>A [p. Gly2704Arg]) who responded positively to dupilumab treatment without experiencing any serious side effects.

Epidermolysis bullosa pruriginosa: A case report of two first cousins.

Genodermatoses are quite frequent in developing countries where consanguinity is common but are usually under reported and undiagnosed. Main reason being lack of accessibility to tertiary health care facilities for people of rural areas as evident in case below. Genetic counselling and pre natal testing is of utmost importance in affected families. Epidermolysis bullosa pruriginosa (EBP) is a rare and less recognized variant of dystrophic epidermolysis bullosa. Reporting the case of two first cousins who presented with intensely pruritic skin lesions since infancy along with the history of siblings with skin problems. EBP provided a unifying diagnosis.

Successful treatment of epidermolysis bullosa pruriginosa by dupilumab.

Epidermolysis bullosa pruriginosa (EBP) is a rare variant of dystrophic epidermolysis bullosa caused by COL7A1 gene mutation. Intense pruritus and nodular prurigo-like lesions are the main features of the disease. To date, the treatment strategies for this condition are not well established. Recent studies have indicated that type 2 inflammation plays a role in the pathophysiology of EBP, suggesting Th2 cytokines could be potential therapeutic targets. In this prospective case series study, we reported three patients with EBP, diagnosed by clinical manifestations, histopathological evaluations, and genetic sequencing, two of whom were treated with dupilumab for 20 weeks. Results showed that the clinical symptoms, pruritus, and quality of life of the patients were significantly improved, as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index, the Visual Analog Scale, and the Children's Dermatology Life Quality Index. Serum immunoglobulin E levels also fell gradually over the 20-week treatment period. Immunotyping of Th1/2/17 cell subsets in peripheral blood by flow cytometry revealed a higher Th2 but parallel Th1 and Th17 cell subsets in patients compared to healthy controls, and a significant decrease in Th2 and an increase in Th17 cells after dupilumab administration. Of note, after 20 weeks of dupilumab treatment, the expression of type VII collagen in the basement membrane of the skin lesion of the patients significantly increased, which was evidenced by immunofluorescence analysis. No treatment-related adverse events were documented. Taken together, targeting type 2 inflammation with dupilumab may be an effective and safe treatment option for EBP.

Rare subtypes of epidermolysis bullosa: three case reports and their pedigree analysis / 中华皮肤科杂志

Objective:To report 3 cases of rare subtypes of hereditary epidermolysis bullosa.Methods:Clinical data were collected from the probands and their relatives, whole-exome sequencing was performed to screen disease-causing mutations in the probands, and Sanger sequencing or qPCR was conducted to verify the mutations in patients and their relatives.Results:Case 1 mainly presented with linear red scars on the back, and the proband, her mother with similar clinical manifestations and her asymptomatic daughter all carried a mutation c.4573G>A (p.Gly1525Arg) in the COL7A1 gene. Case 2 presented with generalized reticular pigmentation all over the body and occasional blisters restricted to the hand and foot, and carried a de novo mutation c.74C>T (p.Pro25Leu) in the KRT5 gene. Case 3 presented with pigmentation abnormalities mainly located at the sun-exposed sites and incomplete syndactyly of the left hand, and carried homozygous deletion mutations in exons 2-6 of the FERMT1 gene, which were inherited from her asymptomatic parents. Case 1 was diagnosed with dominant dystrophic epidermolysis bullosa pruriginosa, case 2 was diagnosed with epidermolysis bullosa simplex with mottled pigmentation, and case 3 was diagnosed with Kindler epidermolysis bullosa. Conclusion:The clinical manifestations of epidermolysis bullosa vary greatly, and gene detection is very important for confirmation of diagnosis of its rare types.

Misdiagnosed dystrophic epidermolysis bullosa pruriginosa: A case report.

BACKGROUND: Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare subtype of DEB, characterized by recurrent pruritus of the extremities, pruritus papules, nodules, and mossy-like plaques. To date, fewer than 100 cases have been reported. We report a misdiagnosed 30-year-old man with sporadic late-onset DEB-Pr who responded well to tacrolimus treatment, thereby serving as a guide to correct diagnosis and treatment. CASE SUMMARY: A 30-year-old man presented with recurrent itching plaques of 1-year duration in the left tibia that aggravated and involved both legs and the back. Examination revealed multiple symmetrical, purple, and hyperpigmented papules and nodules with surface exfoliation involving the tibia and dorsum of the neck with negative Nissl's sign, no abnormalities in the skin, mucosa, hair, or fingernail, and no local lymph node enlargement. Blisters were never reported prior to presentation. Serum immunoglobulin E level was 636 IU/mL. Clinical manifestations suggested DEB-Pr. Histological examination showed subepidermal fissure, scar tissue, and milia. Direct immunofluorescence showed no obvious abnormalities. However, we were unable to perform electron microscopy or genetic research following his choice. We treated him with topical tacrolimus. After 2 wk, the itching alleviated, and the skin lesions began to subside. No adverse reactions were observed during treatment. CONCLUSION: Topical tacrolimus is a safe treatment option for patients with DEB-Pr and can achieve continuous relief of severe itching.

Epidermolysis bullosa pruriginosa treated with dupilumab.

Epidermolysis bullosa pruriginosa (EBP) is a variant of dystrophic epidermolysis bullosa characterized by intense pruritus and prurigo nodularis-like lesions. While medical therapies for EBP exist, current treatments are not consistently effective, and symptoms often cause decreased quality of life. Here, we report two cases of EBP treated with dupilumab, which decreased symptoms of pruritus and improved skin findings. Both patients have been on dupilumab for over one year with sustained improvement and no adverse effects; although in one patient, increased dosing was required to attain optimal control of disease.

Epidermolysis Bullosa Pruriginosa successfully treated with concomitant topical and systemic agents.

Epidermolysis bullosa pruriginosa, a genetic mechanobullous disease, manifests at birth or late in life and is characterised by intense pruritus, resulting in lichenified or nodular prurigo-like lesions and scarring most prominent on the shins. Treatment is unsatisfactory. We report a patient treated with success using a combination of topical and systemic agents.

Epidermolysis bullosa pruriginosa: A rare entity which responded well to thalidomide.

Epidermolysis bullosa pruriginosa is an unusual clinical variant of dystrophic epidermolysis bullosa characterized by sublamina densa blistering and intense pruritus leading to hypertrophic lichenoid nodules, plaques, milia, and variable presence of albopapuloid lesions. Most cases are sporadic but a few cases have autosomal dominant or recessive inheritance. Treatment has been quite disappointing and failed to produce satisfactory or sustained results. We report a case of 39-years-old male with epidermolysis bullosa pruriginosa and its response to thalidomide.

Whole exome sequencing identified two point mutations of COL7A1 and FLG in a Chinese family with dystrophic epidermolysis bullous pruriginosa and ichthyosis vulgaris.

We report a 21-year-old man with recurrent bullous eruptions and severe itching on the lower legs and feet since 5 years of age. Dry, dirty brown, tile-like scales covered his lower legs with dystrophic toenails. Nodular prurigo-like lesions, scarring papules and milia remitted after the bullous eruptions. His father and another two family members had similar but mild presentations with recurrent bullae on the lower legs. Whole exome sequencing detected the heterozygous variants of COL7A1 c.6698G>A and FLG c.7249C>T in this pedigree. COL7A1 c.6698G>A was reported in bullous dermolysis of the newborn and FLG c.7249C>T was reported in ichthyosis vulgaris. Thus, the diagnosis of dystrophic epidermolysis bullosa pruriginosa associated with ichthyosis vulgaris was made.

Coinheritance of 2 New Potentially Damaging Heterozygous COL7A1 Variants in a Family With Autosomal Dominant Epidermolysis Bullosa Pruriginosa.

Epidermolysis bullosa pruriginosa (EBP) is a rare subtype of EB which is characterized by intense pruritus with blistering and nodular or lichenoid lesions most prominent on the lower extremities. It is caused by variants in COL7A1 which encodes for type VII collagen. There is wide phenotypic and genotypic variability between affected individuals. We report 2 potentially pathogenic variants in COL7A1 occurring on the same allele in a family with EBP and autosomal dominant inheritance. Late-onset EBP and incomplete penetrance may lead to delayed presentation in affected family members with the same variants. The broad phenotypic variability seen in EBP suggests that further genotypic and environmental factors may influence presentation. Genetic and histopathological diagnosis is essential, given the considerable overlap with clinically similar presentations such as hypertrophic lichen planus.

Epidermolysis Bullosa Pruriginosa: Case Series and Review of the Literature.

Epidermolysis bullosa (EB) pruriginosa is a rare clinical subtype of dystrophic epidermolysis bullosa (DEB) that is characterized by intense pruritus resulting in hypertrophic, lichenified, prurigo-like plaques and nodules secondary to scratching. The variability in the age of onset, rarity of intact bullae, histologic ambiguities, and close resemblance to other conditions such as acquired inflammatory dermatoses may make diagnosis difficult for this unusual condition, for which fewer than 100 cases have been documented. In this report, we describe 3 cases of EB pruriginosa and review the current literature.

Review of thalidomide use in the pediatric population.

Thalidomide is resurging in the management of adult rheumatologic skin conditions, especially lupus erythematosus. Although use in pediatric patients is reported since the 1990s, there are no systematic reviews describing treatment in children. Thalidomide has immunomodulatory and anti-tumor necrosis factor-α effects as well as antiangiogenic properties, making it useful for a broad spectrum of inflammatory disorders. Thalidomide is second-line treatment for aphthous stomatitis and chronic graft-versus-host disease in children and has been prescribed for many other conditions including actinic prurigo and epidermolysis bullosa pruriginosa. Systemic lupus erythematosus may be less responsive to thalidomide in children than adults. Peripheral neuropathy is observed in both idiosyncratic and dose-dependent relationships; children older than 12 years may be more susceptible to developing this adverse effect than younger patients. There are rare reports of thrombotic complications in children treated for nonmalignant indications. We review the mechanism of action and propose that thalidomide is an alternative treatment for patients who fail or have contraindications to anti-tumor necrosis factor-α biologics.

Epidermolysis bullosa pruriginosa showing good response to low-dose thalidomide - a report of two cases.

Epidermolysis bullosa pruriginosa is a rare distinctive variant of dystrophic epidermolysis bullosa characterized by intense pruritus, lichenified plaques in linear distribution, and anonychia. It is a difficult condition to treat and causes a great deal of distress. The present authors report two cases showing good response to low-dose thalidomide, with clinical and symptomatic improvement. The exact mechanism of action is not yet clear.

Epidermolysis bullosa pruriginosa triggered by scabies infestation.

Epidermolysis bullosa pruriginosa (EB-Pr) is an unusual variant of dystrophic EB. Potential genetic disease modifiers and metabolic factors have been investigated, but thus far no specific insight into this phenotype has emerged. We report an in-depth description of three patients diagnosed as having EB-Pr in whom this particular phenotype developed after scabies infestation and dramatically improved after full treatment. This short communication suggests that scabies infestation could be one of the important triggering factors for the development of the EB-Pr phenotype.

Epidermolisis bulosa distrófica pruriginosa dominante / Dominant dystrophic epidermolysis bullosa pruriginosa

La epidermólisis bulosa distrófica es un trastorno hereditario poco frecuente y clínicamente heterogéneo. Una variante clínica inusual es la epidermolisis bulosa pruriginosa (EBP), que se caracteriza por prurito intenso y lesiones similares a prurigo nodular o liquen simple crónico; y también por la fragilidad de la piel puede conducir a hipertrofia, liquenificación, nódulos y placas. Como en las otras formas de epidermólisis bulosa distrófica, las lesiones se localizan principalmente en extremidades; la patología molecular implica mutaciones en el gen que codifica la proteína fibrilar de anclaje, el colágeno tipo VII (COL7A1). Reportamos el caso de un paciente adulto sin antecedentes patológicos con compromiso cutáneo cuyo tratamiento resultó insatisfactorio, siendo pocos los aportes de la literatura en el manejo exitoso de esta patología.

Dystrophic epidermolysis bullosa is a rare, hereditary, clinically heterogeneous skin disorder. Epidermolysis bullosa pruriginosa is an unusual clinical variant characterized by severe pruritus and simplex lichenoid or nodular prurigo-like lesions; and also by the skin fragility that may lead to hypertrophic, lichenified nodules and plaques. Like other forms of dystrophic epidermolysis bullosa, lesions are located primarily in extremities; molecular pathology involves mutations in the gene encoding the anchoring fibril protein, type VII collagen (COL7A1). We report a case of a previously healthy male adult patient with skin lesions, whose treatment was unsatisfactory, with few contributions from the literature in the successful management of this disease.