Pathological Mechanisms Involved in Epidermolysis Bullosa Simplex: Current Knowledge and Therapeutic Perspectives.

Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of mechanobullous diseases characterized by non-scarring blisters and erosions on the skin and mucous membranes upon mechanical trauma. The simplex form (EBS) is characterized by recurrent blister formation within the basal layer of the epidermis. It most often results from dominant mutations in the genes coding for keratin (K) 5 or 14 proteins (KRT5 and KRT14). A disruptive mutation in KRT5 or KRT14 will not only structurally impair the cytoskeleton, but it will also activate a cascade of biochemical mechanisms contributing to EBS. Skin lesions are painful and disfiguring and have a significant impact on life quality. Several gene expression studies were accomplished on mouse model and human keratinocytes to define the gene expression signature of EBS. Several key genes associated with EBS were identified as specific immunological mediators, keratins, and cell junction components. These data deepened the understanding of the EBS pathophysiology and revealed important functional biological processes, particularly inflammation. This review emphasizes the three EBS subtypes caused by dominant mutations on either KRT5 or KRT14 (localized, intermediate, and severe). It aims to summarize current knowledge about the EBS expression profiling pattern and predicted molecular mechanisms involved and to outline progress in therapy.

Infantile anogenital digitate keratoses.

Infantile anogenital digitate keratoses (IADK) represent a distinct and under-recognized pediatric condition of the perianal area of infants, significantly more frequent in males than females. The average age of onset is 3.2 months, and it is self-remitting by 2 years of age. Perianal spiny keratoses resistant to usual topical therapies are the hallmark of IADK. We present a series of three cases of IADK seen at the dermatology clinic of the CHU Sainte-Justine to raise awareness on this pediatric condition, and to prevent invasive workup.

Multicenter Study of Long-Term Outcomes and Quality of Life in PHACE Syndrome after Age 10.

OBJECTIVE: To characterize long-term outcomes of PHACE syndrome. STUDY DESIGN: Multicenter study with cross-sectional interviews and chart review of individuals with definite PHACE syndrome ≥10 years of age. Data from charts were collected across multiple PHACE-related topics. Data not available in charts were collected from patients directly. Likert scales were used to assess the impact of specific findings. Patient-Reported Outcomes Measurement Information System (PROMIS) scales were used to assess quality of life domains. RESULTS: A total of 104/153 (68%) individuals contacted participated in the study at a median of 14 years of age (range 10-77 years). There were infantile hemangioma (IH) residua in 94.1%. Approximately one-half had received laser treatment for residual IH, and the majority (89.5%) of participants were satisfied or very satisfied with the appearance. Neurocognitive manifestations were common including headaches/migraines (72.1%), participant-reported learning differences (45.1%), and need for individualized education plans (39.4%). Cerebrovascular arteriopathy was present in 91.3%, with progression identified in 20/68 (29.4%) of those with available follow-up imaging reports. Among these, 6/68 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite the prevalence of cerebrovascular arteriopathy, the proportion of those with ischemic stroke was low (2/104; 1.9%). PROMIS global health scores were lower than population norms by at least 1 SD. CONCLUSIONS: PHACE syndrome is associated with long-term, mild to severe morbidities including IH residua, headaches, learning differences, and progressive arteriopathy. Primary and specialty follow-up care is critical for PHACE patients into adulthood.

The Impact of Traumatic Brain Injury on Binaural Processing in Young and Middle-Age Adults.

PURPOSE: This study examined the impact of traumatic brain injury (TBI) on self-perceived hearing and suprathreshold binaural processing in young and middle-age adults. METHOD: Ninety-three adults with normal hearing (thresholds ≤ 25 dB HL, 250-4000 Hz) participated in one of four groups: 38 young adults, 23 young adults with TBI, 16 middle-age adults, and 16 middle-age adults with TBI. Self-perceived hearing difficulty was measured via questionnaires. Binaural processing was measured using dichotic word recognition, the Listening in Spatialized Noise-Sentences Test (LiSN-S), and the 500-Hz masking level difference (MLD). For each participant, a composite binaural processing (CBP) score was calculated to obtain a global metric of binaural processing performance. The CBP was composed of six measures from the three behavioral tests, including the S0N0 and SπN0 thresholds from the 500-Hz MLD, the low- and high-cue speech recognition thresholds from the LiSN-S, and the free and directed recall ear advantages from the dichotic word test. RESULTS: The middle-age TBI group reported significantly greater degrees of self-perceived hearing difficulty than the other groups. On average, the middle-age TBI group performed poorer on the individual binaural processing tests; however, the differences were significant for the S0N0 and SπN0 MLD thresholds only. Results for the global metric of binaural processing revealed significantly poorer CBP scores for the middle-age TBI group compared to the other groups. CONCLUSIONS: Results demonstrate that both age and a positive history of TBI contributed to deficits in suprathreshold binaural processing. Middle-age adults with a history of TBI are at risk for experiencing presenescent deficits in suprathreshold binaural processing deficits, despite having clinically normal hearing.

An investigation of vascular anomalies centers' transition of care practices.

This study aims to examine transition of care (TOC) practices of multidisciplinary vascular anomalies centers (VACs). Thirty-seven of 71 VAC leaders to whom the survey was sent completed the questionnaire. TOC and transfer practices varied with only 16% of VACs having TOC programs. The most frequently cited barriers to developing a TOC program were lack of resources and difficulty finding expert adult providers.

Characterization of wound microbes in epidermolysis bullosa: A focus on Pseudomonas aeruginosa.

The most common bacteria isolated from wound cultures in patients recorded in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database (EBCCOD) are Staphylococcus aureus and Pseudomonas aeruginosa. Given the prevalence of P. aeruginosa in this patient population and prior research implicating P. aeruginosa's potential role in carcinogenesis, we sought to further analyze patients with recorded wound cultures positive for Pseudomonas aeruginosa in the EBCCOD. We provide a descriptive analysis of this subset of patients and highlight potential avenues for future longitudinal studies that may have significant implications in our wound care management for patients with epidermolysis bullosa.

Segmental stiff skin syndrome treated with secukinumab.

Segmental stiff skin syndrome is a rare fibrosing scleroderma-like disorder characterized by progressive indurations of the skin leading to joint contractures, decreased mobility, and pain. Treatment options are limited; we report a patient that showed improvement with anti-IL17 biologic therapy.

Multicenter retrospective review of pulsed dye laser in nonulcerated infantile hemangioma.

BACKGROUND/OBJECTIVES: We sought to describe the experience among members of the Hemangioma Investigator Group with pulsed dye laser (PDL) in the treatment of nonulcerated infantile hemangioma (IH) in pediatric patients in the pre- and post-beta-blocker era. METHODS: A multicenter retrospective cohort study was conducted in patients with nonulcerated IH treated with laser therapy. Patient demographics, IH characteristics, indications for/timing of laser therapy, as well as laser parameters were collected. Responses to laser therapy were evaluated using a visual analog scale (VAS). RESULTS: One hundred and seventeen patients with IH were treated with PDL. 18/117 (15.4%) had early intervention (defined as <12 months of life), and 99/117 (84.6%) had late intervention (≥12 months of life). In the late intervention group, 73.7% (73/99) had additional medical management of their IH. The mean age at PDL initiation for the late intervention group was 46.7 ± 35.3 months of life (range 12-172 months) with total number of treatments to maximal clearing of 4.2 ± 2.8 (range 1-17). Those who received propranolol prior to PDL received fewer sessions (1.1 fewer sessions, approaching significance [p = .056]).     On the VAS, there was a mean 85% overall improvement compared to baseline (range 18%-100%), with most improvement noted in erythema and/or telangiectasias. The incidence of adverse effects was 6/99 (6.1%). CONCLUSIONS: PDL is a useful tool in the treatment of IH, with notable improvement of telangiectasia and erythema and low risk of complications.   PDL is often introduced after the maximal proliferative phase.

Vascular anomalies in childhood: When to treat and when to refer.

Vascular anomalies are heterogeneous conditions that affect blood and/or lymphatic vessels. Affected children may experience pain, functional loss, infection, coagulopathies, and psychological challenges. Diagnosis and management often warrant an interdisciplinary approach. There are seven vascular anomalies clinics in Canada that offer interdisciplinary care. This practice point outlines a treatment approach for the most common paediatric vascular anomaly (hemangioma). It reviews indications for referral to a specialized clinic, with focus on complex vascular anomalies, specifically infantile hemangioma, which can pose complications.

Les anomalies vasculaires pendant l'enfance : quand traiter les patients et quand les diriger vers une ressource spécialisée.

Les anomalies vasculaires sont des affections hétérogènes qui touchent les vaisseaux sanguins ou lymphatiques. Les enfants atteints peuvent éprouver de la douleur ou une perte fonctionnelle, présenter une infection ou une coagulopathie ou être confrontés à des difficultés psychologiques. Le diagnostic et la prise en charge exigent souvent une approche interdisciplinaire. Sept cliniques d'anomalies vasculaires au Canada offrent des soins interdisciplinaires. Le présent point de pratique propose une approche thérapeutique des anomalies vasculaires pédiatriques les plus fréquentes (hémangiomes). On y passe en revue les indications de diriger les patients vers une clinique spécialisée, en s'attardant sur les anomalies vasculaires complexes, et notamment les hémangiomes infantiles, qui peuvent provoquer des complications.

Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic.

BACKGROUND: Lymphedema is due to dysfunction of the lymphatic system. It can be primary or secondary. Pediatric lymphedema is more often primary and is a chronic disease with a heavy burden on quality of life. METHODS: Medical records of patients under 18 years of age referred between 1996 and 2021 to the specialized lymphedema clinic at the Sainte-Justine University Hospital Center were reviewed. Demographic data, sex, age at presentation, location of the lymphedema, clinical features, genetic testing, symptoms, complications, investigations, and treatment were collected. RESULTS: Of 180 referred patients, lymphedema was confirmed in 151, and 137 were primary lymphedema. Median age of apparition of primary lymphedema was 7.00 years and was significantly lower in boys than in girls. Primary congenital lymphedema was more frequent in boys (51.0%, 27.3% in girls, P = .007), and onset of primary lymphedema during adolescence was more frequent in girls (53.4%, 25.0% in boys, P = .001). Lower limbs were the most impacted (88.3%). Sixty patients had genetic testing, and 38 (63.3%) of them were discovered to have a pertinent genetic mutation. The most common mutated gene was the FLT4 gene (in 9 patients). Seven patients (5.1%) had associated extensive/central lymphatic malformation and 24 (17.6%) had a polymalformative syndrome/syndromic lymphedema. CONCLUSIONS: Pediatric lymphedema is more frequent in girls, usually involves lower limb, and is most often sporadic, but often associated with a genetic mutation, and genetic testing should be performed.

Allele-Specific Inactivation of an Autosomal Dominant Epidermolysis Bullosa Simplex Mutation Using CRISPR-Cas9.

Epidermolysis bullosa simplex (EBS) is a rare mechanobullous disease caused by dominant-negative mutations in either keratin 5 (KRT5) or keratin 14 (KRT14) genes. Until now, there is no cure for EBS and the care is primarily palliative. The discovery of the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system raised hope for the treatment of EBS and many other autosomal dominant diseases by mutant allele-specific gene disruption. In this study, we aim to disrupt the mutant allele for the heterozygous EBS pathogenic variation c.449T>C (p.Leu150Pro) within KRT5. This mutation generates, naturally, a novel protospacer-adjacent motif for the endonuclease Streptococcus pyogenes Cas9. Thus, we designed a single-guide RNA that guides the Cas9 to introduce a DNA cleavage of the mutant allele in patient's keratinocytes. Then, transfected cells were single-cell cloned and analyzed by deep sequencing. The expression of KRT5 and KRT14 was quantified, and the keratin intermediate filament stability was assessed. Results showed successful stringent mutant allele-specific knockout. An absence of synthesis of mutant transcript was further confirmed indicating permanent mutant allele-specific inactivation. Edited EBS patient keratinocytes produced a lower amount of K5 and K14 proteins compared with nonedited EBS cells, and no disturbance of cellular properties was observed.

Defining vascular anomaly phenotypes in children based on a systematic literature search: A critical step in developing a single severity score for interventional clinical trials.

INTRODUCTION: Genetically targeted drugs in vascular anomalies (VA) are used despite the absence of a validated severity score. The aim of this study was to evaluate the feasibility of grouping phenotypic VA clinical characteristics into a single severity score. METHODS: A systematic literature review including children treated with sirolimus accompanied by a detailed description of phenotype and management was conducted. Demographic data and clinical features were extracted to define distinct categories of phenotypes. RESULTS: Children with VA display two main phenotypes regardless of VA subtype, which may overlap. A systemic phenotype results from direct invasion and compression of vital structures generally leading to hospitalization and aggressive management in infancy. A functional phenotype is associated with chronic pain and disability manifesting mainly during early adolescence and managed in the outpatient setting. CONCLUSION: The two distinct phenotypes described could be the basis for developing a unified scoring system for VA severity assessment.

Generation of two induced pluripotent stem cell lines (UQACi002-A and UQACi005-A) from two patients with KRT14 epidermolysis bullosa simplex mutations.

More than 107 pathogenic variations were identified in Keratin 14 gene (KRT14) in patients affected by epidermolysis bullosa simplex (EBS), a rare skin disease with still no curative treatment. Disease models as human induced pluripotent stem cells (hiPSCs) are promising tool for further advance the knowledge about this disorder and accelerate therapies development. Here, two hiPSC lines were reprogrammed from skin fibroblasts of two EBS patients carrying mutations within KRT14 by using CytoTune®Sendai virus. These iPSCs display pluripotent cell morphology, pluripotent markers expression, and the capability to differentiate into the three germ layers.

Generation of three induced pluripotent stem cell lines (UQACi003-A, UQACi004-A, and UQACi006-A) from three patients with KRT5 epidermolysis bullosa simplex mutations.

Heterozygous mutations within Keratin 5 (KRT5) are common genetic causes of epidermolysis bullosa simplex (EBS), a skin fragility disorder characterized by blisters, which appear after minor trauma. Using CytoTune®Sendai virus, we generated three human induced pluripotent stem cell (iPSC) lines from three EBS patients carrying respectively the single heterozygous mutations in KRT5, c.449 T > C, c.980 T > C, and c.608 T > C. All lines display normal karyotype, expressed high levels of pluripotent markers, and can differentiate into derivatives of the three germ layers. These iPSCs are helpful for a better understanding of the EBS pathogenesis and developing novel therapeutic approaches.