ABSTRACT
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.
Subject(s)
Keratosis , Humans , Male , Infant , Female , Keratosis/pathology , Keratosis/drug therapy , Anus Diseases/pathology , Anus Diseases/drug therapy , Anal Canal/abnormalities , Anal Canal/pathologyABSTRACT
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.
Subject(s)
Aortic Coarctation , Eye Abnormalities , Neurocutaneous Syndromes , Humans , Infant , Child , Adolescent , Young Adult , Adult , Middle Aged , Aged , Neurocutaneous Syndromes/complications , Eye Abnormalities/complications , Aortic Coarctation/complications , Quality of Life , Cross-Sectional Studies , HeadacheABSTRACT
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.
ABSTRACT
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.
Subject(s)
Patient Transfer , Vascular Malformations , Adult , Humans , Surveys and Questionnaires , Vascular Malformations/diagnosis , Vascular Malformations/therapyABSTRACT
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.
Subject(s)
Epidermolysis Bullosa , Pseudomonas aeruginosa , Humans , Epidermolysis Bullosa/complications , Epidermolysis Bullosa/microbiologyABSTRACT
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.
Subject(s)
Contracture , Skin Diseases, Genetic , Humans , Skin , Skin Diseases, Genetic/drug therapy , Contracture/drug therapyABSTRACT
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.
Subject(s)
Hemangioma, Capillary , Hemangioma , Lasers, Dye , Humans , Child , Retrospective Studies , Lasers, Dye/therapeutic use , Hemangioma, Capillary/radiotherapy , Hemangioma, Capillary/surgery , Hemangioma/radiotherapy , Hemangioma/surgery , Hemangioma/etiology , Adrenergic beta-Antagonists , Treatment OutcomeABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Epidermolysis Bullosa Simplex , Alleles , CRISPR-Cas Systems/genetics , Epidermolysis Bullosa Simplex/genetics , Epidermolysis Bullosa Simplex/metabolism , Epidermolysis Bullosa Simplex/pathology , Gene Editing , Humans , Mutation , PhenotypeABSTRACT
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.
Subject(s)
Lymphedema , Quality of Life , Adolescent , Child , Female , Genetic Testing , Humans , Lower Extremity , Lymphedema/epidemiology , Lymphedema/genetics , Male , Referral and ConsultationABSTRACT
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.
Subject(s)
Vascular Malformations , Humans , Phenotype , Sirolimus/therapeutic use , Vascular Malformations/complications , Vascular Malformations/genetics , Vascular Malformations/therapyABSTRACT
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.
Subject(s)
Epidermolysis Bullosa Simplex , Induced Pluripotent Stem Cells , Epidermolysis Bullosa Simplex/genetics , Epidermolysis Bullosa Simplex/pathology , Humans , Induced Pluripotent Stem Cells/pathology , Keratin-14/genetics , Keratin-5/genetics , Mutation , PhenotypeABSTRACT
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.
Subject(s)
Epidermolysis Bullosa Simplex , Induced Pluripotent Stem Cells , Epidermolysis Bullosa Simplex/genetics , Epidermolysis Bullosa Simplex/pathology , Heterozygote , Humans , Induced Pluripotent Stem Cells/metabolism , Keratin-5/genetics , Mutation/geneticsABSTRACT
BACKGROUND: Cutaneous hematologic malignancies are rare in children, and the literature about them is still sparse. OBJECTIVE: The purpose of our study was to report our experience with pediatric cases of cutaneous hematologic disorders and describe their clinical and histological features. METHODS: Data were retrospectively collected from the histopathologic database of the CHU Sainte-Justine, University of Montreal, Montreal, Canada. All patients up to 18 years of age with a diagnosis of a primary cutaneous lymphoma (including lymphomatoid papulosis), secondary cutaneous lymphoma or cutaneous manifestations of leukemia, followed from 1980 to 2019 at our center were reviewed. RESULTS: Thirty-six patients were included. Age at presentation ranged from birth to 18 years of age (mean 7.83 ± 5.16; median 7.0). Ten different hematologic disorders were identified according to the WHO-EORTC classifications: lymphomatoid papulosis (10 cases), mycosis fungoides (6 cases), anaplastic large cell lymphoma (4 cases), pre-B acute lymphoid leukemia (5 cases), primary cutaneous marginal zone B-cell lymphoma (4 cases), primary cutaneous CD4+medium T-cell lymphoproliferative disorder (1 case), extranodal NK/T-cell lymphoma (1 case), hydroa vacciniforme-like lymphoproliferative disorder (1 case), B-cell lymphoblastic lymphoma (1 case) and acute myeloid leukemia (3 cases). CONCLUSION: The most common subtype of cutaneous hematologic disease in our single institution study was lymphomatoid papulosis (type A and type C), followed by mycosis fungoides. Recognition of this large clinical and histological spectrum by dermatologists is important because diagnosis is often established by biopsy of skin lesions, even in secondary cutaneous cases. Moreover, the clinicopathological correlation is of utmost importance for the final diagnosis of those pathologies.
Subject(s)
Hematologic Diseases , Leukemia , Lymphoma, B-Cell , Lymphoma, T-Cell, Cutaneous , Lymphoma , Lymphomatoid Papulosis , Mycosis Fungoides , Skin Neoplasms , Adolescent , Child , Hematologic Diseases/complications , Humans , Leukemia/complications , Lymphoma/complications , Lymphoma/diagnosis , Lymphoma, B-Cell/complications , Lymphoma, T-Cell, Cutaneous/pathology , Lymphomatoid Papulosis/diagnosis , Mycosis Fungoides/diagnosis , Mycosis Fungoides/pathology , Retrospective Studies , Skin Neoplasms/pathologyABSTRACT
PRECLINICAL STUDIES: have demonstrated a complex cross-talk between Notch and estrogen signaling in ERα-positive breast cancer. Gamma-secretase inhibitors (GSIs) are investigational agents that block the cleavage and activation of Notch receptors. In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. However, results of a clinical trial of a GSI-endocrine therapy combination in the metastatic setting have not been published to date, nor had the safety of such combinations been investigated with longer term treatment. We conducted a phase 1b dose escalation trial (NCT01149356) of GSI RO4929097 with exemestane in patients with ERα+, metastatic breast cancer (MBC) STUDY OBJECTIVES: To determine the safety, tolerability and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of RO4929097 when administered in combination with exemestane in patients with estrogen receptor positive metastatic breast cancer RESULTS: We enrolled 15 patients with MBC. Of 14 evaluable patients, one had a partial response, 6 had stable disease and 7 progressive disease. Twenty % of patients had stable disease for ≥ 6 months. Common toxicities included nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%) and cough (33.0%). Grade 3 toxicities were uncommon, and included hypophosphatemia (13%) and rash (6.3%). Rash was the only DLT observed at 140 mg/d. Results suggest a possible recommended phase 2 dose of 90 mg/d. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination CONCLUSIONS: Our data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer.