DSpace Repository :: Browsing by Author "Palisson, Francis"

Browsing by Author "Palisson, Francis"

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Case Report: Crown Resorption in a Patient With Junctional Epidermolysis Bullosa and Amelogenesis Imperfecta With LAMB3 Gene Mutations
(2021) Urzúa, Blanca; Krämer, Susanne; Morales-Bozo, Irene; Camacho, Claudia; Yubero, María Joao; Palisson, Francis; Fuentes, Ignacia; Ortega-Pinto, Ana
Background: Epidermolysis bullosa (EB) corresponds to a series of conditions characterized by extreme fragility of the skin and/or mucous membranes. Of the four main types of EB, junctional EB (JEB) is the most associated with alterations in the teeth. The purposes of this study were to determine the clinical, histopathological, and ultrastructural characteristics of teeth with amelogenesis imperfecta (AI) in a patient with JEB, and compare them with control teeth, and correlate the findings with the mutations present in the patient. Case Report: The study was conducted on a 10-year-old patient with JEB carrier of two recessive mutations in the LAMB3 gene and absence of the laminin-332 protein (LM-332), determined by immunofluorescence on a skin biopsy. The patient presents hypoplastic AI with very thin and yellow-brown colored enamel. Extraction of two permanent molars was performed due to pain and soft tissue covering the crown, resembling pulp polyp or hyperplastic gingiva. Light and scanning electron microscopy (SEM) revealed very thin enamel varying from complete absence to 60 μm, absence of normal prismatic structure, and presence of a cross-banding with a laminated appearance. The histopathological study revealed granulation tissue causing external crown resorption. Conclusion: Although coronary resorption has been reported in patients with syndromic and non-syndromic AI, this is the first clinicopathological report of coronary resorption in partially erupted teeth in patients with JEB with mutations in the LAMB3 gene and hypoplastic AI. In patients with this condition, the presence of partially erupted teeth with soft tissue covering part of the crown, without a periodontal pocket, and with a radiographic image of partial coronal radiolucency should lead to suspicion of external coronary resorption.
Cells from discarded dressings diferentiate chronic from acute wounds in patients with Epidermolysis Bullosa
(2020) Fuentes, Ignacia; Guttmann‑Gruber, Christina; Tockner, Birgit; Diem, Anja; Klausegger, Alfred; Cofré‑Araneda, Glenda; Figuera, Olga; Hidalgo, Yessia; Morandé, Pilar; Palisson, Francis; Rebolledo-Jaramillo, Boris; Yubero, María Joao; Cho, Raymond J.; Rishel, Heather I.; Marinkovich, M. Peter; Teng, Joyce M. C.; Webster, Timothy G.; Prisco, Marco; Eraso, Luis H.; Hofbauer, Josefina Piñon; South, Andrew P.
Impaired wound healing complicates a wide range of diseases and represents a major cost to healthcare systems. Here we describe the use of discarded wound dressings as a novel, cost effective, accessible, and non-invasive method of isolating viable human cells present at the site of skin wounds. By analyzing 133 discarded wound dressings from 51 patients with the inherited skin-blistering disease epidermolysis bullosa (EB), we show that large numbers of cells, often in excess of 100 million per day, continually infiltrate wound dressings. We show, that the method is able to differentiate chronic from acute wounds, identifying significant increases in granulocytes in chronic wounds, and we show that patients with the junctional form of EB have significantly more cells infiltrating their wounds compared with patients with recessive dystrophic EB. Finally, we identify subsets of granulocytes and T lymphocytes present in all wounds paving the way for single cell profiling of innate and adaptive immune cells with relevance to wound pathologies. In summary, our study delineates findings in EB that have potential relevance for all chronic wounds, and presents a method of cellular isolation that has wide reaching clinical application.
Collagen VII maintains proteostasis in dermal fibroblasts by scaffolding TANGO1 cargo
(2022) Cao, Qingqing; Tartaglia, Grace; Alexander, Michael; Park, Pyung Hung; Poojan, Shiv; Farshchian, Mehdi; Fuentes, Ignacia; Chen, Mei; McGrath, John A.; Palisson, Francis; Salas -Alanis, Julio; South, Andrew P.
Lack of type VII collagen (C7) disrupts cellular proteostasis yet the mechanism remains undescribed. By studying the relationship between C7 and the extracellular matrix (ECM)-associated proteins thrombospondin-1 (TSP1), type XII collagen (C12) and tissue transglutaminase (TGM2) in primary human dermal fibroblasts from multiple donors with or without the genetic disease recessive dystrophic epidermolysis bullosa (RDEB) (n=31), we demonstrate that secretion of each of these proteins is increased in the presence of C7. In dermal fibroblasts isolated from patients with RDEB, where C7 is absent or defective, association with the COPII outer coat protein SEC31 and ultimately secretion of each of these ECM-associated proteins is reduced and intracellular levels are increased. In RDEB fibroblasts, overall collagen secretion (as determined by the levels of hydroxyproline in the media) is unchanged while traffic from the ER to Golgi of TSP1, C12 and TGM2 occurs in a type I collagen (C1) dependent manner. In normal fibroblasts association of TSP1, C12 and TGM2 with the ER exit site transmembrane protein Transport ANd Golgi Organization-1 (TANGO1) as determined by proximity ligation assays, requires C7. In the absence of wild-type C7, or when ECM-associated proteins are overexpressed, C1 proximity and intracellular levels increase resulting in elevated cellular stress responses and elevated TGFβ signaling. Collectively, these data demonstrate a role for C7 in loading COPII vesicle cargo and provides a mechanism for disrupted proteostasis, elevated cellular stress and increased TGFβ signaling in patients with RDEB. Furthermore, our data point to a threshold of cargo loading that can be exceeded with increased protein levels leading to pathological outcomes in otherwise normal cells.
Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility
(2020) Has, C.; Bauer, J. W.; Bodemer, C.; Bolling, M. C.; Bruckner-Tuderman, L.; Diem, A.; Fine, J-D; Heagerty, A.; Hovnanian, A.; Marinkovich, M.P.; Martinez, A.E.; Martinez, J.A.; Moss, C.; Murrell, D.F.; Palisson, Francis; Schwieger-Briel, A.; Sprecher, E.; Tamai, K.; Uitto, J.; Woodley, D.T.; Zambruno, G.; Mellerio, J.E.
Background: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). Objectives: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. Methods: This was a consensus expert review. Results: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Conclusions: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic? Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add? We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care
De Novo COL7A1 mutation in a patient with trisomy 21: coexistence of dystrophic epidermolysis bullosa and Down syndrome
(John Wiley & Sons, 2012) Catalán, Javiera; Rodríguez, Fernando; Yubero, María; Palisson, Francis; Gana, María; Krämer, Susanne; Repetto, Gabriela
BACKGROUND: Down syndrome (DS) is the most common autosomal chromosomal disorder. Epidermolysis bullosa (EB) is a rare genodermatosis characterized by skin and mucous membrane fragility, with formation of blisters and erosions after minor trauma. Dystrophic EB (DEB) is inherited as an autosomal dominant (DDEB) or recessive (RDEB) trait. Both forms are caused by mutations in COL7A1, the gene coding for the type VII collagen. We report a patient affected by both conditions: DS and DDEB. METHODS: A patient with DS developed generalized blisters at the age of three months. Cytogenetic study was performed to confirm DS. Skin biopsies were examined with immunohistochemical and electron microscopy techniques to determine EB subtype. Genomic DNA was extracted from peripheral blood samples. COL7A1 mutations were screened by heteroduplex analysis using conformation-sensitive gel electrophoresis and sequencing. RESULTS: Karyotype analysis revealed trisomy 21. Histological study agreed with a DEB diagnosis. Mutational analysis showed a heterozygous c.6127G>T mutation in COL7A1, which is compatible with DDEB. Parental study suggests that c.6127G>T arises as a de novo mutation. CONCLUSIONS: This report demonstrates that EB can be associated with other common conditions and reports the case of a patient who suffered two de novo independent genetic conditions. It also contributes to expanding the knowledge and database of clinical and molecular aspects of DDEB.
Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy
(2019) Schwieger-Briel, A.; Fuentes, Ignacia; Castiglia, D.; Barbato, A.; Greutmann, M.; Leppert, J.; Duchatelet, S.; Hovnanian, A.; Burattini, S.; Yubero, María; Ibañez-Arenas, Rodrigo; Rebolledo-Jaramillo, Boris; Gräni, C.; Ott, H.; Theiler, M.; Weibel, L.; Paller, A.S.; Zambruno, G.; Fischer, J.; Palisson, Francis; Has, C.
Inherited epidermolysis bullosa (EB) comprises rare heterogeneous disorders characterized by cutaneous and mucosal fragility. Most of the 20 proteins affected have structural functions. Recently, a previously undescribed type of EB simplex (EBS), caused by gain-of-function mutations in KLHL24, encoding KLHL24 has been identified (He et al., 2016; Lin et al., 2016). This protein seems to be involved in protein ubiquitination. Patients carrying monoallelic mutations in the translation initiation codon of KLHL24 have a characteristic clinical phenotype, showing skin defects and blistering at birth and unusual stellate scarring, skin fragility, and whorled or macular hyperpigmentation or hypopigmentation in childhood (Figure 1a–e).
Epidermolysis bullosa simplex-generalized severe due to p.Glu477Lys mutation in keratin 5: a genotype-phenotype correlation with in silico modeling analysis
(2019) Lalor, Leah; Titeux, Matthias; Palisson, Francis; Fuentes, Ignacia; Yubero, María; Tasanen, Kaisa; Huilaja, Laura; Has, Cristina; Tadini, Gianluca; Haggstrom, Anita N.; Hovnanian, Alain; Lucky, Anne W.
Background/Objectives: Epidermolysis bullosa is a group of diseases caused by mutations in skin structural proteins. Availability of genetic sequencing makes identification of causative mutations easier, and genotype‐phenotype description and correlation are important. We describe six patients with a keratin 5 mutation resulting in a glutamic acid to lysine substitution at position 477 (p.Glu477Lys) who have a distinctive, severe and sometimes fatal phenotype. We also perform in silico modeling to show protein structural changes resulting in instability. Methods: In this case series, we collected clinical data from six patients with this mutation identified from their national or local epidermolysis bullosa databases. We performed in silico modeling of the keratin 5‐keratin 14 coil 2B complex using CCBuilder and rendered with Pymol (Schrodinger, LLC, New York, NY). Results: Features include aplasia cutis congenita, generalized blistering, palmoplantar keratoderma, onychodystrophy, airway and developmental abnormalities, and a distinctive reticulated skin pattern. Our in silico model of the keratin 5 p.Glu477Lys mutation predicts conformational change and modification of the surface charge of the keratin heterodimer, severely impairing filament stability. Conclusions: Early recognition of the features of this genotype will improve care. In silico analysis of mutated keratin structures provides useful insights into structural instability.
Epithelial HMGB1 Delays Skin Wound Healing and Drives Tumor Initiation by Priming Neutrophils for NET Formation
(2019) Hoste, Esther; Maueröder, Christian; Hove, Lisette van; Catrysse, Leen; Vikkula, Hanna-Kaiza; Sze, Mozes; Maes, Bastiaan; Karjosukarso, Dyah; Martens, Liesbet; Goncalves, Amanda; Parthoens, Eef; Roelandt, Ria; Declercq, Wim; Fuentes, Ignacia; Palisson, Francis; Gonzalez, Sergio; Salas-Alanis, Julio C.; Boon, Louis; Huebener, Peter; Mulder, Klaas Willem; Ravichandran, Kodi; Saeys, Yvan; Schwabe, Robert Felix; Loo, Geert van
Regenerative responses predispose tissues to tumor formation by largely unknown mechanisms. High-mobility group box 1 (HMGB1) is a dangerassociated molecular pattern contributing to inflammatory pathologies. We show that HMGB1 derived from keratinocytes, but not myeloid cells, delays cutaneous wound healing and drives tumor formation. In wounds of mice lacking HMGB1 selectively in keratinocytes, a marked reduction in neutrophil extracellular trap (NET) formation is observed. Pharmacological targeting of HMGB1 or NETs prevents skin tumorigenesis and accelerates wound regeneration. HMGB1-dependent NET formation and skin tumorigenesis is orchestrated by tumor necrosis factor (TNF) and requires RIPK1 kinase activity. NETs are present in the microenvironment of keratinocyte-derived tumors in mice and lesional and tumor skin of patients suffering from recessive dystrophic epidermolysis bullosa, a disease in which skin blistering predisposes to tumorigenesis. We conclude that tumorigenicity of the wound microenvironment depends on epithelial-derived HMGB1 regulating NET formation, thereby establishing a mechanism linking reparative inflammation to tumor initiation.
Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.
(2019) Atanasova, Velina S.; Pourreyron, Celine; Farshchian, Mehdi; Christian A., Brown IV; Watt, Stephen A.; Wright, Sheila; Warkala, Michael; Guttmann-Gruber, Christina; Piñón Hofbauer, Josefina; Fuentes, Ignacia; Prisco, Marco; Rashidghamat, Elham; Has, Cristina; Palisson, Francis; Hovnanian, Alain; McGrath, John A.; Mellerio, Jemima E.; Bauer, Johann; South, Andrew P.
Purpose: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo. Results: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. Conclusions: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC. Translational Relevance Collectively, our data support a clinical trial of rigosertib for treatment of recessive dystrophic epidermolysis bullosa–associated squamous cell carcinoma, an inherently aggressive subtype of squamous cell carcinoma with extremely low 5-year survival. Currently, there are no effective treatments for this devastating cancer, and often times, initial squamous cell carcinoma will recur and readily metastasize; any effective systemic therapy that reduces tumor burden will improve quality of life in this patient population.
Life-threatening complications following orthognathic surgery in a patient with undiagnosed hereditary angioedema
(Elsevier, 2013) Cifuentes, Julio; Palisson, Francis; Valladares, Salvador; Jerez, Daniel
As described in the literature, hereditary angioedema (HAE) is an autosomal dominant disease that presents with recurrent events of angioedema caused by a) deficiency or b) functional alteration of the plasma protein C1 inhibitor (C1-inh); this enzyme is involved in the regulation of the complement, kallikrein-kinin, fibrinolytic, and coagulation systems. HAE is characterized by episodes of edema in the larynx, facial structures and tissues, gastrointestinal tract, or extremities. Laryngeal edema has been reported to occur predominantly after oral surgery. We describe the case of an 18-year-old Asiatic male, reporting an unremarkable medical history, who experienced complications following orthognathic surgery. Thirty hours post-op, the patient developed severe facial, pharyngeal, and glottic edema that compromised the airway, and an emergency tracheal intubation was performed. He was tested for C1-inh plasma levels, showing a sub-normal concentration and indicating a diagnosis of HAE. The patient received fresh-frozen plasma and improved throughout the day as his condition stabilized. Several cases of HAE following oral surgery have been reported, but, to the authors' knowledge, this is the first case reported following orthognathic surgery. This patient's treatment will be described, and a literature review of the disease and management methods will be provided.
Longitudinal study of wound healing status and bacterial colonisation of Staphylococcus aureus and Corynebacterium diphtheriae in epidermolysis bullosa patients
(2022) Fuentes, Ignacia; Joao, María; Morandé, Pilar; Varela, Carmen; Orostica, Karen; Acevedo, Francisco; Rebolledo, Boris; Arancibia, Esteban; Porte, Lorena; Palisson, Francis
Epidermolysis bullosa (EB) is an inherited disorder characterised by skin fragility and the appearance of blisters and wounds. Patient wounds are often colonised or infected with bacteria, leading to impaired healing, pain and high risk of death by sepsis. Little is known about the impact of bacterial composition and susceptibility in wound resolution, and there is a need for longitudinal studies to understand healing outcomes with different types of bacterial colonisation. A prospective longitudinal study of 70 wounds from 15 severe EB patients (Junctional and Recessive Dystrophic EB) from Chile. Wounds were selected independently of their infected status. Wound cultures, including bacterial species identification, composition and Staphylococcus aureus (SA) antibiotic susceptibility were registered. Wounds were separated into categories according to their healing capacity, recognising chronic, and healing wounds. Hundred-one of the 102 wound cultures were positive for bacterial growth. From these, 100 were SA-positive; 31 were resistant to Ciprofloxacin (31%) and only seven were methicillin-resistant SA (7%). Ciprofloxacin-resistant SA was found significantly predominant in chronic wounds (**P < .01). Interestingly, atoxigenic Corynebacterium diphtheriae (CD) was identified and found to be the second most abundant recovered bacteria (31/101), present almost always in combination with SA (30/31). CD was only found in Recessive Dystrophic EB patients and not related to wound chronicity. Other less frequent bacterial species found included Pseudomonas aeruginosa, Streptococus spp. and Proteus spp. Infection was negatively associated with the healing status of wounds.
Maintenance of chronicity signatures in fibroblasts isolated from recessive dystrophic epidermolysis bullosa chronic wound dressings under culture conditions
(2023) De Gregorio, Cristian; Catalán, Evelyng; Garrido, Gabriel; Morandé, Pilar; Castillo, Jimena; Muñoz, Catalina; Cofré, Glenda; Huang, Ya-Lin; Cuadra, Bárbara; Murgas, Paola; Calvo, Margarita; Altermatt, Fernando; Joao, María; Palisson, Francis; South, Andrew; Ezquer, Marcelo; Ezquer, Marcelo; Fuentes, Ignacia
Background: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare inherited skin disease caused by variants in the COL7A1 gene, coding for type VII collagen (C7), an important component of anchoring fibrils in the basement membrane of the epidermis. RDEB patients suffer from skin fragility starting with blister formation and evolving into chronic wounds, inflammation and skin fibrosis, with a high risk of developing aggressive skin carcinomas. Restricted therapeutic options are limited by the lack of in vitro models of defective wound healing in RDEB patients. Results: In order to explore a more efficient, non-invasive in vitro model for RDEB studies, we obtained patient fibroblasts derived from discarded dressings) and examined their phenotypic features compared with fibroblasts derived from non-injured skin of RDEB and healthy-donor skin biopsies. Our results demonstrate that fibroblasts derived from RDEB chronic wounds (RDEB-CW) displayed characteristics of senescent cells, increased myofibroblast differentiation, and augmented levels of TGF-β1 signaling components compared to fibroblasts derived from RDEB acute wounds and unaffected RDEB skin as well as skin from healthy-donors. Furthermore, RDEB-CW fibroblasts exhibited an increased pattern of inflammatory cytokine secretion (IL-1β and IL-6) when compared with RDEB and control fibroblasts. Interestingly, these aberrant patterns were found specifically in RDEB-CW fibroblasts independent of the culturing method, since fibroblasts obtained from dressing of acute wounds displayed a phenotype more similar to fibroblasts obtained from RDEB normal skin biopsies. Conclusions: Our results show that in vitro cultured RDEB-CW fibroblasts maintain distinctive cellular and molecular characteristics resembling the inflammatory and fibrotic microenvironment observed in RDEB patients’ chronic wounds. This work describes a novel, non-invasive and painless strategy to obtain human fibroblasts chronically subjected to an inflammatory and fibrotic environment, supporting their use as an accessible model for in vitro studies of RDEB wound healing pathogenesis. As such, this approach is well suited to testing new therapeutic strategies under controlled laboratory conditions.
Multidisciplinary care of epidermolysis bullosa during the COVID-19 pandemic-Consensus: Recommendations by an international panel of experts
(2020) Murrell, Dedee F; Lucky, Anne W; Salas-Alanis, Julio C; Woodley, David T; Palisson, Francis; Natsuga, Ken; Nikolic, Milos; Ramirez-Quizon, Mae; Paller, Amy S; Lara-Corrales, Irene; Barzegar, Mohammadreza Amir; Sprecher, Eli; Has, Cristina; Laimer, Martin; Bruckner, Anna L; Bilgic, Asli; Nanda, Arti; Purvis, Diana; Hovnanian, Alain; Murat-Sušić, Slobodna; Bauer, Johannes; Kern, Johannes S; Bodemer, Christine; Martin, Linda K; Mellerio, Jemima; Kowaleski, Cezary; Robertson, Susan J; Bruckner-Tuderman, Leena; Pope, Elena; Marinkovich, M Peter; Tang, Jean Y; Su, John; Uitto, Jouni; Eichenfield, Lawrence F; Teng, Joyce; Aan Koh, Mark Jean; Lee, Sang Eun; Khuu, Phuong; Rishel, Heather I; Sommerlund, Mette; Wiss, Karen; Hsu, Chao-Kai; Chiu, Tor Wo; Martinez, Anna E
Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis
(2010) Lin, Ming-Wei; Lee, Ding-Dar; Liu, Tze-Tze; Lin, Yong-Feng; Chen, Shang-Yi; Huang, Chih-Cheng; Weng, Hui-Ying; Liu, Yu-Fen; Tanaka, Akio; Arita, Ken; Lai-Cheong, Joey; Palisson, Francis; Chang, Yun-Ting; Wong, Chu-Kwan; Matsuura, Isao; McGrath, John A; Tsai, Shih-Feng
Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superficial dermis. The disease is relatively common in Southeast Asia and South America. Autosomal dominant PCA has been mapped earlier to 5p13.1–q11.2 and two pathogenic missense mutations in the OSMR gene, which encodes the interleukin-6 family cytokine receptor oncostatin M receptor beta (OSMRb), were reported. Here, we investigated 29 Taiwanese pedigrees with PCA and found that 10 had heterozygous missense mutations in OSMR: p.D647V (one family), p.P694L (six families), and p.K697T (three families). The mutation p.P694L was associated with the same haplotype in five of six families and also detected in two sporadic cases of PCA. Of the other 19 pedigrees that lacked OSMR pathology, 8 mapped to the same locus on chromosome 5, which also contains the genes for 3 other interleukin-6 family cytokine receptors, including interleukin-31 receptor A (IL31RA), which can form a heterodimeric receptor with OSMRb through interleukin-31 signaling. In one family, we identified a point mutation in the IL31RA gene, c.1562C4T that results in a missense mutation, p.S521F, which is also sited within a fibronectin type III-like repeat domain as observed in the OSMR mutations. PCA is a genetically heterogeneous disorder but our study shows that it can be caused by mutations in two biologically associated cytokine receptor genes located on chromosome 5. The identification of OSMR and IL31RA gene pathology provides an explanation of the high prevalence of PCA in Taiwan as well as new insight into disease pathophysiology
Outcomes and Predictors for Re-stenosis of Esophageal Stricture in Epidermolysis Bullosa: A Multicenter Cohort Study
(2020-09) Pope, Elena; Mansour, Mark; Berseneva, María; Liy-Wong, Carmen; Salas, Julio; Fuentes, Ignacia; Yubero, Maria Joao; Palisson, Francis; Martinez, Anna; Mellerio, Jemima; Lara-Corrales, Irene; Yang, Anes; Murrell, Dedee; Torres-Pradilla, Mauricio; Lucky, Anne
Background: Esophageal strictures are the common gastrointestinal complications in patients with epidermolysis bullosa (EB) requiring dilation. There is limited information on the best type of intervention, outcomes, and predictors for re-stenosis. Objectives: We aimed to investigate the frequency, clinical presentation of esophageal strictures in EB patients, and to ascertain the predictors of re-stenosis. Methods: We conducted a retrospective, multicenter cohort study involving 7 specialized, international EB centers on patients who were 0 to 50 years of age. Descriptive statistics and hazard risks for re-stenosis were calculated. Results: We identified 125 patients with 497 esophageal stricture episodes over a mean period of observation of 17 (standard deviation [SD]¼ 11.91) years. Dilations were attempted in 90.74% of episodes, using guided fluoroscopy 45.23%, retrograde endoscopy 33.04%, and antegrade endoscopy 19.07%. Successful dilation was accomplished in 99.33% of attempts. Patients experienced a median of 2 (interquartile range [IQR]: 1–7) stricture episodes with a median interval between dilations of 7 (IQR: 4–12) months. Predictors for re-stenosis included: number of strictures (2 vs 1 stricture:x2¼ 4.293,P¼ 0.038, hazard ratio [HR]¼ 1.294 (95% confidence interval [CI]: 1.014–1.652 and 3 vs 1 stricture:x2¼ 7.986, P¼ 0.005, HR¼ 1.785 [95% CI: 1.194, 2.667]) and a long (1 cm) segment stricture (x2¼ 4.599, P¼ 0.032, HR¼ 1.347 (95% CI: 1.026– 1.769). Complications were more common with the endoscopic approach (8/86, antegrade endoscopy; 2 /149, retrograde endoscopy vs 2/204, fluoroscopy; x2¼ 17.39, P-value <0.000). Conclusions: We found excellent dilation outcomes irrespective of the dilation procedure; however, with higher complications in the endoscopic approach. Long (>1 cm) segment involvement and multiple locations were predictive of stricture reoccurrence.
Perioperative care of patients with epidermolysisbullosa: proceedings of the 5th internationalsymposium on epidermoly sis bullosa, SantiagoChile, December 4–6, 2008
(2010) GOLDSCHNEIDER, KENNETH; W.LUCKY, ANNE; MELLERIO, JEMIMA E.; Palisson, Francis; VIÑUELA MIRANDA, MARIA DEL CARMEN
a epidermólisis ampollosa (EB) se ha reconocido como un trastorno multisistémico que plantea una serie de desafíos pre, intra y posoperatorios. Si bien los anestesiólogos han apreciado durante mucho tiempo la posible dificultad de la intubación en pacientes con EB, otros sistemas pueden verse afectados por este trastorno. Las deficiencias hematológicas, cardíacas, esqueléticas, gastrointestinales, nutricionales y metabólicas son focos de atención médica preoperatoria, además de los problemas de las vías respiratorias. Por lo tanto, la planificación multidisciplinaria de la atención operatoria es imperativa. Un panel multinacional e interdisciplinario de expertos reunidos en Santiagio, Chile, para revisar las mejores prácticas para la atención perioperatoria de pacientes con EB. Este artículo presenta pautas que representan una síntesis de los enfoques basados en la evidencia y el consenso de expertos de este panel y están destinados a ayudar a los médicos nuevos en el cuidado de pacientes con EB cuando está indicado el manejo quirúrgico. Con la optimización médica adecuada y la atención a los detalles en el quirófano, los pacientes con EB pueden tener un curso perioperatorio sin incidentes.
Pro-inflammatory chemokines and cytokines dominate the blister fluid molecular signature in patients with epidermolysis bullosa and affect leukocyte and stem cell migration
(Elsevier, 2017) Alexeev, Vitali; Salas, Julio; Palisson, Francis; Mukhtarzada, Lila; Fortuna, Giulio; Uitto, Jouni; South, Andrew; Igoucheva, Olga
Hereditary epidermolysis bullosa (EB) is associated with skin blistering and the development of chronic nonhealing wounds. Although clinical studies have shown that cell-based therapies improve wound healing, the recruitment of therapeutic cells to blistering skin and to more advanced skin lesions remains a challenge. Here, we analyzed cytokines and chemokines in blister fluids of patients affected by dystrophic, junctional, and simplex EB. Our analysis revealed high levels of CXCR1, CXCR2, CCR2, and CCR4 ligands, particularly dominant in dystrophic and junctional EB. In vitro migration assays demonstrated the preferential recruitment of CCR4+ lymphocytes and CXCR1+ , CXCR2+ , and CCR2+ myeloid cells toward EB-derived blister fluids. Immunophenotyping of skininfiltrating leukocytes confirmed substantial infiltration of EB-affected skin with resting (CD45RA+ ) and activated (CD45RO+ ) T cells and CXCR2+ CD11b+ cells, many of which were identified as CD16b+ neutrophils. Our studies also showed that abundance of CXCR2 ligand in blister fluids also creates a favorable milieu for the recruitment of the CXCR2+ stem cells, as validated by in vitro and in-matrix migration assays. Collectively, this study identified several chemotactic pathways that control the recruitment of leukocytes to the EB-associated skin lesions. These chemotactic axes could be explored for the refinement of the cutaneous homing of the therapeutic stem cells.
Recessive dystrophic epidermolysis bullosa results in painful small fibre neuropathy
(Springer, 2017) von Bischhoffshausen, Sofia; Ivulic, Dinka; Alvarez, Paola; Schuffeneger, Victor C.; Idiaquez, Juan; Fuentes, Constanza; Morande, Pilar; Fuentes, Ignacia; Palisson, Francis; Bennett, David L. H.; Calvo, Margarita
Small fibres in the skin are vulnerable to damage in metabolic or toxic conditions such as diabetes mellitus or chemotherapy resulting in small fibre neuropathy and associated neuropathic pain. Whether injury to the most distal portion of sensory small fibres due to a primary dermatological disorder can cause neuropathic pain is still unclear. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare condition in which mutations of proteins of the dermo-epidermal junction lead to cycles of blistering followed by regeneration of the skin. Damage is exclusive to the skin and mucous membranes, with no known direct compromise of the nervous system. It is increasingly recognized that most RDEB patients experience daily pain, the aetiology of which is unclear but may include inflammation (in the wounds), musculoskeletal (due to atrophy and retraction scars limiting movement) or neuropathic pain. In this study we investigated the incidence of neuropathic pain and examined the presence of nerve dysfunction in RDEB patients. Around three quarters of patients presented with pain of neuropathic characteristics, which had a length-dependent distribution. Quantitative sensory testing of the foot revealed striking impairments in thermal detection thresholds combined with an increased mechanical pain sensitivity and wind up ratio (temporal summation of noxious mechanical stimuli). Nerve conduction studies showed normal large fibre sensory and motor nerve conduction; however, skin biopsy showed a significant decrease in intraepidermal nerve fibre density. Autonomic nervous system testing revealed no abnormalities in heart rate and blood pressure variability however the sympathetic skin response of the foot was impaired and sweat gland innervation was reduced. We conclude that chronic cutaneous injury can lead to injury and dysfunction of the most distal part of small sensory fibres in a length-dependent distribution resulting in disabling neuropathic pain. These findings also support the use of neuropathic pain screening tools in these patients and treatment algorithms designed to target neuropathic pain.
Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa
(2010) CONGET, PAULETTE; RODRIGUEZ, FERNANDO; KRAMER, SUSANNE; ALLERS, CAROLINA; SIMON, VALESKA; Palisson, Francis; GONZALEZ, SERGIO; YUBERO, MARIA J.
In animal models it has been shown that mesenchymal stromal cells (MSC) contribute to skin regeneration and accelerate wound healing. We evaluated whether allogeneic MSC administration resulted in an improvement in the skin of two patients with recessive dystrophic epidermolysis bullosa (RDEB; OMIM 226600). Patients had absent type VII collagen immunohistofl uorescence and since birth had suffered severe blistering and wounds that heal with scarring. Vehicle or 0.5 106 MSC were infused intradermally in intact and chronic ulcerated sites. One week after intervention, in MSC-treated skin type VII collagen was detected along the basement membrane zone and the dermal–epidermal junction was continuous. Re-epithelialization of chronic ulcerated skin was observed only near MSC administration sites. In both patients the observed clinical benefi t lasted for 4 months. Thus intradermal administration of allogeneic MSC associates with type VII collagen replenishment at the dermal–epidermal junction, prevents blistering and improves wound healing in unconditioned patients with RDEB.

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