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1.
Mol Ther ; 32(5): 1497-1509, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38429928

ABSTRACT

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. InĀ vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB.


Subject(s)
Cell Adhesion , Epidermolysis Bullosa , Laminin , Lentivirus , Humans , Laminin/metabolism , Laminin/genetics , Epidermolysis Bullosa/genetics , Epidermolysis Bullosa/metabolism , Epidermolysis Bullosa/therapy , Epidermolysis Bullosa/pathology , Child , Lentivirus/genetics , Male , Female , Child, Preschool , Genetic Therapy/methods , Genetic Vectors/genetics , Epithelial Cells/metabolism , Cells, Cultured , Gene Expression , Adolescent , Infant
2.
Br J Dermatol ; 188(1): 75-83, 2023 01 23.
Article in English | MEDLINE | ID: mdl-36689522

ABSTRACT

BACKGROUND: Desmosomes are complex cell junction structures that connect intermediate filaments providing strong cell-to-cell adhesion in tissues exposed to mechanical stress. OBJECTIVES: To identify causal variants in individuals with woolly hair and skin fragility of unknown genetic cause. METHODS: This research was conducted using whole-genome sequencing, whole-exome sequencing, clinical phenotyping, haplotype analysis, single-cell RNA sequencing data analysis, immunofluorescence microscopy and transmission electron microscopy. RESULTS: We identified homozygous predicted loss-of-function tuftelin-1 (TUFT1) variants in nine individuals, from three families, with woolly hair and skin fragility. One donor splice-site variant, c.60+1G>A, was present in two families, while a frameshift variant, p.Gln189Asnfs*49, was found in the third family. Haplotype analysis showed the c.60+1G>A substitution to be a founder variant in the Irish population that likely arose approximately 20 generations ago. Human and mouse single-cell RNA sequencing data showed TUFT1 expression to be enriched in the hair dermal sheath and keratinocytes. TUFT1 expression was highly correlated with genes encoding desmosomal components implicated in diseases with phenotypes that overlap with the cohort presented here. Immunofluorescence showed tuftelin-1 to be mainly localized to the peripheral cell membranes of keratinocytes in normal skin. Skin samples from individuals with TUFT1 variants showed markedly reduced immunoreactivity for tuftelin-1, with a loss of the keratinocyte cell membrane labelling. Light microscopy revealed keratinocyte adhesion, mild hyperkeratosis and areas of superficial peeling. Transmission electron microscopy showed panepidermal acantholysis with widening of intercellular spaces throughout the epidermis and desmosomal detachment through the inner plaques. CONCLUSIONS: Biallelic loss-of-function TUFT1 variants cause a new autosomal recessive skin/hair disorder characterized by woolly hair texture and early-onset skin fragility. Tuftelin-1 has a role in desmosomal integrity and function.


Subject(s)
Hair Diseases , Skin Abnormalities , Humans , Mice , Animals , Hair Diseases/genetics , Skin , Keratinocytes/metabolism , Hair
3.
Pediatr Allergy Immunol ; 34(1): e13914, 2023 01.
Article in English | MEDLINE | ID: mdl-36705039

ABSTRACT

BACKGROUND: Netherton syndrome (NS; OMIM: 256500) is a rare autosomal recessively inherited disease due to SPINK5 mutations. Hair and inflammatory skin involvement are variable along with allergies. Morbidity and mortality are high, particularly in infancy. A detailed clinical analysis of a NS patient cohort should broaden the understanding of nutritional challenges and allergic comorbidities. METHODS: In this retrospective monocentric cohort study, medical and dietetic records of pediatric NS patients, presenting between 1999 and 2018, were reviewed. The severity of skin involvement was assessed according to the extent of the body surface area (BSA) affected by erythema. RESULTS: We identified 21 patients with NS (median age 11.6 years). Within the first 6Ā months of life, requirements for fluid and kcals/protein were high for all patients (average 228 ml/kg/day) and infants had an average of 1.9 feed changes (range 0-4) due to food intolerance. Clinical evidence for IgE-mediated food allergy was present in 84.2% (16/19 children, 2 no data) with a range of 1-12 food allergies per patient. In 75%, more than one food had to be avoided. Specific IgE levels were falsely positive in 38.3% and 8/18 patients (44.4%). One-third (5/15; 6 no data) of patients, all with severe disease, had anaphylactic reactions following ingestion of fish (nĀ = 2), sesame (nĀ = 1), cow's milk (nĀ = 1), and both peanut and egg (nĀ = 1). CONCLUSIONS: Our data emphasize feeding difficulties in children with NS and reveal an unexpectedly higher prevalence of food allergies that gives evidence to the importance of early coordinated multidisciplinary care for overcoming these challenges in NS.


Subject(s)
Food Hypersensitivity , Malnutrition , Milk Hypersensitivity , Netherton Syndrome , Animals , Humans , Allergens , Cohort Studies , Immunoglobulin E , Malnutrition/complications , Netherton Syndrome/epidemiology , Netherton Syndrome/complications , Prevalence , Retrospective Studies , Risk Factors , Child
4.
Pediatr Dermatol ; 40(6): 1010-1014, 2023.
Article in English | MEDLINE | ID: mdl-37496109

ABSTRACT

BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a subtype of an inherited skin disorder characterized by skin and mucosal fragility due to collagen VII (COL7A1) gene mutations. Esophageal strictures leading to chronic dysphagia and acute episodes are well recognized complications within this subtype. Sloughing of esophageal mucosa and the treatment of this emergency have heretofore received limited attention in the EB literature. METHODS: We retrospectively reviewed the electronic medical records of the patients who had an acute episode of sloughing of the esophageal lining between 2008 and 2021 and extracted the information regarding their clinical presentation and management. RESULTS: Six patients out of 210 with recessive DEB severe (RDEB-S) (n = 4), RDEB intermediate (RDEB-I) (n = 1) and dominant DEB (DDEB) (n = 1) were identified. The mean age at the time of the episode was 2.7 years. All patients had early-onset severe gastroesophageal reflux. Clinically, they presented with a coughing episode (n = 6), hematemesis (n = 6), vomiting (n = 6), and choking (n = 3), followed by coughing up a string like tissue of variable length, part of the esophageal mucosal lining. Four patients recovered with medical management only, two patients required gastrostomy insertions for feeding due to severe persistent dysphagia and one also required a Nissen's fundoplication to manage severe reflux. One patient had aspiration pneumonia. CONCLUSIONS: Sloughing of varying lengths of segments of the esophagus is an emergency. The lining coughed up needs to be cut at the mouth not pulled and the emergency services called immediately for urgent assessment and management. Expert multidisciplinary care is needed to manage this rare but serious condition.


Subject(s)
Deglutition Disorders , Epidermolysis Bullosa Dystrophica , Humans , Child , Child, Preschool , Epidermolysis Bullosa Dystrophica/complications , Epidermolysis Bullosa Dystrophica/therapy , Epidermolysis Bullosa Dystrophica/genetics , Retrospective Studies , Deglutition Disorders/etiology , Deglutition Disorders/therapy , Phenotype , Collagen Type VII/genetics , Mutation
5.
Br J Dermatol ; 186(5): 843-848, 2022 05.
Article in English | MEDLINE | ID: mdl-34927719

ABSTRACT

BACKGROUND: The National Health Service (NHS) epidermolysis bullosa (EB) service, established in 2002, offers comprehensive, free care to all patients in England and Wales. OBJECTIVES: To quantify prevalence, incidence and mortality of EB in England and Wales. METHODS: Demographic data for patients in England and Wales were collected on a secure electronic database, prospectively from January 2002 to April 2021 and retrospectively for cases prior to 2002. Vital status was verified using central NHS data. RESULTS: By March 2021, 2594 individuals were registered, of whom 2361 were living, which yielded a prevalence of 34Ā·8 per million of the population for all EB types [EB simplex (EBS) 17 per million, dystrophic EB (DEB) 10Ā·7 per million, junctional EB (JEB) 1 per million and Kindler EB 0Ā·3 per million]. We recorded 1200 babies with EB born since 2002. The average incidence per million live births for EBS, DEB, JEB and Kindler EB was 32Ā·5, 26Ā·1, 8Ā·9 and 0Ā·9, respectively (total incidence for all types of EB was 67Ā·8 per million). Birth rates fell progressively over the 19-year period for JEB-severe (JEB-S) (r = -0Ā·56) and recessive DEB-severe (r = -0Ā·44) and also for milder types of EB. We observed longer survival in JEB-S over the 19-year period (r2 = 0Ā·18) with a median survival of 12Ā·7 months over the past 5 years. CONCLUSIONS: In this study, we provide the first accurate epidemiological data for EB in England and Wales. We believe the observed reduction in birth incidence of severe types of EB reflects an uptake of genetic counselling advice, whereas the reduction in milder types may be due to delayed presentation. A potential small trend towards longer survival of babies with JEB-S may reflect improved multidisciplinary care.


Subject(s)
Epidermolysis Bullosa, Junctional , Epidermolysis Bullosa , Epidermolysis Bullosa/epidemiology , Epidermolysis Bullosa/genetics , Humans , Infant , Retrospective Studies , State Medicine , Wales/epidemiology
6.
Clin Exp Dermatol ; 2022 Nov 11.
Article in English | MEDLINE | ID: mdl-36763734

ABSTRACT

BACKGROUND: Children and adolescents with severe recessive dystrophic epidermolysis bullosa (RDEB-S) often have severe constipation in addition to gastrointestinal dysbiosis, due to frequent antibiotic use and reduced oral diet. Constipation is treated with long-term use of high daily doses of macrogol gel (Movicol Paediatric PlainTM or LaxidoTM). Constipation is refractory to increases in fibre and fluids, and impacts severely on quality of life. AIM: To study the initial impact andĀ efficacy of using aĀ multistrainĀ probiotic supplement daily for 12 weeks in patients with RDEB-S.Ā The authors sought to determine the impact of such a supplement onĀ  gastrointestinal symptoms, stool consistencyĀ and the use of macrogol gel to treat constipation, as well asĀ understandingĀ patient reaction, palability andĀ ease of use. METHODS: Patients were identified through the epidermolysis bullosa tertiary multidisciplinary team clinic in July 2021. Patients were included if they had a diagnosis of RDEB-S, prescribed at least one sachet of macrogol gel and provided written consent to take part. Patients were provided, proprietary liquid multistrain probiotic supplement (Symprove™) with a high bacterial count, at a dose of 1 mLĆ¢Ā€Ā…kg-1 once a day. Each patient completed an anonymous, nine-question, electronic survey to document symptoms and report overall findings at the start and end of a 12-week trial period. RESULTS: Four patients with RDEB-S (two boys and two girls; age range 7-14 years) who met the inclusion criteria were approached to take part. All patients had chronic constipation requiring daily macrogol gel use (range 2-5 sachets per day). Three out of four (75%) completed the 12-week course. At baseline (before supplementation commenced), all three (100%) patients reported poor oral appetite, constipation, flatulence, abdominal bloating and pain, and frequent skin infections requiring oral antibiotics, with two of the three (66%) patients also having nausea. After 12 weeks of supplementation, all three patients (100%) reported a significant improvement in abdominal pain and bloating, nausea, stool consistency, stool frequency, flatulence and increased appetite. Two of the three patients (66%) were able to reduce their macrogol gel usage and the third patient (33%) was able to stop macrogol gel usage altogether during the study period. All three patients said they would choose to continue using the supplement if it was available. CONCLUSION: We have shown in this case series that giving a multistrain probiotic supplement in patients with RDEB-S has the potential to improve stool consistency and reduce or prevent the need for chronic macrogol gel use. Future larger-scale, placebo-controlled trials are needed to confirm these results.

7.
Clin Exp Dermatol ; 47(7): 1307-1313, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35245948

ABSTRACT

BACKGROUND: Paediatric patients with recessive dystrophic epidermolysis bullosa (RDEB) are at risk of vitamin D deficiency, owing to lack of sunlight from reduced mobility and having large areas of skin being covered with dressings, and to impaired nutritional intake and status. AIM: To establish an appropriate level of vitamin D supplementation in paediatric patients with RDEB. METHODS: Patients with RDEB attending the EB tertiary multidisciplinary team clinic were enrolled. Serum levels of total 25(OH)D were retrospectively recorded for the study period 2012-2018. Data from clinical records on supplements, bone mineral density (BMD) Z scores, compliance, and use of enteral feeds and/or formula were also recorded. RESULTS: In total, 24 patients met the inclusion criteria: 20 with severe RDEB, 3 with RDEB inversa and 1 with intermediate RDEB. Of the 24 patients, 21 (88%) were advised to take a vitamin D3 supplement in line with Department of Health Guidelines (UK), with the remaining 3 patients receiving sufficient intake from formula or enteral feeds. Thirteen of the 24 (54%) had vitamin D deficiency or insufficiency despite advice to supplement; 9 of these 13 (69%) subsequently started or increased the dosage of vitamin D supplements and levels became sufficient (> 50 nmol/L), while the remaining 4 patients (31%) continued to have persistent insufficient levels due to noncompliance with supplements. Reasons for noncompliance were palatability, cost and forgetting to take the tablets. The dose required to maintain sufficient serum levels increased with age, up to 300% of the reference nutrient intake (RNI). CONCLUSION: All patients with RDEB require a supplement or a formula or enteral/sip feed containing vitamin D to maintain sufficient serum vitamin D. The dose required increases with age and can be up to three times higher than the RNI for the normal population. Compliance may improve using a once-weekly loading dose of vitamin D3. Vitamin D deficiency was not solely causative of a low BMD Z score.


Subject(s)
Epidermolysis Bullosa Dystrophica , Epidermolysis Bullosa , Vitamin D Deficiency , Child , Cholecalciferol/therapeutic use , Dietary Supplements , Epidermolysis Bullosa Dystrophica/complications , Humans , Retrospective Studies , Vitamin D/therapeutic use , Vitamin D Deficiency/complications , Vitamin D Deficiency/drug therapy
8.
Clin Exp Dermatol ; 47(7): 1346-1349, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35080258

ABSTRACT

Epidermolysis bullosa acquisita is a highly uncommon condition in the paediatric population. This article describes three children with this disease, different clinical presentation and management. It also reviews the most relevant articles on this topic.


Subject(s)
Epidermolysis Bullosa Acquisita , Epidermolysis Bullosa , Child , Epidermolysis Bullosa Acquisita/diagnosis , Epidermolysis Bullosa Acquisita/drug therapy , Humans
9.
Acta Derm Venereol ; 101(8): adv00523, 2021 Aug 24.
Article in English | MEDLINE | ID: mdl-34230977

ABSTRACT

Epidermolysis bullosa (EB), notably severe recessive dystrophic EB (RDEB-S), is associated with increased risk of aggressive mucocutaneous squamous cell carcinomas, the major cause of mortality in early adulthood. This observational, retrospective case review describes a series of EB patients with cutaneous squamous cell carcinomas over a 28-year period. Forty-four EB patients with squamous cell carcinomas were identified with a total of 221 primary tumours. They comprised: 31 (70%) with RDEB-S, 4 (9%) with other RDEB subtypes, 5 (11.4%) with dominant dystrophic EB, 3 (6.8%) with intermediate junctional EB and 1 (2.3%) with Kindler EB. Squamous cell carcinomas occurred earlier in RDEB-S (median age 29.5 years; age range 13-52 years) than other groups collectively (median age 47.1 years; age range 30-89 years) and most had multiple tumours (mean 5.8; range 1-44). Squamous cell carcinoma-associated mortality was high in RDEB-S (64.5%), with median survival after first squamous cell carcinoma of 2.4 years (range 0.5-12.6 years), significantly lower than previous reports, highlighting the need for early surveillance and better treatments.


Subject(s)
Carcinoma, Squamous Cell , Epidermolysis Bullosa Dystrophica , Epidermolysis Bullosa , Skin Neoplasms , Adolescent , Adult , Carcinoma, Squamous Cell/therapy , Epidermolysis Bullosa Dystrophica/complications , Epidermolysis Bullosa Dystrophica/diagnosis , Humans , Middle Aged , Retrospective Studies , Young Adult
10.
Pediatr Dermatol ; 38(5): 1094-1101, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34514630

ABSTRACT

BACKGROUND/OBJECTIVES: Laryngo-onycho-cutaneous syndrome (LOC) is a rare subtype of junctional epidermolysis bullosa (JEB), featuring aberrant granulation tissue formation in the skin, larynx, and eyes. So far, three mutations including the specific (founder) mutation in exon 39 of LAMA3 (c.151dup) have been identified, but sparse data exists regarding the natural history, the genotype-phenotype correlation, and its differentiation from other JEB types. METHODS: We reviewed our pediatric EB database to identify English children with clinical and genetically diagnosed LOC within the last 15Ā years. Their demographic, clinical, and laboratory data were examined. We searched three databases for case reports of LOC between January 1986 and November 2020 and extracted clinical and molecular details. RESULTS: We identified 6 LOC patients, all female (mean age 5.4Ā years). Periungual hypergranulation and skin fragility were the earliest presenting signs (0-3Ā months), followed by laryngeal stenosis, symblepharon (mean onset 10.7 and 11.8Ā months, respectively), and dental abnormalities. Five children developed anemia at an average of 19.2Ā months. We identified 22 published studies in English with 31 cases. CONCLUSIONS: This study delineates the disease course of LOC and highlights the overlap with some forms of JEB. Classical signs/symptoms including anemia appear early in life. Genetic analysis revealed three new LOC-associated variants and underscores the finding that interpretation of skin immunolabeling and molecular diagnostics can be challenging. We provide recommendations on management of this complex syndrome.


Subject(s)
Conjunctival Diseases , Epidermolysis Bullosa, Junctional , Laryngeal Diseases , Skin Abnormalities , Child , Child, Preschool , Female , Humans , Skin
13.
Pediatr Dermatol ; 34(6): e328-e330, 2017 Nov.
Article in English | MEDLINE | ID: mdl-29144034

ABSTRACT

Netherton syndrome is an autosomal recessive ichthyosis caused by mutations in SPINK5, with the classic triad of linearis circumflexa, trichorrhexis invaginata, and atopy. There are few reports of surgical management in individuals with Netherton syndrome and clinicians may be reluctant to operate for fear of wound-healing complications. This report describes a pediatric case of a Buschke-Lowenstein tumor of the natal cleft in a patient with Netherton syndrome that had failed to respond to medical management. We reviewed the literature for previous cases of surgery in individuals with Netherton syndrome using MEDLINE and PubMed searches. Our patient underwent surgery to remove the lesion without complication. Using conventional dressings and topical negative-pressure therapy, the wound was managed and healed within a reasonable time frame despite the underlying skin condition. This case indicates that surgery and topical negative-pressure therapy is a safe and reasonable treatment for individuals with Netherton syndrome.


Subject(s)
Buschke-Lowenstein Tumor/surgery , Netherton Syndrome/surgery , Adolescent , Buschke-Lowenstein Tumor/complications , Humans , Male , Negative-Pressure Wound Therapy/methods , Netherton Syndrome/complications , Skin/pathology
14.
Am J Hum Genet ; 91(6): 1115-21, 2012 Dec 07.
Article in English | MEDLINE | ID: mdl-23176819

ABSTRACT

The Rab GTPase Rab27B and one of its effector proteins, Slac2-b (also known as EXPH5, exophilin-5), have putative roles in intracellular vesicle trafficking but their relevance to human disease is not known. By using whole-exome sequencing, we identified a homozygous frameshift mutation in EXPH5 in three siblings with inherited skin fragility born to consanguineous Iraqi parents. All three individuals harbor the mutation c.5786delC (p.Pro1929Leufs(∗)8) in EXPH5, which truncates the 1,989 amino acid Slac2-b protein by 52 residues. The clinical features comprised generalized scale-crusts and occasional blisters, mostly induced by trauma, as well as mild diffuse pigmentary mottling on the trunk and proximal limbs. There was no increased bleeding tendency, no neurologic abnormalities, and no increased incidence of infection. Analysis of an affected person's skin showed loss of Slac2-b immunostaining (C-terminal antibody), disruption of keratinocyte adhesion within the lower epidermis, and an increased number of perinuclear vesicles. A role for Slac2-b in keratinocyte biology was supported by findings of cytoskeletal disruption (mainly keratin intermediate filaments) and decreased keratinocyte adhesion in both keratinocytes from an affected subject and after shRNA knockdown of Slac2-b in normal keratinocytes. Slac2-b was also shown to colocalize with Rab27B and Ɵ4 integrin to early adhesion initiation sites in spreading normal keratinocytes. Collectively, our findings identify an unexpected role for Slac2-b in inherited skin fragility and expand the clinical spectrum of human disorders of GTPase effector proteins.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Germ-Line Mutation , Hair Diseases/congenital , Hair Diseases/genetics , Adaptor Proteins, Signal Transducing/metabolism , Base Sequence , Female , Hair Diseases/diagnosis , Humans , Keratinocytes/metabolism , Keratinocytes/pathology , Male , Pedigree , Skin/pathology , Skin/ultrastructure , rab GTP-Binding Proteins/metabolism
16.
J Am Acad Dermatol ; 72(1): 108-14, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25440430

ABSTRACT

BACKGROUND: Azathioprine is efficacious in the treatment of severe childhood atopic dermatitis; however, robust data on adverse effects in this population are lacking. OBJECTIVE: We sought to assess adverse effects of azathioprine treatment in a pediatric atopic dermatitis cohort, and make recommendations for monitoring based on these data. METHODS: Blood test results for all 82 children prescribed oral azathioprine for atopic dermatitis in our department between 2010 and 2012 were collated prospectively, and clinical notes were reviewed retrospectively. RESULTS: Mean age at commencing azathioprine was 8.3 years (SEM 0.4). Mean maximum doses were 2.4Ā mg/kg (SEM 0.1) and 1.5 mg/kg (SEM 0.1) for normal and reduced serum thiopurine-S-methyltransferase levels, respectively. Adverse effects on blood indices occurred in 34 of 82 patients (41%), with pronounced effects in 18 of 82 (22%) after a median time of 0.4 years. Two patients stopped therapy as a result of abnormal blood indices. Clinical adverse effects occurred in 16 of 82 (20%), two resulting in cessation of therapy. Incidence of adverse effects was unaffected by age, sex, thiopurine-S-methyltransferase level, and drug dose on multivariate regression. LIMITATIONS: Comparison with other studies is limited by varying definitions of adverse effects. CONCLUSION: Oral azathioprine was associated with few pronounced adverse effects for the duration ofĀ useĀ and dosage in this cohort. Recommendations for monitoring are made.


Subject(s)
Azathioprine/adverse effects , Dermatitis, Atopic/drug therapy , Immunosuppressive Agents/adverse effects , Administration, Oral , Azathioprine/administration & dosage , Child , Drug Monitoring , Drug-Related Side Effects and Adverse Reactions , Female , Humans , Immunosuppressive Agents/administration & dosage , Male , Practice Guidelines as Topic , Retrospective Studies
17.
J Am Acad Dermatol ; 83(4): 1222-1224, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32682031
18.
BMC Med ; 12: 178, 2014 Oct 09.
Article in English | MEDLINE | ID: mdl-25603875

ABSTRACT

BACKGROUND: Inherited epidermolysis bullosa (EB) comprises a group of rare disorders that have multi-system effects and patients present with a number of both acute and chronic pain care needs. Effects on quality of life are substantial. Pain and itching are burdensome daily problems. Experience with, and knowledge of, the best pain and itch care for these patients is minimal. Evidence-based best care practice guidelines are needed to establish a base of knowledge and practice for practitioners of many disciplines to improve the quality of life for both adult and pediatric patients with EB. METHODS: The process was begun at the request of Dystrophic Epidermolysis Bullosa Research Association International (DEBRA International), an organization dedicated to improvement of care, research and dissemination of knowledge for EB patients worldwide. An international panel of experts in pain and palliative care who have extensive experience caring for patients with EB was assembled. Literature was reviewed and systematically evaluated. For areas of care without direct evidence, clinically relevant literature was assessed, and rounds of consensus building were conducted. The process involved a face-to-face consensus meeting that involved a family representative and methodologist, as well as the panel of clinical experts. During development, EB family input was obtained and the document was reviewed by a wide variety of experts representing several disciplines related to the care of patients with EB. RESULTS: The first evidence-based care guidelines for the care of pain in EB were produced. The guidelines are clinically relevant for care of patients of all subtypes and ages, and apply to practitioners of all disciplines involved in the care of patients with EB. When the evidence suggests that the diagnosis or treatment of painful conditions differs between adults and children, it will be so noted. CONCLUSIONS: Evidence-based care guidelines are a means of standardizing optimal care for EB patients, whose disease is often times horrific in its effects on quality of life, and whose care is resource-intensive and difficult. The guideline development process also highlighted areas for research in order to improve further the evidence base for future care.


Subject(s)
Epidermolysis Bullosa/therapy , Pain Management/standards , Palliative Care/standards , Adult , Child , Epidermolysis Bullosa/complications , Epidermolysis Bullosa/psychology , Humans , Integrative Medicine/methods , Integrative Medicine/standards , Male , Pain/etiology , Pain Management/methods , Palliative Care/methods , Psychotherapy/methods , Psychotherapy/standards , Quality of Life
19.
J Am Acad Dermatol ; 70(6): 1103-26, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24690439

ABSTRACT

BACKGROUND: Several new targeted genes and clinical subtypes have been identified since publication in 2008 of the report of the last international consensus meeting on diagnosis and classification of epidermolysis bullosa (EB). As a correlate, new clinical manifestations have been seen in several subtypes previously described. OBJECTIVE: We sought to arrive at an updated consensus on the classification of EB subtypes, based on newer data, both clinical and molecular. RESULTS: In this latest consensus report, we introduce a new approach to classification ("onion skinning") that takes into account sequentially the major EB type present (based on identification of the level of skin cleavage), phenotypic characteristics (distribution and severity of disease activity; specific extracutaneous features; other), mode of inheritance, targeted protein and its relative expression in skin, gene involved and type(s) of mutation present, and--when possible--specific mutation(s) and their location(s). LIMITATIONS: This classification scheme critically takes into account all published data through June 2013. Further modifications are likely in the future, as more is learned about this group of diseases. CONCLUSION: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and molecular features of each EB subtype, and has sufficient flexibility incorporated in its structure to permit further modifications in the future.


Subject(s)
Epidermolysis Bullosa/classification , Epidermolysis Bullosa/genetics , Genetic Predisposition to Disease/epidemiology , Consensus , Epidermolysis Bullosa/diagnosis , Female , Gene Expression Regulation , Humans , Incidence , Male , Prognosis , Sensitivity and Specificity , Severity of Illness Index
20.
Orphanet J Rare Dis ; 19(1): 375, 2024 Oct 11.
Article in English | MEDLINE | ID: mdl-39394129

ABSTRACT

BACKGROUND: Pain is common in the genetic skin fragility disorder epidermolysis bullosa (EB), from skin and mucosal injury and inflammation as well as extra-mucocutaneous sites. Individuals living with EB have identified pain as a priority for better treatments. OBJECTIVES: The Prospective EB Longitudinal Evaluation Study (PEBLES) is a prospective register study exploring the natural history of RDEB across all ages from birth to death. Here, we investigated the characteristics and treatment of pain in different RDEB subtypes. METHODS: Information was collected from individuals with different RDEB subtypes over an 8-year period. Data included visual analogue scale (VAS) ratings of background and procedural pain, its location, intensity and impact on sleep, as well as pain medication. Disease severity scores and quality of life measures were correlated to pain scores. RESULTS: Sixty-one participants (13 children, 48 adults) completed a total of 361 reviews. Pain was common, experienced by 93% of participants at index review, with 80% suffering both background and procedural pain. Across all RDEB patients, the median VAS for background pain was 40 (out of 100) [interquartile range 20,60] and for those having regular dressing changes, median procedural pain was 52 [40,80]. Severe (RDEB-S) and pruriginosa (RDEB-Pru) groups had the greatest increase in procedural compared to background pain of 20 and 22 VAS points, respectively. Correlations between disease severity and quality of life impairment were observed across most groups, particularly RDEB-S. Over half of those studied experienced pain frequently or constantly, and in one third pain disturbed sleep at least 4 nights per week. Skin was the commonest source of pain in all subtypes except inversa RDEB where the mouth was the main site. Despite frequent and severe pain, one third of participants used no medication for pain and, in those that did, pain levels remained high suggesting ineffectiveness of current pain management approaches and a significant unmet need in RDEB. CONCLUSION: The frequency, severity, and impact of pain in all RDEB patients is significant, particularly in RDEB-S and RDEB-Pru. Our findings highlight that current RDEB pain management is poorly effective and that further research is needed to address this symptom.


Subject(s)
Epidermolysis Bullosa Dystrophica , Pain , Quality of Life , Humans , Epidermolysis Bullosa Dystrophica/complications , Prospective Studies , Male , Female , Longitudinal Studies , Child , Adult , Adolescent , Child, Preschool , Young Adult , Middle Aged , Pain Measurement , Infant
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