Osteoporosis and bone health in pediatric patients with epidermolysis bullosa: A scoping review.

Nutritional compromise, low levels of vitamin D, chronic inflammation, abnormal growth, and physical inactivity affect bone metabolism and compromise long-term bone health in individuals with epidermolysis bullosa (EB). The result is a high risk for osteopenia, osteoporosis, and pathologic fractures, but this important consequence of EB has been the focus of few investigations. Our scoping review found 21 publications that assessed the current understanding and clinical practices for monitoring of osteoporosis and its treatment in EB. Recommendations summarized from 13 of these publications include early nutritional and weight assessments before 2 years of age; bloodwork every 6-12 months starting at birth; Tanner stage assessments every 6 months to detect any pubertal delay; DEXA scans starting at age 6 years with repeated scans every 1-2 years, except in mild cases; and vitamin D supplementation of 80-320 IU daily for children 0-7 years and 720 IU for patients >8 years.

A homozygous p.Leu813Pro gain-of-function NLRP1 variant causes phenotypes of different severity in two siblings.

BACKGROUND: A trio exome sequencing study identified a previously unreported NLRP1 gene variant resulting in a p.Leu813Pro substitution of the LRR (leucine-rich repeats) domain of the NLRP1 protein (NACHT, LRR and PYD domains-containing protein 1). This homozygous mutation was shared by two sisters with different clinical presentation: the younger sister had generalized inflammatory nodules with keratotic plugs, clinically resembling multiple keratoacanthomas, while the older had manifestations of familial keratosis lichenoides chronica. OBJECTIVES: To analyse the consequences of this NLRP1 variant in two siblings with a different clinical spectrum of severity. METHODS: To demonstrate the pathogenicity, p.Leu813Pro was recombinantly expressed, and its effect on inflammasome assembly was assessed. Exome sequencing and RNA-Seq were performed to identify factors with potentially modifying effects on the severity of the skin manifestation between each sibling. RESULTS: The variant p.Leu813Pro triggered activation of the NLRP1 inflammasome leading to ASC (apoptosis-associated speck-like protein containing a CARD) speck formation and interleukin (IL)-1ß release. The more severely affected sister had several additional genomic variants associated with atopy and psoriasis that were not present in her sibling. IL-5 and IL-17 emerged as dominant cytokines driving prominent inflammation in the skin of the severely affected sibling. CONCLUSIONS: To the best of our knowledge, this is the first report of a NLRP1 variant that leads to a different clinical spectrum of severity within the same sibship. IL-5 and IL-17 were the main cytokines expressed in the inflammatory lesions of the severely affected patient and might be regarded as disease modifying factors, and therefore may be considered as therapeutic targets.

Epidemiology of inherited epidermolysis bullosa in Germany.

BACKGROUND: Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity. OBJECTIVE: Epidemiological data from different countries have been published, but none are available from Germany. METHODS: In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization. RESULTS: Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries. CONCLUSIONS: Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision-making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.

Do socioeconomic factors impact atopic dermatitis outcome? A single-center study.

BACKGROUND: Race and socioeconomic status are thought to influence the severity of atopic dermatitis (AD), but findings differ between countries and measures used. The role of social determinants of health versus biologic factors in causing these differences is poorly understood. OBJECTIVE: We hypothesized that spatially-derived factors correlate with AD severity and patient-reported outcome (PRO) in a pediatric cohort from Chicago, USA. METHODS: Children with AD and caregivers were enrolled from February 2018 to April 2019 in this single-site cross-sectional study. Severity was self- and physician-assessed using validated measures. Patient addresses were geocoded and linked to census tract IDs. Deprivation index (DI) was calculated using variables of the 2018 American Community Survey. RESULTS: Among 216 children aged 5-17 years old, 111 (51.4%) lived in urban, 104 (48.1%) suburban, and one (0.5%) in rural areas. Race was self-classified as White in 31.0%, Black 24.5%, other or mixed 25.0%, and Asian 19.4%; 24.5% were Hispanic. Median DI was 0.32 (range 0.03-0.72), with higher scores indicating more deprivation. DI correlated with insurance type, family income, ethnicity, race, and parental education, and weakly with selected PRO T-scores. However, no correlations between any AD severity score and DI, race, ethnicity, income, education, or insurance type were found. CONCLUSION: The impact of socioeconomic factors on AD severity in our study population was less pronounced than expected. This could be because of regional differences, including access to high-quality care. The role of access as a deciding factor in the impact of socioeconomic status on AD outcome deserves further investigation.

A call for implementing augmented intelligence in pediatric dermatology.

Augmented intelligence (AI), the combination of artificial based intelligence with human intelligence from a practitioner, has become an increased focus of clinical interest in the field of dermatology. Technological advancements have led to the development of deep-learning based models to accurately diagnose complex dermatological diseases such as melanoma in adult datasets. Models for pediatric dermatology remain scarce, but recent studies have shown applications in the diagnoses of facial infantile hemangiomas and X-linked hypohidrotic ectodermal dysplasia; however, we see unmet needs in other complex clinical scenarios and rare diseases, such as diagnosing squamous cell carcinoma in patients with epidermolysis bullosa. Given the still limited number of pediatric dermatologists, especially in rural areas, AI has the potential to help overcome health disparities by helping primary care physicians treat or triage patients.

Gastrostomy tube feeding in epidermolysis bullosa: A multi-center assessment of caregiver satisfaction.

BACKGROUND/OBJECTIVES: Gastrostomy tubes (G-tubes) are a feasible intervention for nutritional support in patients with epidermolysis bullosa (EB) who suffer from gastrointestinal involvement. However, some parents may be apprehensive about this surgical intervention. The purpose of this study is to assess caregiver satisfaction and experiences after G-tube insertion in children with EB. METHODS: Nine institutions sent an anonymous 89-item online questionnaire to caregivers of patients with EB and active G-tubes during an 8-week study period. The questionnaire consisted of eight sections and was formatted with multiple choice, Likert scales, dichotomous scales (yes/no), and free text. RESULTS: Twenty caregiver surveys were completed. All caregivers were parents (100%). The average age of G-tube placement was 2.7 years (SD: 2.1, range 0-8) and duration of the G-tube utilization was an average of 12.0 years (SD: 7.8, range 1-25). EB subtypes were dystrophic (n = 15/20, 75%), junctional (n = 3/20, 15%), and simplex (n = 2/10, 10%). Almost all caregivers (n = 18/20, 90%) reported high levels of satisfaction with G-tube management (scores > 20 on the modified SAGA-8 scale). More than half of caregivers (n = 12/20, 60%) reported that, retrospectively, they would have desired earlier adoption of the G-tube. Caregivers rated mealtimes as more enjoyable and easier both for themselves and the individual with EB post-G-tube placement. CONCLUSION: The survey demonstrates a high rate of satisfaction for G-tube use among caregivers of patients with EB across varying ages and household settings. The free-text responses provide unique insight into caregiver's individual experiences regarding G-tubes to be considered for future studies.

Therapies for cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa: a systematic review of 157 cases.

BACKGROUND: Invasive cutaneous squamous cell carcinomas (cSCC) are a leading cause of death in recessive dystrophic epidermolysis bullosa (RDEB), a rare blistering genodermatosis. Outcomes of RDEB-cSCC therapies have primarily been described in case reports. Systematic studies are scarce. This systematic review aims to assess the pathophysiology, clinical characteristics, and outcomes of RDEB-cSCCs, with a focus on results and mechanisms of recent immunotherapies and anti-EGFR treatments. RESULTS: A systematic literature search of epidermolysis bullosa and cSCC was performed in February 2024, using PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and EudraCT databases. Cases with administration of systematic therapies and unpublished outcomes regarding death were tracked with corresponding authors. Data extraction and risk of bias assessment was performed by two independent reviewers. Of 1132 references in the original search, 163 relevant articles were identified, representing 59 case reports, 7 cohort studies, 49 abstracts, 47 in-vitro/in-vivo experiments, and 1 bioinformatic study. From these, 157 cases of RDEB-cSCCs were included. The majority of RDEB-cSCCs were well-differentiated (64.1%), ulcerated (59.6%), and at least 2 cm in size (77.6%), with a median age at diagnosis of 30 years old (range 6-68.4). Surgery was the primary form of treatment (n = 128), followed by chemotherapy and radiotherapy. Anti-EGFR therapy and immunotherapy was also reported beginning in 2009 and 2019, respectively. Survival time from first cSCC diagnosis to death was available in 50 cases. When stratified by their treatment regimen, median survival time was 1.85 years (surgery + chemotherapy, n = 6), 2 years (surgery only, n = 19), 4.0 years (+ anti-EFGR therapy, n = 10), 4 years (surgery + radiotherapy, n = 9), 4.6 years (+ immunotherapy, n = 4), and 9.5 years (surgery + chemotherapy + radiotherapy; n = 2). Treatment-related adverse events were primarily limited to impaired wound healing for immunotherapies and nausea and fatigue for anti-EGFR therapies. CONCLUSIONS: Despite the challenges of a limited sample size in a rare disease, this systematic review provides an overview of treatment options for cSCCs in RDEB. When surgical treatment options have been exhausted, the addition of immunotherapy and/or anti-EGFR therapies may extend patient survival. However, it is difficult to attribute extended survival to any single treatment, as multiple therapeutic modalities are often used to treat RDEB-cSCCs.

Predominance of Staphylococcus Correlates with Wound Burden and Disease Activity in Dystrophic Epidermolysis Bullosa: A Prospective Case-Control Study.

Recessive dystrophic epidermolysis bullosa is characterized by skin blistering and wounds. To uncover the changes in the skin and mucosal microbiome related to age and disease progression and microbiome impact on clinical and inflammatory laboratory parameters, swabs from wounded and unwounded skin, oral mucosa, and stool samples of 28 children with recessive dystrophic epidermolysis bullosa and 28 healthy controls were subjected to 16S-ribosomal RNA gene sequencing. Skin microbiome of patients with recessive dystrophic epidermolysis bullosa showed significantly reduced alpha diversity compared with that of healthy controls and showed significantly early, age-dependent predominance of Staphylococcus aureus, first in wounded skin and then in unwounded skin. These findings were more pronounced in the severe disease with higher abundances of S. aureus than in intermediate disease. S. aureus abundance correlated significantly with both acute and chronic wound burden. Changes in oral mucosal and gut microbiome were discrete, with no significant differences in alpha diversity. Our findings show that children with recessive dystrophic epidermolysis bullosa experience skin microbiome changes early in life. Longitudinal studies should confirm that dysbiosis starts in wounds and later extends to unwounded skin. The predominance of S. aureus significantly correlates with wound burden and disease activity and, to some extent, with systemic inflammation.