Iron status and burden of anemia in children with recessive dystrophic epidermolysis bullosa.

BACKGROUND AND OBJECTIVES: To describe the prevalence, severity, and management of anemia in a cohort of children with recessive dystrophic epidermolysis bullosa (RDEB) and to highlight the use of soluble transferrin receptor (sTfR) to diagnose iron deficiency in this chronic inflammatory state. METHODS: We studied a cohort of 114 patients with RDEB followed at a pediatric hospital-based Epidermolysis Bullosa Center from 2010 to 2020; data were prospectively tracked in a comprehensive clinical database that captured all visits, laboratory tests, iron infusions, and transfusions. The primary outcome was occurrence of anemia, which was assessed by age and sex, with and without transfusion support. Secondary outcomes included iron status using a combination of ferritin and sTfR levels, the cumulative incidence of parenteral iron therapy and transfusions, and survival. RESULTS: In RDEB, anemia begins in the first year of life and becomes more frequent and severe with age. The prevalence of iron deficiency anemia (IDA) estimated by ferritin was 33.6% (37/110), but the sTfR/log10 -ferritin ratio indicated a 1.5-fold higher true prevalence of IDA of 50.6% (41/81). 53.5% (61/114) received parenteral iron infusions, transfusions, or both. Higher ferritin was associated with earlier mortality. CONCLUSIONS: Individuals with RDEB have a high burden of anemia (IDA and anemia of inflammation) that requires frequent medical interventions. The sTfR/log10 -ferritin ratio improves the detection of iron deficiency in the context of inflammation and guides therapy.

Prevalence of delayed puberty and low bone density in patients with epidermolysis bullosa: Insight from a large single center's experience.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare genetic skin conditions that result in skin fragility. EB can be quite severe with chronic inflammation and malnutrition impairing growth and pubertal development. These factors have potential consequences for skeletal health. We aimed to determine the prevalence of delayed puberty and low bone mineral density (BMD) for age in children and young adults with EB. METHODS: Electronic medical records (EMR) of patients with confirmed EB <30 years of age at time of initial encounter at Cincinnati Children's Hospital Medical Center between January 1, 2010 and September 30, 2020 were reviewed. Natural language processing software was used to categorize pubertal status of patients with EB as early, normal or delayed. BMD was measured by dual energy x-ray absorptiometry and categorized as low if height adjusted Z-score was <-2.0 using age, sex and race specific reference ranges. RESULTS: 29% of individuals with EB had low BMD with most cases occurring prior to 10 years of age. Of patients who reached adolescence, 23% failed to develop any signs of puberty in the normal range (before age 13 in females or 14 in males) and BMD Z-scores further declined in these individuals. CONCLUSION: Delayed puberty is an under-recognized comorbidity of individuals with EB, especially in those with recessive dystrophic EB, and can have a significant impact on BMD.

Assessing pain catastrophizing and functional disability in pediatric epidermolysis bullosa patients.

BACKGROUND/OBJECTIVES: The primary objective was to assess pain catastrophizing and functional disability in pediatric patients with epidermolysis bullosa (EB) and their parents/guardians. Secondary objectives included examining relationships between pain catastrophizing, functional disability, and correlations with other factors (e.g., age, disease severity, and percent of body surface area (BSA) involved). METHODS: Patients with EB ages 8-16 and their parents/guardians who were English or Spanish speaking completed a one-time online survey. Parent measures included: demographics questionnaire, Pain Catastrophizing Scale-Parent (PCS), and Parent Functional Disability Inventory (FDI). Child measures included: PCS child and child FDI. Higher scores on both scales indicate higher levels of catastrophizing and functional disability. RESULTS: Of 31 children, the mean age was 11.47 years and the majority (70.97%) had dystrophic EB. Mean scores were: 35.84 = PCS parent; 34.58 = PCS child; 30.87 = parent FDI; 29.77 = child FDI. Total scores for PCS parent, parent FDI, and child FDI increased significantly with disease severity and percentage of involved BSA (p < .01 for all). Total scores for PCS child increased significantly with percent of EB skin involvement (p = .04) but not disease severity. Older children reported more functional disability than their parents and younger children (p = .02). CONCLUSIONS: Our results demonstrate significant positive correlations between negative thoughts related to pain and the experience of functional difficulties in patients with EB and their caregivers. Psychological, psychiatric, and/or behavioral interventions to help managing chronic pain may be effective for patients with EB.

A retrospective analysis of diagnostic testing in a large North American cohort of patients with epidermolysis bullosa.

BACKGROUND: Accurate diagnosis of epidermolysis bullosa (EB) has significant implications for prognosis, management, and genetic counseling. OBJECTIVE: To describe diagnostic testing patterns and assess diagnostic concordance of transmission electron microscopy (TEM), immunofluorescence mapping (IFM), and genetic analysis for EB. METHODS: A retrospective cohort included patients enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database from January 1, 2004, to July 8, 2019. Tests concluding the same EB type (EB simplex, junctional EB, dominant dystrophic EB, and recessive dystrophic EB) were considered concordant; those concluding different EB types were considered discordant; and those with nonspecific/nondefinitive results were equivocal. RESULTS: A total of 970 diagnostic tests were conducted from 1984 to 2018 in 771 patients. Genetic analyses were performed chronologically later than IFM or TEM (P < .001). The likelihood of undergoing genetic analysis was greater for junctional EB and recessive dystrophic EB, and the same for dominant dystrophic EB as compared with EB simplex. TEM results in 163 patients were equivocal (55%), concordant (42%), and discordant (3%). IFM results in 185 patients were equivocal (54%), concordant (42%), and discordant (4%). LIMITATIONS: Retrospective design. CONCLUSIONS: Diagnostic testing has shifted in favor of genetic analysis. TEM and IFM frequently offer equivocal findings when compared to the specificity afforded by genetic analysis.

Enteral iron absorption in patients with recessive dystrophic epidermolysis bullosa.

BACKGROUND/OBJECTIVES: To determine whether iron was being enterally absorbed in anemic patients with recessive dystrophic epidermolysis bullosa (RDEB). METHODS: Anemic patients with RDEB who were refractory or had poor adherence to oral or gastrostomy-given iron underwent enteral iron absorption challenges. Subjects were given 2 mg/kg of elemental iron. Successful iron absorption was defined as a two- to threefold increase of serum iron or a rise to above 100 µg/dL. RESULTS: Nine of 12 iron challenges did not show increased iron absorption. Only three of the ten subjects demonstrated elevated iron absorption. All patients had elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), low serum albumin, and hemoglobin levels. Eight challenges were in patients with elevated soluble transferrin receptor (STFR)/log ferritin levels, indicating iron deficiency. The three challenges with elevated iron absorption also had elevated STFR/log ferritin as well as elevated ESR and CRP, but these inflammatory markers were, in general, less elevated than those in non-absorbers. CONCLUSIONS: Enteral iron is routinely prescribed for anemic patients with RDEB assuming a component of iron deficiency. Adherence to enteral iron tends to be unreliable due to unpalatable taste and gastrointestinal complaints. Enteral iron absorption tests are relatively noninvasive and appear to be well tolerated. Poor gastrointestinal iron absorption may be an important factor in failure to improve anemia in RDEB enterally. It may be prudent to test patients with RDEB who are anemic and not responding well to conventional iron supplements with iron absorption tests and to consider replacement with intravenous iron in iron-deficient patients.

Comparison of Alternative Tumor Size Classifications for Posterior Uveal Melanomas.

Purpose: Determine which posterior uveal melanoma (PUM) size classification with three categories has the best prognostic discrimination. Methods: Single-institution study of 424 consecutive patients with PUM. The tumor's largest basal diameter (LBD), smallest basal diameter (SBD), and thickness (TH) were estimated by fundus mapping and ultrasonography. Tumors were assigned to "small," "medium," or "large" size categories defined by 11 different classifications (Linear LBD, Rectangular LBD × TH, Cubic LBD × SBD × TH, Warren Original, Warren Modified, Augsburger, COMS Original, COMS Revised, TNM 2002, and modified TNM 2010 classification [a,b]). Prognostic significance of classifications was evaluated by Kaplan-Meier event curves with computation of log rank test for trend statistic. Results: In six classification systems (Warren Original, Warren Modified, COMS Revised, TNM 2002, TNM 2010a, TNM 2010b) >50% of tumors fell within one subgroup. In the Warren Original classification <5% of tumors fell within one subgroup. Separation of Kaplan-Meier curves among three size categories was judged "excellent" in four classifications (Linear LBD, Cubic Volume, TNM 2010a, and TNM 2010b) and "very poor" in the Warren Original. Linear LBD classification was associated with highest log rank statistic value. TNM 2010a, TNM 2010b, TNM 2002, Augsburger, and Cubic Volume classifications were also determined to be quite good. Conclusions: Linear LBD classification was the best three-size category discriminator among low-, intermediate-, and high-risk subgroups. Considering our findings, it seems possible that the arduous work required to apply complex classifications, especially for three-category systems, for PUM may not be justified in routine clinical practice.

Frequency and implications of discordant gene expression profile class in posterior uveal melanomas sampled by fine needle aspiration biopsy.

PURPOSE: To determine the frequency of discordant gene expression profile (GEP) classification of posterior uveal melanomas sampled at 2 tumor sites by fine-needle aspiration biopsy (FNAB). DESIGN: Prospective single-institution longitudinal study performed in conjunction with a multicenter validation study of the prognostic value of GEP class of posterior uveal melanoma cells for metastasis and metastatic death. METHODS: FNAB aspirates of 80 clinically diagnosed primary choroidal and ciliochoroidal melanomas were obtained from 2 tumor sites prior to or at the time of initial ocular tumor treatment and submitted for independent GEP testing and classification. Frequency of discordant GEP classification of these specimens was determined. RESULTS: Using the support vector machine learning algorithm favored by the developer of the GEP test employed in this study, 9 of the 80 cases (11.3% [95% confidence interval: 9.0%-13.6%]) were clearly discordant. If cases with a failed classification at 1 site or a low confidence class assignment by the support vector machine algorithm at 1 or both sites are also regarded as discordant, then this frequency rises to 13 of the 80 cases (16.3% [95% confidence interval: 13.0%-19.6%]). CONCLUSION: Sampling of a clinically diagnosed posterior uveal melanoma at a single site for prognostic GEP testing is associated with a substantial probability of misclassification. Two-site sampling of such tumors with independent GEP testing of each specimen may be advisable to lessen the probability of underestimating an individual patient's prognostic risk of metastasis and metastatic death.