Topical everolimus therapy for epidermal nevi associated with woolly hair nevus in a patient with a mosaic HRAS mutation.

A patient with woolly hair nevus syndrome, presented with epidermal facial nevi by the age of 12 years. Despite transient improvement with topical 1% sirolimus cream, the facial nevus grew larger. The patient was then treated with topical 1% everolimus cream resulting in a reduction in the size of the nevus. This case highlights a novel use of topical 1% everolimus cream, which previously has not been used to treat epidermal nevi.

Characterization of wound microbes in epidermolysis bullosa: A focus on Pseudomonas aeruginosa.

The most common bacteria isolated from wound cultures in patients recorded in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database (EBCCOD) are Staphylococcus aureus and Pseudomonas aeruginosa. Given the prevalence of P. aeruginosa in this patient population and prior research implicating P. aeruginosa's potential role in carcinogenesis, we sought to further analyze patients with recorded wound cultures positive for Pseudomonas aeruginosa in the EBCCOD. We provide a descriptive analysis of this subset of patients and highlight potential avenues for future longitudinal studies that may have significant implications in our wound care management for patients with epidermolysis bullosa.

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.

Diagnosis and Care of the Newborn with Epidermolysis Bullosa.

Epidermolysis bullosa (EB) is a group of rare genetic disorders that are characterized by fragile skin. Because of its rarity, many neonatologists may not be familiar with the current diagnosis and treatment recommendations for EB. The classification of EB was updated in 2020. The diagnosis of EB is now more heavily based on genetic rather than clinical or histologic features. In this review, we summarize the basic classification of EB, the preferred methods of diagnosis including a panel of next-generation sequencing for all types of EB, as well as specific immunofluorescence and electron microscopy of skin biopsies in special circumstances. We also review the principles of skin care for the newborn with EB and discuss the possible associated comorbidities including infectious, gastrointestinal, respiratory, and genitourinary complications. Lastly, we discuss the approach to educating the family about the diagnosis, prognosis, and care of an infant with EB and describe resources for the successful transition of the infant from the hospital to the home.

Hematopoietic stem cell transplant for erythropoietic porphyrias in pediatric patients.

Cutaneous, hematopoietic, and hepatic manifestations of congenital erythropoietic porphyria (CEP) and erythropoietic protoporphyria (EPP) can be debilitating. We present our institution's experience with five patients with porphyria who underwent hematopoietic stem cell transplant (HSCT). Four patients with CEP, including three under age 2, received myeloablation. One patient with EPP, with prior liver transplant, received reduced intensity conditioning (RIC). Four patients are alive without porphyria symptomology and with full donor chimerism. HSCT corrects the defective heme pathway and should be considered early in patients with severe erythropoietic porphyrias to minimize end-organ damage. RIC regimens can minimize toxicity in patients with comorbidities.

Characterization of wound microbes in epidermolysis bullosa: Results from the epidermolysis bullosa clinical characterization and outcomes database.

BACKGROUND/OBJECTIVES: Patients with epidermolysis bullosa (EB) require care of wounds that are colonized or infected with bacteria. A subset of EB patients are at risk for squamous cell carcinoma, and bacterial-host interactions have been considered in this risk. The EB Clinical Characterization and Outcomes Database serves as a repository of information from EB patients at multiple centers in the United States and Canada. Access to this resource enabled broad-scale analysis of wound cultures. METHODS: A retrospective analysis of 739 wound cultures from 158 patients from 13 centers between 2001 and 2018. RESULTS: Of 152 patients with a positive culture, Staphylococcus aureus (SA) was recovered from 131 patients (86%), Pseudomonas aeruginosa (PA) from 56 (37%), and Streptococcus pyogenes (GAS) from 34 (22%). Sixty-eight percent of patients had cultures positive for methicillin-sensitive SA, and 47%, methicillin-resistant SA (18 patients had cultures that grew both methicillin-susceptible and methicillin-resistant SA at different points in time). Of 15 patients with SA-positive cultures with recorded mupirocin susceptibility testing, 11 had mupirocin-susceptible SA and 6 patients mupirocin-resistant SA (2 patients grew both mupirocin-susceptible and mupirocin-resistant SA). SCC was reported in 23 patients in the entire database, of whom 10 had documented wound cultures positive for SA, PA, and Proteus species in 90%, 50%, and 20% of cases, respectively. CONCLUSIONS: SA and PA were the most commonly isolated bacteria from wounds. Methicillin resistance and mupirocin resistance were reported in 47% and 40% of patients tested, respectively, highlighting the importance of ongoing antimicrobial strategies to limit antibiotic resistance.

Pediatric trichodysplasia spinulosa: A report of 2 cases and review of the literature.

Trichodysplasia spinulosa is a rare disorder caused by the ubiquitous trichodysplasia spinulosa-associated polyomavirus (TSPyV) and characterized clinically by predominately centrofacial, but often generalized, folliculocentric papules with protuberant keratinaceous spines. Although seroprevalence reaches up to 70% in adult populations, TSPyV causes clinical manifestations in a small percentage of patients who are immunosuppressed. Diagnosis can be made using typical clinical and histologic features, SV40T antibody immunostaining, and PCR of various tissues including the keratinaceous spine, skin, serum, urine, and CSF. Various topical and systemic medications have demonstrated variable success. Decreasing or discontinuing immunosuppression has also been shown to improve or alleviate clinical manifestations.

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.

Assessment of the Timing of Milestone Clinical Events in Patients With Epidermolysis Bullosa From North America.

Importance: Children with epidermolysis bullosa (EB) comprise a rare population with high morbidity and mortality. An improved understanding of the clinical trajectory of patients with EB, including age at time of clinical diagnosis and major clinical events, is needed to refine best practices and improve quality of life and clinical outcomes for patients with EB. Objectives: To describe demographics, clinical characteristics, milestone diagnostic and clinical events (such as initial esophageal dilation), and outcomes in patients with EB using the Epidermolysis Bullosa Clinical Characterization and Outcomes Database and to determine what characteristics may be associated with overall EB severity and/or disease progression. Design, Setting, and Participants: This cohort study included data on patients with EB who were enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database from January 1, 2011, to June 30, 2017; 17 participating EB centers in the United States and Canada contributed data to this study. Exposures: Type of EB, including recessive dystrophic epidermolysis bullosa (RDEB), junctional epidermolysis bullosa (JEB), dominant dystrophic epidermolysis bullosa (DDEB), and epidermolysis bullosa simplex (EBS). Main Outcomes and Measures: Demographic information, clinical characteristics (including age at onset of signs of EB and subsequent clinical diagnosis), types of diagnostic testing performed, and milestone clinical events for patients with RDEB. Results: Of 644 enrolled patients from 17 sites included in this study, 323 were male (50.2%), with a mean (SD) age of 14.4 (11.7) years; 283 (43.9%) had RDEB, 194 (30.1%) had EBS, 104 (16.2%) had DDEB, and 63 (9.8%) had JEB. Signs of disease were present at birth in 202 patients with RDEB (71.4%), 39 with JEB (61.9%), 60 with DDEB (57.7%), and 74 with EBS (38.1%). For those with signs of disease at birth, a clinical diagnosis was made at the time of birth in 135 patients with RDEB (67.0%), 31 with DDEB (52.6%), 35 with EBS, (47.3%) and 18 with JEB (46.2%). Patients with JEB had the highest rate of any confirmatory testing (51 of 63 [81.0%]), followed by RDEB (218 of 283 [77.0%]), DDEB (71 of 104 [68.3%]), and EBS (100 of 194 [51.5%]). For all types of EB, both electron microscopy and immunofluorescence microscopy were performed at younger ages than genetic analysis. Among 283 patients with RDEB, 157 (55.5%) had esophageal dilation, 104 (36.7%) had gastrostomy tube placement, 62 (21.9%) had hand surgery, 18 (6.4%) developed squamous cell carcinoma, and 19 (6.7%) died. Conclusions and Relevance: The findings suggest that diagnostic testing for EB is more common for patients with severe phenotypes. Earlier diagnostic testing may enable improved characterizations of patients so that appropriate counseling and clinical care may be offered, especially pertaining to milestone events for those with RDEB.

Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.

The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

Idiopathic Facial Aseptic Granuloma: Review of an Evolving Clinical Entity.

Idiopathic facial aseptic granuloma (IFAG), originally termed pyodermite froide du visage, describes a generally asymptomatic facial nodule presenting in childhood with clinical resemblance to pyoderma or cystic, granulomatous, or vascular lesions. Clinical understanding is constantly evolving, with recent observations indicating that IFAG may represent a subtype of childhood rosacea. We present a case of IFAG associated with eyelid chalazions in a 19-month-old boy. Although his clinical course paralleled previously reported IFAG cases, we observed a unique ultrasound variation during initial diagnostic examination. Further delineation of clinical, imaging, and histologic properties of IFAG may reveal insights into etiologic associations and ideal management.

Development and Validation of a Quality-of-Life Instrument for Infantile Hemangiomas.

Infantile hemangiomas (IH) are common tumors for which there is no validated disease-specific instrument to measure the quality of life in infants and their parents/caregivers during the critical first months of life. This study prospectively developed and validated a quality-of-life instrument for patients with IH and their parents/caregivers and correlated demographic and clinical features to the effects on the quality of life. A total of 220 parents/caregivers completed the 35-item Infantile Hemangioma Quality-of-Life (IH-QoL) instrument and provided demographic information. The dimensionality of the items was evaluated using factor analysis, with results suggesting four factors: child physical symptoms, child social interactions, parent emotional functioning, and parent psychosocial functioning. Each factor fit the Rasch measurement model with acceptable fit index (mean square <1.4) and demonstrated excellent internal consistency, with alpha ranging from 0.76 to 0.88. The final instrument consists of four scales with a total of 29 items. Content validity was verified by analyzing parents' responses to an open-ended question. Test-retest reliability at a 48-hour interval was supported by a total IH-QoL intraclass correlation coefficient of 0.84. Certain clinical characteristics of hemangioma, including those located on the head and neck, in the proliferative stage, and requiring treatment, are associated with a greater impact on QoL.

Hand function and quality of life in children with epidermolysis bullosa.

Patient-reported outcomes are becoming increasingly important to clinical care. Epidermolysis bullosa (EB), a rare genetic skin disorder, can result in severe hand impairment, but parent and patient perceptions of hand function have never been assessed. This study aimed to quantify parent- and patient-reported hand function and assess its relationship with quality of life (QOL) in children with EB. This cross-sectional study included children with EB treated at an interdisciplinary EB center. Hospital records were searched for demographic characteristics and medical history. Eligible families were invited to complete two surveys by mail or telephone. The ABILHAND-Kids questionnaire assessed manual hand ability for 21 functions. The Quality of Life in Epidermolysis Bullosa questionnaire assessed EB-related QOL. Hand function and QOL of various subtypes were compared using Mann-Whitney tests. Seventy-one parents and patients ages 2 to 18 years with EB from 20 states in the United States completed questionnaires. Children with recessive dystrophic EB reported the worst hand function and QOL. Bimanual functions involving finger mobility were the most challenging for all EB subtypes. QOL was highly related to the degree of hand function, being correlated with 20 of the 21 individual hand functions and most associated with the ability to perform unimanual functions. Parent- and patient-reported hand function can be measured in children with EB using the ABILHAND-Kids questionnaire. Hand impairment is strongly associated with worse QOL, probably due to difficulty performing daily activities. The effect of interventions such as hand surgery could be prospectively evaluated using this questionnaire.

Pyloric atresia with epidermolysis bullosa: fetal MRI diagnosis with postnatal correlation.

Pyloric atresia is an uncommon congenital gastric outlet obstruction, accounting for only 1% of gastrointestinal atresias. Up to 55% of cases have associated anomalies, the most common of which is epidermolysis bullosa. Fetal MRI findings of the epidermolysis bullosa-pyloric atresia association have not been previously reported. We present a case of this association diagnosed by prenatal MRI with corroborative postnatal imaging and surgical findings.

Measuring the severity of infantile hemangiomas: instrument development and reliability.

OBJECTIVES: To develop instruments that measure the severity of infantile hemangiomas (Hemangioma Severity Scale [HSS]) and the complications of infantile hemangiomas for longitudinal use (Hemangioma Dynamic Complication Scale [HDCS]). DESIGN: Instrument development and reliability study. SETTING: Academic research. PARTICIPANTS: The HSS and the HDCS were developed through the collaborative effort of members of the Hemangioma Investigator Group Research Core, an expert multi-institutional research group. After development of the scales, 13 pediatric dermatologists used the HSS to score 20 different hemangiomas. In addition, 12 pediatric dermatologists used the HDCS to score hemangioma-related complications for 24 clinical scenarios. Interrater and intrarater reliability was measured for both scales. MAIN OUTCOME MEASURES: Interrater and intrarater reliability. RESULTS: For the HSS, interrater reliability and intrarater reliability exceeded 99%. Similarly, the HDCS had a high rate of interrater agreement; for individual items, agreement among raters was 67% to 100%, with most clinical scenarios demonstrating greater than 90% agreement. Intrarater reliability was excellent for all individual items of the HDCS. CONCLUSION: The HSS and the HDCS are reliable scales that can be used to measure the severity of infantile hemangiomas, including the severity of complications for longitudinal use.

Five cases of anti-tumor necrosis factor alpha-induced psoriasis presenting with severe scalp involvement in children.

Although anti-tumor necrosis factor alpha (TNF-α) agents are commonly used to treat psoriasis and other inflammatory diseases in adults and children, numerous reports have documented new-onset or flaring psoriasis in adults treated for the other conditions. Individual case reports have documented similar observations in three children. We report a series of anti-TNF-α-induced psoriasis in children with juvenile idiopathic arthritis or inflammatory bowel disease treated at a large children's hospital. All five patients presented with severe scalp involvement. One child was treated with adalimumab for juvenile idiopathic arthritis, and four received infliximab for inflammatory bowel disease. The five patients developed psoriasis 2 to 10 months after initiating anti-TNF-α therapy. They presented with erythematous, scaly, crusted scalp lesions. Three of the five patients were initially treated with griseofulvin for presumed tinea capitis. The anti-TNF-α agent was discontinued at the time of diagnosis in two cases. Topical steroids were the mainstay of psoriasis therapy, with improvement in four of five patients. Anti-TNF-α agents have been associated with the onset or worsening of psoriasis in adults, but this has rarely been reported in children. We describe five pediatric cases of anti-TNF-α-induced psoriasis presenting with severe scalp involvement and review their subsequent management. We hope that clinicians caring for patients receiving anti-TNF-α agents will consider psoriasis from the onset of cutaneous symptoms and institute appropriate therapy or referral.

Upper airway complications of junctional epidermolysis bullosa.

OBJECTIVE: To assess the incidence of upper airway pathology in patients with junctional epidermolysis bullosa (JEB). STUDY DESIGN: We conducted a retrospective chart review of all patients with JEB who came to an interdisciplinary epidermolysis bullosa center at a tertiary care institution between 2004 and 2010. RESULTS: Twenty-five patients with JEB were identified, and 12 patients were seen in the otolaryngology clinic (age range, 2 months-15 years; 8 male, 4 female). Of the 12 patients, 8 underwent rigid laryngoscopy and bronchoscopy for upper respiratory tract symptoms; 7 of these patients displayed laryngeal pathology, and 5 of them underwent surgical intervention with successful resolution of symptoms. Furthermore, none of these patients had any short- or long-term complications from their surgery. A strict protocol and a precise problem-focused cold surgical technique were used in these cases to protect skin and mucus membranes. CONCLUSION: With appropriate precautions, endoscopic laryngeal surgery can be safe and effective in patients with JEB and larygnotracheal disease. Endoscopic laryngeal surgery is feasible when indicated for these patients.