Stigmatization and Mental Health Impact of Chronic Pediatric Skin Disorders.

Importance: Chronic skin disorders in children frequently are visible and can cause stigmatization. However, the extent of stigmatization from chronic skin disease and association with mental health needs further study. Objective: To examine the extent of stigma, dependence on disease visibility and severity, and association with mental health and quality of life (QOL) in chronic pediatric skin disease. Design, Setting, and Participants: A cross-sectional, single-visit study was conducted at 32 pediatric dermatology centers in the US and Canada from November 14, 2018, to November 17, 2021. Participants included patients aged 8 to 17 years with chronic skin disease and 1 parent. Main Outcomes and Measures: Using the Patient-Reported Outcomes Measurement Instrumentation System (PROMIS) Stigma-Skin, the extent of stigma with child-, caregiver-, and physician-assessed disease visibility (primary outcome) and severity was compared, as well as reduced QOL (assessed by Skindex-Teen), depression, anxiety, and poor peer relationships (PROMIS child and proxy tools) (secondary outcomes). Results: The study included 1671 children (57.9% female; mean [SD] age, 13.7 [2.7] years). A total of 56.4% participants had self-reported high disease visibility and 50.5% had moderate disease severity. Stigma scores significantly differed by level of physician-assessed and child/proxy-assessed disease visibility and severity. Among children with chronic skin disorders, predominantly acne, atopic dermatitis, alopecia areata, and vitiligo, only 27.0% had T scores less than 40 (minimal or no stigma) and 43.8% had at least moderate stigma (T score ≥45) compared with children with a range of chronic diseases. Stigma scores correlated strongly with reduced QOL (Spearman ρ = 0.73), depression (ρ = 0.61), anxiety (ρ = 0.54), and poor peer relationships (ρ = -0.49). Overall, 29.4% of parents were aware of bullying of their child, which was strongly associated with stigma (Cohen d = -0.79, with children who were not bullied experiencing lower levels of stigma). Girls reported more stigma than boys (Cohen d = 0.26). Children with hyperhidrosis and hidradenitis suppurativa were most likely to have increased depression and anxiety. Conclusions and Relevance: The findings of this study suggest that physician assessment of disease severity and visibility is insufficient to evaluate the disease impact in the patient/caregiver. Identifying stigmatization, including bullying, and tracking improvement through medical and psychosocial interventions may be a key role for practitioners.

Inflammatory linear verrucous epidermal nevus (ILVEN) encompasses a spectrum of inflammatory mosaic disorders.

BACKGROUND: Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disease characterized by pruritic erythematous scaly plaques distributed along the lines of Blaschko. Two cases of ILVEN with CARD14 mutations and one case with a GJA1 mutation have been previously reported. OBJECTIVE: To elucidate the genetic cause of a cohort of patients diagnosed based on clinical and histopathological evaluation with ILVEN. METHODS: We recruited patients diagnosed with ILVEN based on clinical and histopathological criteria. Exome sequencing of affected skin with or without blood/saliva was performed and germline and somatic pathogenic variants were identified. RESULTS: Five patients were enrolled. All had skin lesions from birth or early childhood. Two patients developed psoriasis vulgaris after the diagnosis of ILVEN. The first had a germline heterozygous CARD14 mutation and a post-zygotic hotspot mutation in KRT10. The histopathologic evaluation did not show epidermolytic hyperkeratosis. The second had a post-zygotic hotspot mutation in HRAS. Her ILVEN became itchy once psoriasis developed. One patient was re-diagnosed with linear porokeratosis based on a germline mutation in PMVK and a post-zygotic second-hit mutation. Two patients were re-diagnosed with congenital hemidysplasia with ichthyosiform nevus and limb defect nevus based on germline NSDHL mutations. CONCLUSION: ILVEN is a clinical descriptor for a heterogenous group of mosaic inflammatory disorders. Genetic analysis has the potential to more precisely categorize ILVEN and permits pathogenesis-directed therapies in some cases.

Toxic epidermal necrolysis-like acute graft-versus-host disease in pediatric bone marrow transplant patients: Case series and review of the literature.

BACKGROUND/OBJECTIVES: Complications of hematopoietic stem cell transplant (HSCT) include acute graft-versus-host disease (aGVHD). Severe cutaneous aGVHD can present with generalized erythroderma, desquamation, and bullae which can mimic toxic epidermal necrolysis (TEN). TEN occurs in response to a culprit medication. Transplant patients are often on many medications, making it difficult to distinguish between the two conditions. Given that TEN-like aGVHD is rare, we describe a case series of pediatric patients and review the literature. METHODS: This is a multi-institutional case series of children who developed TEN-like aGVHD following bone marrow transplantation. Demographic, clinical, and treatment information was collected. RESULTS: Ten patients were identified. Median age at transplantation was 8.5 years (range 0.12-17 years). Median time from transplant to first skin symptoms was 35 days (range 6-110 days) and to first TEN-like symptoms was 40 days (range 16-116 days). 7/10 had other organ GVHD involvement. All patients were on concurrent medications at time of first skin symptoms including immunosuppression for GVHD prophylaxis, infection prophylaxis or treatment, and pain medication. Treatments for TEN-like aGVHD included immunosuppression. CONCLUSIONS: We observe that patients with > or equal to 50% BSA involvement of their skin with TEN-like aGVHD, extracutaneous GVHD, and lack of reepithelization tend to have poor outcomes. Given the rarity of this condition, multidisciplinary care of these patients is important for accurate and timely diagnosis and treatment.

Molecular and Clinical Outcomes After Intravenous Gentamicin Treatment for Patients With Junctional Epidermolysis Bullosa Caused by Nonsense Variants.

IMPORTANCE: Junctional epidermolysis bullosa (JEB) is an incurable blistering skin disorder with high infant mortality often caused by nonsense variants in the genes that encode laminin 332. OBJECTIVE: To evaluate the safety and outcomes following intravenous gentamicin readthrough therapy and subsequent laminin 332 expression in patients with JEB. DESIGN, SETTING, AND PARTICIPANTS: This open-label, pilot nonrandomized clinical trial assessed 1 course of low- or high-dose intravenous gentamicin, including follow-up at 30 and 90 days after treatment. Five pediatric patients with JEB (2 with intermediate JEB and 3 with severe JEB) and confirmed nonsense variants in LAMA3 or LAMB3 in 1 or 2 alleles and decreased expression of laminin 332 at the dermal-epidermal junction of their skin participated in the study, which was performed at a single institution in collaboration with physicians and home infusion services near the patients from April 1, 2019, to February 28, 2021, with follow-up until May 31, 2021. INTERVENTIONS: Three patients received gentamicin at 7.5 mg/kg daily for 14 days, and 2 patients received gentamicin at 10 mg/kg daily for 24 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were change in expression of laminin 332 in patients' skin and assessments for safety (ototoxic effects, nephrotoxic effects, and autoimmune response). Secondary outcomes included wound healing in monitored wounds and Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) score. RESULTS: After gentamicin treatment, all 5 patients (age range, 3 months to 10 years, 4 [80%] female) exhibited increased laminin 332 in the dermal-epidermal junction. By 1 month, 7 of 9 wounds in patients receiving low-dose intravenous gentamicin and all wounds in patients receiving high-dose intravenous gentamicin exhibited at least 50% wound closure. By 3 months, 8 of 9 wounds in patients receiving low-dose gentamicin and all wounds in patients receiving high-dose intravenous gentamicin exhibited greater than 85% closure. All 3 patients who were evaluated with EBDASI showed a decrease in total activity scores that met minimal clinically important differences 1 month after treatment. All 5 patients completed the study, and no ototoxic effects, nephrotoxic effects, or anti-laminin 332 antibodies were detected. CONCLUSIONS AND RELEVANCE: In this nonrandomized clinical trial, intravenous gentamicin therapy was associated with induced readthrough of nonsense variants in patients with JEB, restored functional laminin 332 in their skin, and wound closure during the 3-month study period. Although long-term safety and efficacy requires further evaluation, a single cycle of intravenous gentamicin may be a safe and readily available therapy in the short term for this population of patients with JEB. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT03526159 and NCT04140786.

Trends in office visits and treatment for urticaria in children in the United States, 1998-2016.

BACKGROUND/OBJECTIVES: Urticaria is a common condition with an estimated prevalence of up to 23% in the pediatric population. Studies characterizing visits and treatments for urticaria in the pediatric population are unavailable. Understanding visit and treatment trends for urticaria in the pediatric population may help inform care for patients with urticaria. METHODS: A total of 108 278 outpatient records from the National Ambulatory Medical Care Survey representing 3.4 billion visits by patients of age 18 and younger were analyzed. This study included the calendar years 1998 through 2016. RESULTS: Pediatricians saw the largest proportion of all visits (52.7%). Male and female patients accounted for approximately equal proportions of all visits for urticaria. There was a slight male predominance in visits to pediatricians (53.7%), whereas dermatologists saw female patients more frequently (63.3%). Most visits for urticaria were by non-Hispanic (78.1%) and White (78.2%) patients. H1 antihistamines were the most commonly prescribed treatment (70.3%), whereas topical corticosteroids were prescribed least frequently (4.9%). Topical corticosteroids were most frequently prescribed by dermatologists (7.7%). Non-H1 antihistamine and non-corticosteroid therapy were prescribed in 9.7% of all visits and in 4.5% of visits to pediatricians. Most visits for urticaria were to physicians in metropolitan areas (88.8%). Pediatricians saw the highest number of non-metropolitan area visits (56.3%). CONCLUSIONS: H1 antihistamines were the most commonly used therapy (70%), consistent with established treatment guidelines. Male and female pediatric patients present equally often for urticaria, but sex differences were seen with visit frequencies to certain specialties.

Persistent dysesthesias in involuted infantile hemangiomas: An uncommon complication in a common condition.

BACKGROUND/OBJECTIVES: Infantile hemangiomas (IHs) are common benign vascular tumors of infancy. IHs tend to grow in the first few months of life and then gradually involute over years, often leaving fibrofatty residua or textural changes in their place. Classically, these lesions are painless throughout their entire natural history; however, we now report on seven patients with involuted IH with intermittent but persistent sensory symptoms. METHODS: This is a multicenter case series in which members of the Birthmarks Focused Study Group of the Pediatric Dermatology Research Alliance (PeDRA) and the Hemangioma Investigator Group contributed patients with IH and dysesthesias from their clinical practices. Charts were then reviewed to document clinical details. RESULTS: Seven patients were included, presenting at an average age of 14.6 years (range 3-48 years) for complaints related to discomfort in the region of involuted IH. The majority (6/7) reported pain or tenderness to the area. One patient reported pruritus. All patients reported intermittent symptoms. The length of symptoms ranged between 4 months and 5 years. Treatment was attempted in 5/7 patients. Ice, oral propranolol, topical capsaicin, and intralesional triamcinolone partially improved symptoms. CONCLUSIONS: Persistent cutaneous dysesthesias were present in seven patients, in most cases many years after completion of involution. Further research is needed to fully elucidate the pathophysiology and optimal treatments for this IH complication.

Epidermolysis bullosa pruriginosa treated with dupilumab.

Epidermolysis bullosa pruriginosa (EBP) is a variant of dystrophic epidermolysis bullosa characterized by intense pruritus and prurigo nodularis-like lesions. While medical therapies for EBP exist, current treatments are not consistently effective, and symptoms often cause decreased quality of life. Here, we report two cases of EBP treated with dupilumab, which decreased symptoms of pruritus and improved skin findings. Both patients have been on dupilumab for over one year with sustained improvement and no adverse effects; although in one patient, increased dosing was required to attain optimal control of disease.

Treatment of MEK inhibitor-induced paronychia with doxycycline.

A 12-year-old girl with neurofibromatosis type 1 and a large facial plexiform neurofibroma had been participating in a selumetinib clinical trial for the past 5 years. Despite decreased tumor size, she developed recalcitrant selumetinib-induced paronychia. Various antibiotics, topical medications, and surgeries were only minimally effective. Full-dose doxycycline resolved the paronychia, and sub-antimicrobial dosing has prevented recurrences for several months, permitting her to continue her selumetinib course.

Post-zygotic ACTB mutations underlie congenital smooth muscle hamartomas.

BACKGROUND: Congenital smooth muscle hamartomas (CSMHs) are benign lesions that share clinical and histopathological features with Becker nevus, a mosaic disorder associated with post-zygotic ACTB mutations. Given the clinical and histopathological overlap between CSMH and Becker nevus, we hypothesized that post-zygotic mutations in ACTB may underlie CSMH. METHODS: Direct sequencing of ACTB gene in affected and unaffected tissue isolated from one case of hemihypertrichosis and hemihypertrophy corresponding to giant segmental CSMH and hemihypertrophy. This was followed by direct sequencing with and without enrichment assay for hotspot ACTB mutations in affected tissue from 12 samples of isolated CSMH from unrelated individuals. RESULTS: In total we identified somatic missense ACTB mutations in 9 out of 13 CSMHs (69%). Mutations were either novel or previously reported in Becker nevi and Becker nevus syndrome. CONCLUSIONS: CSMHs result from post-zygotic ACTB mutations. This study proves that CSMHs and Becker nevi are nosologically related, and expand the phenotypic spectrum of ACTB mutations.

Off-label use of dupilumab for pediatric patients with atopic dermatitis: A multicenter retrospective review.

BACKGROUND: Atopic dermatitis (AD) is a common, chronic type 2 inflammatory skin disease, typically starting in infancy, with increased risk for subsequent extracutaneous atopic morbidities. Dupilumab is the first biologic agent targeting type 2 inflammation approved by the U.S. Food and Drug Administration (USFDA); it was licensed in 2017 for adults with moderate to severe AD and 2 years later for adolescents. Systemic treatment for pediatric AD remains a significant unmet medical need. OBJECTIVE: To analyze off-label use of dupilumab in children with AD. METHODS: Multicenter retrospective review that evaluated children who were prescribed dupilumab for moderate to severe AD. RESULTS: One hundred eleven of 124 patients (89.5%) gained access to dupilumab after a mean of 9 weeks. The dosing range was 4 to 15.5 mg/kg for the loading dose and 2.0 to 15.3 mg/kg every other week for maintenance. The range was widest for 6- to 11-year-olds and was related to use of either full or half of adult dosing. Associated morbidities, treatment response, and adverse events were comparable to those in previous adolescent and adult trials. LIMITATIONS: The retrospective design of the study limited uniform data collection. CONCLUSION: Access to dupilumab was achievable for the majority of children after a mean 9-week delay because of insurance payment denial. This review supports dupilumab response and tolerability in children. Optimal dosing for patients younger than 12 years has not been defined. Availability of the drug in 2 different concentrations is an important safety issue.

Histopathologic findings characteristic of CARD14-associated papulosquamous eruption.

BACKGROUND: Pathogenic mutations in caspase recruitment domain-containing protein 14 (CARD14) lead to CARD14-associated papulosquamous eruption, which shares clinicopathologic findings with psoriasis and pityriasis rubra pilaris. We aimed to describe distinguishing histopathologic features of CARD14-associated papulosquamous eruption. METHODS: This retrospective study examined the histopathologic features of specimens from patients with confirmed CARD14-associated papulosquamous eruption and adult patients with plaque psoriasis and pityriasis rubra pilaris. RESULTS: Lesional skin biopsies from patients with CARD14-associated papulosquamous eruption consistently showed alternating checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis, and dilated vessels in the dermal papillae, with some cases also showing follicular plugging. CONCLUSION: CARD14-associated papulosquamous eruption has a range of findings, with a predominance of features typically associated with pityriasis rubra pilaris.

Phenotypic expansion of POFUT1 loss of function mutations in a disorder featuring segmental dyspigmentation with eczematous and folliculo-centric lesions.

Appearance of mosaic disorders in thin Blaschko lines suggests that somatic mutations in keratinocyte precursors underlie their pathogenesis. Germline heterozygous mutations in POFUT1 gene cause Dowling-Degos disease (DDD), a skin disease that features flexural reticulated hyperpigmentation and follicular-based lesions. POFUT1 mosaicism has not been described to date. Here, we describe a 9-year-old female with segmental hyper- and hypopigmented patches with overlying eczematous plaques and follicular papules. Employing paired whole exome sequencing of saliva and keratinocytes isolated from affected skin, we found a novel germline heterozygous POFUT1 deletion causing frameshift and premature codon termination and somatic copy-neutral loss of heterozygosity on chromosome 20 encompassing POFUT1. Expression levels of POFUT1 as well as other key regulators of the notch signaling pathway-NOTCH1, NOTCH2, and HES1-were reduced in affected keratinocytes compared with normal keratinocytes. Our findings provide the first evidence of POFUT1 postzygotic mutation and a phenotypic expansion of POFUT1 loss of function mutations. We show that a recessive loss of function mutation in POFUT1 produces a distinct clinical presentation with features (e.g., dermatitis) that are absent in the generalized form of DDD. This study demonstrates how analysis of mosaic disorders can reveal unexpected phenotypes for known genes.

Tufted angioma with associated Kasabach-Merritt phenomenon caused by somatic mutation in GNA14.

Tufted angioma (TA) is a rare vascular tumor characterized by histologic tufts of proliferating capillaries that occurs in infancy or early childhood, with a poorly understood pathogenesis. Though benign, TA can be associated with the Kasabach-Merritt phenomenon (KMP), a life-threatening consumptive coagulopathy and thrombocytopenia. Here, we explored the genetic mechanism underlying a case of TA associated with KMP via targeted sequencing of laser capture micro-dissected lesion and blood DNA, and identified a somatic, activating GNA14 mutation specific to the tumor. Our findings support aberrant GNA14 activation underlies the pathogenesis of TA associated with KMP.

Review of genodermatoses with characteristic histopathology and potential diagnostic delay.

Advances in human genetics have enabled discovery of new genes for inherited skin diseases and cutaneous malformations as well as refined categorization of genodermatoses. Careful phenotyping has been central to genetic discoveries, and it provides critical clues for clinical diagnoses, particularly when the skin disorder is not congenital. This article will review several lesser-known genodermatoses that often present after infancy with recognizable histopathologic features.