Multicenter Study of Long-Term Outcomes and Quality of Life in PHACE Syndrome after Age 10.

OBJECTIVE: To characterize long-term outcomes of PHACE syndrome. STUDY DESIGN: Multicenter study with cross-sectional interviews and chart review of individuals with definite PHACE syndrome ≥10 years of age. Data from charts were collected across multiple PHACE-related topics. Data not available in charts were collected from patients directly. Likert scales were used to assess the impact of specific findings. Patient-Reported Outcomes Measurement Information System (PROMIS) scales were used to assess quality of life domains. RESULTS: A total of 104/153 (68%) individuals contacted participated in the study at a median of 14 years of age (range 10-77 years). There were infantile hemangioma (IH) residua in 94.1%. Approximately one-half had received laser treatment for residual IH, and the majority (89.5%) of participants were satisfied or very satisfied with the appearance. Neurocognitive manifestations were common including headaches/migraines (72.1%), participant-reported learning differences (45.1%), and need for individualized education plans (39.4%). Cerebrovascular arteriopathy was present in 91.3%, with progression identified in 20/68 (29.4%) of those with available follow-up imaging reports. Among these, 6/68 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite the prevalence of cerebrovascular arteriopathy, the proportion of those with ischemic stroke was low (2/104; 1.9%). PROMIS global health scores were lower than population norms by at least 1 SD. CONCLUSIONS: PHACE syndrome is associated with long-term, mild to severe morbidities including IH residua, headaches, learning differences, and progressive arteriopathy. Primary and specialty follow-up care is critical for PHACE patients into adulthood.

Risk factors and outcomes of melanoma in children and adolescents: A retrospective multicenter study.

BACKGROUND: Pediatric melanoma presents with distinct clinical features compared to adult disease. OBJECTIVE: Characterize risk factors and negative outcomes in pediatric melanoma. METHODS: Multicenter retrospective study of patients under 20 years diagnosed with melanoma between January 1, 1995 and June 30, 2015 from 11 academic medical centers. RESULTS: Melanoma was diagnosed in 317 patients, 73% of whom were diagnosed in adolescence (age ≥11). Spitzoid (31%) and superficial spreading (26%) subtypes were most common and 11% of cases arose from congenital nevi. Sentinel lymph node biopsy was performed in 68% of cases and positive in 46%. Fatality was observed in 7% of cases. Adolescent patients with melanoma were more likely to have family history of melanoma (P = .046) compared to controls. LIMITATIONS: Retrospective nature, cohort size, control selection, and potential referral bias. CONCLUSION: Pediatric melanoma has diverse clinical presentations. Better understanding of these cases and outcomes may facilitate improved risk stratification of pediatric melanoma.

Childhood atopic dermatitis is associated with cognitive dysfunction: A National Health Interview Survey study from 2008 to 2018.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease in children and adults. Little is known regarding the association of childhood AD with cognitive dysfunction. OBJECTIVE: To evaluate the association of AD and cognitive dysfunction, including memory impairment, developmental delays and attention deficit (hyperactivity) disorder in US children (age <18 years). METHODS: Data was analyzed from the National Health Interview Survey 2008 to 2018, which used a multistage, clustered, cross-sectional design. RESULTS: The prevalences of cognitive dysfunction, such as memory impairment (0.87% vs 0.42%), developmental delays (6.96% vs 3.87%), and attention deficit (hyperactivity) disorder (10.78% vs 8.10%), were higher in children with vs without AD. In multivariable logistic regression models adjusting for age, sex, race, region, socioeconomic factors, allergic conditions, and mental health, childhood AD was associated with higher odds of memory impairment (adjusted odds ratio [95% confidence interval]: 1.84 [1.34-2.51]), developmental delays (1.54 [1.40-1.70]), and attention deficit (hyperactivity) disorder (1.31 [1.20-1.42]) compared with children without AD. Childhood atopic disease (defined as comorbid AD, asthma, allergic rhinitis, and food allergies) further increased the prevalence of developmental delays to 13.44% (2.10 [1.20-3.70]) in boys but not in girls. CONCLUSION: In a nationally representative sample of the US population, a statistically significant and positive association between childhood AD and atopic disease with cognitive dysfunction was identified (P < .001). Furthermore, a dimorphic relationship with developmental delays was identified between sexes.

Is prolonged monitoring necessary? An updated approach to infantile hemangioma treatment with oral propranolol.

BACKGROUND/OBJECTIVES: Infantile hemangiomas (IH) are the most common soft-tissue tumors in childhood, occurring in up to 1 in 10 infants. Oral propranolol has been well established as the first-line treatment of complicated hemangiomas; however, variability in the administration protocol remains. We sought to evaluate our current propranolol treatment protocols to determine if the level of monitoring and follow-up predicts immediate or future adverse events by comparing one in-person visit vs two in-person visits versus teledermatology for treatment initiation and dose escalation. METHODS: We analyzed retrospective data on 279 patients diagnosed with IH and treated with oral propranolol on an in-person or virtual telemedicine outpatient basis from January 01, 2015 through May 31, 2020. Data were collected via chart review on all aspects of patient demographics, treatment indication, treatment initiation, adverse events, and follow-up visits. RESULTS: Two monitoring visits (Protocol 1) versus one (Protocol 2) was not associated with decreased adverse outcomes (P = .255). The odds of having an adverse event in Protocol 1 compared to Protocol 2 was insignificant (OR: 0.64; CI: 0.30-1.38). The most frequently reported adverse event among patients in both protocols was sleep disturbance. However, it did not vary significantly among the groups (P = .980, OR: 0.98, CI: 0.35-2.69). CONCLUSION: Prolonged in-office monitoring of propranolol initiation and dose escalation (Protocol 1) may not be necessary for the setting of adequate prescreening as it does not predict immediate or future adverse events.

Assessing vaccination reactions in pediatric patients with maculopapular cutaneous mastocytosis.

Immunization compliance in the United States is declining, in part due to misinformation and fear surrounding adverse vaccination reactions. Recently, there have been data published in the allergy and immunology literature to show that there may be a relationship between routine vaccinations and induction of symptoms in cutaneous mastocytosis patients; however, this has not yet been explored in the dermatology literature. We sought to uncover the prevalence of vaccine reactions due to mast cell activation within our cohort of maculopapular cutaneous mastocytosis (MPCM) patients in order to contribute to ensuring administration safety, managing familial expectations, and encouraging continued adherence. Our results indicate that while incidence of reaction rates may be higher than the national average, they are mild and families should be counseled to follow recommended immunization schedule guidelines.

TH2 sensitization in the skin-gut-brain axis: How early-life Th2-mediated inflammation may negatively perpetuate developmental and psychologic abnormalities.

We recently reported children with comorbid atopic dermatitis (AD), asthma, allergic rhinitis, and food allergies displaying a 2.7-fold increase in developmental delays.2 To this end, we hypothesize unregulated increases in T helper-2 (Th2)-driven inflammation, such as those seen in atopic diseases, can exert deleterious effects on the developing brain. Recognizing that available information is incomplete and that many potential associations are not firmly established, we speculate these effects underlie the association between Th2 sensitization and cognitive dysfunction in children. In this review, we explore the role of Th2 sensitization in the skin-gut-brain axis and explain how it can lead to reduced connectivity and transmission in the developing brain. With a focus on AD, we explore the association between Th2 sensitization and developmental abnormalities such as developmental delays, memory impairment, autism spectrum disorder (ASD), and epilepsy/seizures. As such, we review the available literature to examine the impact of increased IL-4 exposure in early life on the brain. We explore the possible association between Th2 sensitization and psychologic dysfunction such as attention-deficit/hyperactivity disorder (ADHD), depression, anxiety, and suicidal ideation. We also examine the impact that increased exposure to glucocorticoids and neurotrophins in early life exerts on the developing brain. Last, we discuss future directions for the advancement of our knowledge as a scientific community including possible interventions to reduce developmental and psychologic aberrations in children.

Pruritus assessment tools for 6 to 7-year-old children: KidsItchyQoL and ItchyQuant.

BACKGROUND/OBJECTIVES: Measures of pruritus severity and quality of life (QoL) are necessary for the development of therapeutics for children with chronic pruritus. In children, questionnaires need to be developed for specific age groups given the differences in cognitive levels. In this study, we aimed to develop tools to assess QoL and pruritus severity in children 6 to 7-years-old with chronic pruritus. METHODS: Based on open interviews with children, we developed a cartoon-annotated QoL instrument, KidsItchyQoL, and validated an existing pruritus severity instrument, ItchyQuant, that measures pruritus impact and severity for the preceding week. Both instruments were administered to 100 children aged 6-7 years with chronic pruritus. The data were analyzed for reliability, reproducibility, construct validity, and responsiveness. RESULTS: We found the 14-item KidsItchyQoL to be reliable (Cronbach's α = 0.846) and reproducible (intraclass correlation coefficient (ICC) = 0.66) as was the ItchyQuant (ICC = 0.47). With respect to construct validity, examination of eigenvalues of the inter-item polychoric correlation matrix suggested three dominant factors. A subsequent confirmatory factor analysis suggested that a 3-dimensional simple structure model with correlated factors provided a reasonable data representation. The responsiveness of KidsItchyQoL and ItchyQuant (P = .005, GLM procedure) were demonstrated with scores changing as expected with the self-reported change of itch severity. CONCLUSIONS: These results demonstrate promise for a new set of reliable research tools to assess QoL and pruritus severity in children 6 to 7 years of age.

Tools to study the severity of itch in 8- to 17-year-old children: Validation of TweenItchyQoL and ItchyQuant.

BACKGROUND/OBJECTIVES: Validated pruritus-specific quality of life and self-reported severity instruments exist primarily for adults. Clinical trials to develop therapeutics for children with chronic pruritus are hampered by the paucity of appropriate outcome measures. To address this gap, we aimed to develop validated instruments to measure itch-specific quality of life and self-reported severity in children. METHODS: We conducted in-depth, open-ended interviews of itchy children and generated concepts to develop TweenItchyQoL. We administered TweenItchyQoL, ItchyQuant, a cartoon-annotated self-reported pruritus severity numeric rating scale (NRS), and a non-cartoon NRS to 175 itchy children aged 8-17 years. We analyzed the data for feasibility, preference, reliability, construct validity, and responsiveness. RESULTS: Average completion time was 4.8 minutes for TweenItchyQoL and 33 seconds for ItchyQuant. The majority of patients either preferred ItchyQuant or found no difference between ItchyQuant and the NRS. Cronbach's alpha for TweenItchyQoL total and subscales ranged from 0.84 to 0.95. Test-retest reliability coefficients were ≥0.7 for TweenItchyQoL and 0.4 for ItchyQuant. A 3-dimensional bifactor model was most appropriate (RMSEA = 0.048) on the confirmatory factor analyses. As a function of those reporting worsening, improvement, or no change at their final visit, TweenItchyQoL and ItchyQuant scores in those cohorts changed as expected. CONCLUSIONS: This new set of validated and feasible instruments shows promise to quantify itch severity and QoL impact in older children.

Pediatric maculopapular cutaneous mastocytosis: Retrospective review of signs, symptoms, and associated conditions.

BACKGROUND/OBJECTIVES: Though maculopapular cutaneous mastocytosis is the most common form of pediatric mastocytosis, it remains unclear which patients will experience severe symptoms. We sought to better define the presentation and the cutaneous and systemic signs and symptoms in patients with maculopapular cutaneous mastocytosis. METHODS: We analyzed retrospective data on 227 patients diagnosed with maculopapular cutaneous mastocytosis prior to age 15 years from five US clinical sites. We collected data on signs, symptoms, age of onset, and laboratory testing. RESULTS: Median age of onset of maculopapular cutaneous mastocytosis was 3 months, with 94% of patients presenting prior to age 2 (range 0-15 years). Patients presenting before age 2 had significantly lower serum tryptase level (P = .019). Greater number of skin lesions (P = .006), number of reported skin signs and symptoms (P < .001), and higher tryptase levels (P < .001) were associated with more systemic symptoms. CONCLUSION: Children with maculopapular cutaneous mastocytosis, who have greater skin involvement, higher serum tryptase level, and more skin signs and symptoms, are more likely to have systemic symptoms.

Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents.

Topical and systemic retinoids have long been used in the treatment of ichthyoses and other disorders of cornification. Due to the need for long-term use of retinoids for these disorders, often beginning in childhood, numerous clinical concerns must be considered. Systemic retinoids have known side effects involving bone and eye. Additionally, potential psychiatric and cardiovascular effects need to be considered. Contraceptive concerns, as well as the additive cardiovascular and bone effects of systemic retinoid use with hormonal contraception must also be deliberated for patients of childbearing potential. The Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group was formed to address these issues and to establish best practices regarding the use of retinoids in ichthyoses based on available evidence and expert opinion.

A retrospective multicenter study of fatal pediatric melanoma.

BACKGROUND: Pediatric melanoma is rare and diagnostically challenging. OBJECTIVE: To characterize clinical and histopathologic features of fatal pediatric melanomas. METHODS: Multicenter retrospective study of fatal melanoma cases in patients younger than 20 years diagnosed between 1994 and 2017. RESULTS: Of 38 cases of fatal pediatric melanoma identified, 57% presented in white patients and 19% in Hispanic patients. The average age at diagnosis was 12.7 years (range, 0.0-19.9 y), and the average age at death was 15.6 years (range, 1.2-26.2 y). Among cases with known identifiable subtypes, 50% were nodular (8/16), 31% were superficial spreading (5/16), and 19% were spitzoid melanoma (3/16). One fourth (10/38) of melanomas arose in association with congenital melanocytic nevi. LIMITATIONS: Retrospective nature, cohort size, and potential referral bias. CONCLUSIONS: Pediatric melanoma can be fatal in diverse clinical presentations, including a striking prevalence of Hispanic patients compared to adult disease, and with a range of clinical subtypes, although no fatal cases of spitzoid melanoma were diagnosed during childhood.

Salivary levels of angiopoietin-2 in infants with infantile haemangiomas treated with and without systemic propranolol.

Infantile haemangiomas (IHs) with functional or cosmetic concerns necessitate systemic treatment for which propranolol is the preferred treatment. However, the mechanism of action is unknown. Mouse models suggest the angiopoietin-2 (Ang2)/Tie-2 system is implicated. Ang2 can promote endothelial growth or induce apoptosis depending on the presence of vascular endothelial growth factor. This pilot study investigates the saliva Ang2 levels in infants with IH treated with and without systemic propranolol. Patients with clinically confirmed IHs were recruited from an academic paediatric dermatology centre. Treatment was based on clinical evaluation. Saliva samples were collected over 6 months. An enzyme-linked immunosorbent assay determined Ang2 levels. Ang2 levels were detectable in 45% of samples. However, by the late time point, only 28% had detectable levels. There were no changes of Ang2 over time, and there were no differences in Ang2 levels between groups. However, Ang2 levels were correlated with baseline size and changes in size from baseline. Ang2 is detectable in saliva of affected infants, but does not decrease with propranolol treatment. However, Ang2 levels are positively correlated with size and changes in size. Thus, Ang2 is not the primary factor in the mechanism of propranolol resulting in IH reduction.

Propranolol for infantile hemangiomas in developing countries.

BACKGROUND: Propranolol is the treatment of choicefor complicated infantile hemangiomas (IH). However,in some locations, propranolol has not yet becomestandard of care. To our knowledge, until 2014,propranolol had not been used in Afghanistan totreat IH. OBJECTIVES: To raise further awareness thatpropranolol is the treatment of choice for complicatedIH, suggest a propranolol induction, maintenance,and taper protocol, show an example of therapeuticsuccess in a resource-limited country, and discusspotential challenges. METHODS: At an academicteaching hospital in Kabul, Afghanistan, we conducteda retrospective chart review of patients treated withpropranolol for IH from 2014-2015. RESULTS: Seventeenpatients were treated using a modified protocol basedon consensus recommendations. Average age was 6.3months (range 2.5 to 18 months). Thirteen patientshad focal IH and four had large segmental facial IH.Three patients were lost to follow-up. The remaining14 had good response and very few complications,including one patient co-managed by utilizing storeand-forward teledermatology. CONCLUSIONS: Patientsin resource-limited countries can be managedsuccessfully using a modified version of a propranololinduction, maintenance, and taper protocol. Indeveloping countries where dermatologists arescarce, we suggest IH may be co-managed withprimary care physicians via teledermatology.

Severity of cutaneous findings predict the presence of systemic symptoms in pediatric maculopapular cutaneous mastocytosis.

Although the prognosis of maculopapular cutaneous mastocytosis (MPCM), also referred to as urticaria pigmentosa, is often benign, clinicians lack evidence to reliably predict those at risk of associated systemic manifestations. We sought to elucidate clinical markers of disease severity to provide better treatment and prognostic information for individuals with MPCM. A retrospective chart review querying characteristics of children diagnosed with MPCM in the Emory Dermatology Clinic was performed. Follow-up was obtained through a clinical encounter or telephone interview. Linear regression was used to determine predictors of the number of MPCM-related systemic symptoms. Of 67 subjects, 57% were male, and the mean age of onset was 4.5 months. The maximum number of MPCM lesions was 1 to 10 in 16%, 11 to 30 in 33%, 31 to 50 in 25%, 51 to 100 in 6%, and more than 100 in 20% of subjects. For their MPCM lesions, 46% of subjects reported itching, 34% flushing, and 25% blistering. Reported systemic symptoms included diarrhea (22%), abdominal pain (15%), wheezing or dyspnea (13%), vomiting (10%), bone pain (10%), headaches (8%), cough (10%), rhinorrhea (8%), irritability (6%), and anaphylaxis (1.5%). In a multivariate linear regression analysis, the maximum number of MPCM lesions (p = 0.02) and the number of skin symptoms (p < 0.01) were statistically significant predictors of the number of systemic symptoms, controlling for age of onset, body sites involved, and sex. The correlation between cutaneous findings and symptomatology could aid clinicians in identifying individuals with MPCM who might warrant systemic evaluation and therapy.

Anti-laminin-332 mucous membrane pemphigoid in a 9-year old girl.

Mucous membrane pemphigoid (MMP), an autoimmune subepithelial blistering disease that predominantly affects the mucous membranes, is usually diagnosed in elderly adults. Early diagnosis of MMP is crucial because it tends to run a chronic and progressive course with the potential for devastating scarring of the mucous membranes that may lead to blindness and airway compromise. A subtype of MMP, anti-laminin-332 MMP, is a rare blistering disorder in which autoantibodies are directed against laminin-332 (formerly epiligrin), a structural protein of the epidermal basement membrane. Herein we report what we believe to be the youngest patient diagnosed with anti-laminin-332 MMP, a 9-year-old girl with disease affecting only the oral, pharyngeal, and laryngeal mucosa, with no skin involvement.

Diagnosis of Vascular Anomalies in Patients with Skin of Color.

Vascular anomalies can be broadly classified as vascular tumors or vascular malformations, depending on the degree of endothelial involvement. These lesions can be subtle and challenging to diagnose in individuals with darker skin tones, which can lead to a delay in treatment. Improving diagnostic accuracy of these lesions may prevent progression and potential adverse outcomes when left untreated. Here, we present a review of common vascular anomalies with a focus on diagnostic considerations in individuals with skin of color.

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.

Comparison of Work Relative Value Units for Outpatient Pediatric and Adult Dermatology Encounters.

Importance: Dermatologists with specialty training in pediatric dermatology are scarce, which can mean extended wait times and reduced access to care for patients. Lower compensation for pediatric dermatology visits compared with adult visits may affect physician career choice and contribute to workforce shortages. Objective: To evaluate differences in work relative value units (wRVUs) generated by pediatric and adult outpatient dermatology encounters. Design, Setting, and Participants: This cross-sectional study used data from outpatient dermatology encounters at a single-site academic center in Atlanta, Georgia, from September 1, 2016, to March 31, 2020. Encounters with patients younger than 18 years were classified as pediatric, and encounters with those 18 years or older were classified as adult. Encounters with missing data were excluded as were those generating 0 wRVUs, inpatient visits, nursing visits, postoperative encounters, cosmetic procedures, phototherapy visits, and Mohs surgery encounters. Main Outcomes and Measures: Work relative value units generated per encounter type were assessed through multivariable linear regression models adjusted for the potential confounder of sex. Results: The study included 12 989 pediatric dermatology encounters (mean [SD] age, 7.3 [5.2] years; 7586 [58.4%] girls) and 78 057 adult dermatology encounters (mean [SD] age, 54.9 [18.9] years; 45 724 [58.6%] women). Pediatric encounters were associated with 0.23 (95% CI, 0.21-0.25; P < .001) fewer wRVUs than adult encounters after adjusting for sex. In a mediation analysis, biopsies and destruction of premalignant lesions explained 74.1% (95% CI, 69.6%-77.9%; P < .001) of the wRVU difference between pediatric and adult encounters. Conclusions and Relevance: This cross-sectional study found significant differences in wRVUs generated between adult and pediatric dermatology encounters that were largely attributable to biopsies and destruction of premalignant lesions. Policies that increase the value of cognitive services to be on par with procedural care may mitigate wRVU differences and improve reimbursement for pediatric dermatologists.