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.

In-person validation of the Ichthyosis Scoring System.

BACKGROUND: Ichthyoses are a heterogeneous group of skin disorders characterized by scaling and erythema. Recognizing the variability of scale and erythema by region and ichthyosis subtype, we developed the Ichthyosis Scoring System (ISS) to quantify severity. We previously found ISS to have high inter- and intrarater reliability in evaluating photographic images. To confirm ISS clinical utility, we examined its performance at the 2022 Foundation for Ichthyosis and Related Skin Types conference. METHODS: Sixty-five participants were evaluated by 3 of 9 medical professionals trained to score ichthyosis scale and erythema using ISS. Intrarater and interrater intraclass correlation coefficients (ICC) were analyzed using one-way and two-way random effects models, respectively. RESULTS: Intrarater reliability was excellent (ICC = 0.931, 95% CI, 0.921-0.940) for scale and good (ICC = 0.876, 95% CI, 0.853-0.899) for erythema scoring. Compared to photo validation with excellent intrarater reliability ratings for both scale (ICC = 0.956, 95% CI, 0.925-0.974) and erythema (ICC = 0.913, 95% CI, 0.855-0.949), ISS demonstrated equivalent reliability for live use. Overall interrater reliability for 10 body sites showed excellent (ICC >0.9) and good (ICC >0.75) agreement and consistency for both scale and erythema. Palms were an exception, demonstrating moderate (ICC >0.5) interrater agreement and consistency for erythema evaluation. CONCLUSIONS: ISS is a reliable measure of global and regional ichthyosis severity during in-person evaluations. Ease-of-use, accessibility, and content validity in both live and photographic evaluation endorse ISS as a standard for ichthyosis severity analysis.

Ultra-rapid somatic variant detection via real-time targeted amplicon sequencing.

Molecular markers are essential for cancer diagnosis, clinical trial enrollment, and some surgical decision making, motivating ultra-rapid, intraoperative variant detection. Sequencing-based detection is considered the gold standard approach, but typically takes hours to perform due to time-consuming DNA extraction, targeted amplification, and library preparation times. In this work, we present a proof-of-principle approach for sub-1 hour targeted variant detection using real-time DNA sequencers. By modifying existing protocols, optimizing for diagnostic time-to-result, we demonstrate confirmation of a hot-spot mutation from tumor tissue in ~52 minutes. To further reduce time, we explore rapid, targeted Loop-mediated Isothermal Amplification (LAMP) and design a bioinformatics tool-LAMPrey-to process sequenced LAMP product. LAMPrey's concatemer aware alignment algorithm is designed to maximize recovery of diagnostically relevant information leading to a more rapid detection versus standard read alignment approaches. Using LAMPrey, we demonstrate confirmation of a hot-spot mutation (250x support) from tumor tissue in less than 30 minutes.

Successful use of telemedicine for evaluation of infantile hemangiomas during the early COVID-19 pandemic: A cross-sectional study.

BACKGROUND/OBJECTIVES: The COVID-19 pandemic prompted a rapid expansion in the use of telemedicine. This study aimed to assess the experiences of hemangioma specialists utilizing telemedicine during the COVID-19 pandemic to evaluate and manage infantile hemangiomas (IH), including perceived effectiveness of different modalities and barriers to care delivery. METHODS: Multicenter cross-sectional study asking providers to describe their experiences using telemedicine for initial evaluation of IH from March to September 2020. RESULTS: The study included 281 patients from 15 medical centers internationally. Median time from referral to evaluation was 17 days. Median physician confidence in performing evaluations via telemedicine was 95.0 (IQR 90.0-100.0). Most evaluations were performed via video communication with photographs or audio communication with photographs; when not initially available, photographs were requested in 51.4%. Providers preferred follow-up modalities that included photographs. CONCLUSIONS: Physicians with extensive expertise in managing IH are confident in their abilities to assess and manage IH via telemedicine including initiating treatment in patients without risk factors for beta-blocker therapy. There was a preference for hybrid modalities that included photographs. The data suggest that telemedicine can be effective for managing IH and may decrease wait times and improve specialist reach to underserved areas.

Diagnostic outcomes from a combined Pediatric Dermatology-Genetics clinic.

Multispecialty clinics can be exceedingly helpful for diagnostically challenging and clinically complicated patients. This study highlights the diagnostic outcomes of the multispecialty Pediatric Dermatology-Genetics clinic at Children's Mercy-Kansas City over a 5-year period.

Development and Initial Validation of a Novel System to Assess Ichthyosis Severity.

IMPORTANCE: A comprehensive, user-friendly system to assess global ichthyosis disease burden is imperative to improving the care of patients with ichthyosis, identifying appropriate participants for clinical trials, and quantifying treatment outcomes. To our knowledge, there is currently no validated scale to objectively and systematically measure ichthyosis severity across the entire body. OBJECTIVE: To create and evaluate a comprehensive and user-friendly instrument to measure total body ichthyosis severity in adults and children. DESIGN, SETTING, PARTICIPANTS: In this qualitative study, ichthyosis experts participated in the content development of the Ichthyosis Scoring System (ISS). The body was divided into 10 regions, and Likert scales (0-4) were created to quantify scale and erythema, with extensive descriptors and photographic standards. An 83-image teaching set was created from photographs of participants with ichthyosis. Two cohorts of dermatologists (11 total) independently scored all test photographs twice to evaluate interrater and intrarater reliabilities. Participants were enrolled worldwide from referral centers and patient advocacy groups. Participants of all ages, races, and ethnicities were included in the creation of ISS, and dermatologists with varying experience and areas of expertise participated as raters to evaluate the ISS. The study was conducted from 2019 to 2021, and the data were analyzed in 2021. MAIN OUTCOMES AND MEASURES: Intraclass correlation coefficients determined overall reliabilities. RESULTS: Across both cohorts of 11 dermatologists in total, the intraclass correlation coefficients for total, scale and erythema scores were greater than 0.90 (95% CI, 0.77-0.97), greater than 0.91 (95% CI, 0.79-0.98), and greater than 0.88 (95% CI, 0.72-0.97), respectively. Most body sites exhibited moderate to good interrater reliabilities for scale and erythema. Intrarater reliabilities were good to excellent. CONCLUSIONS AND RELEVANCE: The results of this qualitative study demonstrate reproducibility and suggest that the ISS is a reliable system to measure global ichthyosis severity in adults and children.

TERT Promoter Mutations in Keratinizing and Nonkeratinizing Squamous Metaplasia of the Urinary Tract.

We identified urothelial tract biopsy and resection specimens with keratinizing squamous metaplasia (KSM), nonkeratinizing squamous metaplasia (NKSM), and urothelial and squamous carcinomas over a 20-yr period, focusing on cases with neurogenic lower urinary tract dysfunction (NLUTD) and/or those with spatial or temporal variation in sampling. TERT promoter mutations as assessed via allele-specific polymerase chain reaction were surprisingly common in our testing cohort, identified not only in 15 (94%) invasive cancer foci but also in 13 (68%) examples of KSM and seven (70%) examples of NKSM. TERT promoter mutations were present in 23 foci from NLUTD specimens and 11 foci from bladder diverticula, including in foci of KSM, NKSM, and unremarkable urothelium from cases with no clinical association with previous, concurrent, or subsequent cancer. Our demonstration of temporally and spatially persistent TERT promoter mutation in examples of KSM and NKSM in cases of bladder cancer and in morphologically benign cases with neurogenic dysfunction suggests a molecular mechanism by which such pre-neoplastic lesions can potentially progress and develop into overt carcinoma. Given the interest in TERT promoter mutations as a potential biomarker for the development of bladder cancer, these findings possibly explain the association between conditions with chronic urinary bladder injury (such as the natural history of NLUTD) and higher risk of bladder cancer. TERT promoter mutations may represent an early event in bladder cancer tumorogenesis, and our findings expand on the clinical ramifications and predictive value of TERT promoter mutations in this context. PATIENT SUMMARY: Mutations in the TERT gene are the most common genetic changes in bladder cancer. We found that these mutations are also sometimes present in patients with chronic bladder irritation such as neurogenic bladder dysfunction and changes to the lining of the bladder that pathologists would consider "benign." This finding might explain why such conditions are associated with the development of bladder cancer.

Attenuation of Autoimmune Phenomena in a Patient with Autoimmune Polyglandular Syndrome Type 1.

Autoimmune polyglandular syndrome type 1 (APS1) is a progressive life-threatening illness with no known cure. Current treatments involve replacement of the hormone deficiencies that result from autoimmune destruction of multiple endocrine organs. We report on a girl whose disease was progressing rapidly until she began on immunosuppressive agents. A healthy 6-year-old girl with no remarkable medical history presented with new onset hypocalcemic seizures and primary hypoparathyroidism. Howell-Jolly bodies consistent with autoimmune hyposplenism were also noted. Genetic testing revealed compound heterozygosity for 2 disease-associated variants in the autoimmune regulator (AIRE) gene. She later developed elevated liver enzymes, primary adrenal insufficiency, and alopecia totalis. Serologic testing revealed antibodies to 21-hydroxylase, intrinsic factor, and smooth muscle. Hydrocortisone was initiated for adrenal insufficiency. Shortly afterwards, her liver enzymes normalized, and her smooth muscle antibody levels began to decline. Serologic testing performed at age 11 revealed seropositivity for glutamic acid decarboxylase (GAD) antibodies, antinuclear antibodies, and Sjögren syndrome A (SSA) antibodies. At age 12, she was given 2 doses of rituximab. Hair loss rapidly progressed to alopecia totalis and then to alopecia universalis, at which time oral methotrexate treatment was initiated. For the past 7 years while on glucocorticoid and methotrexate treatment, our patient has displayed normalization of 2 antibodies, a lack of progression to additional autoimmune diseases, and experienced reversal of alopecia universalis.

Delayed diagnosis of holocarboxylase synthetase deficiency in three patients with prominent skin findings.

Holocarboxylase deficiency (HLCSD) is caused by biallelic pathogenic variants in HLCS and is associated with poor feeding, emesis, lethargy, seizures, life-threatening metabolic acidosis, and hyperammonemia. Skin involvement in HLCSD is typically described as scaly, erythrodermic, seborrhea-like, or ichthyosiform, but there is a paucity of reports. We report three patients, including two siblings, with HLCSD and significant cutaneous manifestations including ichthyosiform dermatitis and a presentation with features of annular pustular psoriasis. In this report, we show that persistent, unexplained rash, even in the absence of other clinical findings, should warrant consideration and potential workup for HLCSD.

Limited utility of repeated vital sign monitoring during initiation of oral propranolol for complicated infantile hemangioma.

BACKGROUND: Initial propranolol recommendations for infantile hemangioma published in 2013 were intended as provisional best practices to be updated as evidence-based data emerged. METHODS: A retrospective multicenter study was performed to evaluate utility of prolonged monitoring after first propranolol dose and escalation(s). Inclusion criteria included diagnosis of hemangioma requiring propranolol of greater than or equal to 0.3 mg/kg per dose, younger than 2 years, and heart rate monitoring for greater than or equal to 1 hour. Data collected included demographics, dose, vital signs, and adverse events. RESULTS: A total of 783 subjects met inclusion criteria; median age at initiation was 112 days. None of the 1148 episodes of prolonged monitoring warranted immediate intervention or drug discontinuation. No symptomatic bradycardia or hypotension occurred during monitoring. Mean heart rate change from baseline to 1 hour was -8.19/min (±15.54/min) and baseline to 2 hours was -9.24/min (±15.84/min). Three preterm subjects had dose adjustments because of prescriber concerns about asymptomatic vital sign changes. No significant difference existed in pretreatment heart rate or in heart rate change between individuals with later adverse events during treatment and those without. CONCLUSION: Prolonged monitoring for initiation and escalation of oral propranolol rarely changed management and did not predict future adverse events. Few serious adverse events occurred during therapy; none were cardiovascular.

Management of infantile hemangiomas during the COVID pandemic.

The COVID-19 pandemic has caused significant shifts in patient care including a steep decline in ambulatory visits and a marked increase in the use of telemedicine. Infantile hemangiomas (IH) can require urgent evaluation and risk stratification to determine which infants need treatment and which can be managed with continued observation. For those requiring treatment, prompt initiation decreases morbidity and improves long-term outcomes. The Hemangioma Investigator Group has created consensus recommendations for management of IH via telemedicine. FDA/EMA-approved monitoring guidelines, clinical practice guidelines, and relevant, up-to-date publications regarding initiation and monitoring of beta-blocker therapy were used to inform the recommendations. Clinical decision-making guidelines about when telehealth is an appropriate alternative to in-office visits, including medication initiation, dosage changes, and ongoing evaluation, are included. The importance of communication with caregivers in the context of telemedicine is discussed, and online resources for both hemangioma education and propranolol therapy are provided.

Evaluation of Genotypic Antiviral Resistance Testing as an Alternative to Phenotypic Testing in a Patient with DOCK8 Deficiency and Severe HSV-1 Disease.

Antiviral resistance frequently complicates the treatment of herpes simplex virus (HSV) infections in immunocompromised patients. Here we present the case of an adolescent boy with dedicator of cytokinesis 8 (DOCK8) deficiency, who experienced recurrent infections with resistant HSV-1. We used both phenotypic and genotypic methodologies to characterize the resistance profile of HSV-1 in the patient and conclude that genotypic testing outperformed phenotypic testing. We also present the first analysis of intrahost HSV-1 evolution in an immunocompromised patient. While HSV-1 can remain static in an immunocompetent individual for decades, the virus from this patient rapidly acquired genetic changes throughout its genome. Finally, we document a likely case of transmitted resistance in HSV-1 between the patient and his brother, who also has DOCK8 deficiency. This event demonstrates that resistant HSV-1 is transmissible among immunocompromised persons.

Evaluating the Safety of Oral Propranolol Therapy in Patients With PHACE Syndrome.

Importance: Oral propranolol is widely considered to be first-line therapy for complicated infantile hemangioma, but its use in patients with PHACE (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies) syndrome has been debated owing to concerns that the cardiovascular effects of the drug may increase the risk for arterial ischemic stroke. Objective: To assess the incidence of adverse events among patients with PHACE syndrome receiving oral propranolol for infantile hemangioma. Design, Setting, and Participants: This multicenter retrospective cohort study assessed the incidence of adverse events among 76 patients with PHACE syndrome receiving oral propranolol for infantile hemangioma at 11 tertiary care, academic pediatric dermatology practices. Medical records from January 1, 2010, through April 25, 2017, were reviewed. Exposures: Patients received oral propranolol, 0.3 mg/kg/dose or more. Main Outcomes and Measures: The main outcome was the rate and severity of adverse events occurring throughout the course of treatment with oral propranolol, as documented in the medical records. Adverse events were graded from 1 to 5 using a scale derived from the Common Terminology Criteria for Adverse Events and were considered to be serious if they were grade 3 or higher. Results: A total of 76 patients (59 girls and 17 boys; median age at propranolol initiation, 56 days [range, 0-396 days]) met the inclusion criteria. There were no reports of serious adverse events (ie, stroke, transient ischemic attack, or cardiovascular events) during treatment with oral propranolol. A total of 46 nonserious adverse events were reported among 29 patients (38.2%); the most commonly reported nonserious adverse events were sleep disturbances and minor gastrointestinal tract and respiratory tract symptoms. In a comparison with 726 infants who received oral propranolol for hemangioma but did not meet criteria for PHACE syndrome, there was no significant difference in the rate of serious adverse events experienced during treatment (0 of 76 patients with PHACE syndrome and 3 of 726 patients without PHACE syndrome [0.4%]). Conclusions and Relevance: This study found that oral propranolol was used to treat infantile hemangioma in 76 patients with PHACE syndrome and that no serious adverse events were experienced. These data provide support for the safety of oral propranolol in this patient population.

Localized infantile hemangiomas of the face and scalp: Predilection for the midline and periorbital and perioral skin.

BACKGROUND/OBJECTIVES: Infantile hemangiomas are common vascular tumors. Identifying sites of predilection may provide insight into pathogenesis. Previous studies have suggested a predilection for the boundary of facial metameres. The objective was to observe patterns of localized hemangiomas on the face and scalp, determine sites of predilection, and place these patterns in a developmental context. METHODS: A retrospective review of photographic archives at 10 Hemangioma Investigator Group pediatric dermatology centers identified localized infantile hemangiomas of the face and scalp. Heat map software was used to identify areas of predilection. Dot maps were used to assess frequency, and densities of infantile hemangiomas were compared between facial units using t-testing. The scalp was divided into quintiles to assess relative frequencies. RESULTS: Four thousand one hundred fifty-three focal face and scalp infantile hemangiomas were mapped, of which 2962 (71%) were mapped to a frontal facial template. On the face, 73.8% (2186/2962) of hemangiomas occurred along the midline axis or perpendicularly across the ocular axis in a cross-shaped area of predilection intersecting at the glabella. Scalp hemangiomas show a predilection for the midline, with 149/295 (50.5%) noted on the top of the scalp at the midline (P < 0.001). Localized hemangiomas do not demonstrate a preferential laterality. CONCLUSION: The distribution of localized infantile hemangiomas of the face and scalp is not random. There is preferential involvement of the midline face and scalp and the ocular axis. The regions corresponding to the boundaries between the embryonic facial segments, including the maxillary and mandibular metameres, are not accentuated in the distribution of infantile hemangiomas.