Pediatric Gender Diversity Beyond the Binary: An Exploration of Gender-Affirming Care for Nonbinary and Genderqueer Youth Seen Over Time at a Single Institution Gender Center.

Purpose: The nonbinary and genderqueer (NBGQ) youth population is growing, yet scant research focuses on this distinct group. We aim to gain a deeper understanding of desired gender-affirming care and interventions pursued by NBGQ youth. Methods: A retrospective chart review of NBGQ patients seen at the University of California, San Francisco Child and Adolescent Gender Center from January 1, 2009, to December 31, 2020, was performed. Demographic information, desired gender-affirming care, and gender-affirming interventions pursued at initial and most recent visits were collected. Results: Initial visit charts of 116 NBGQ youth who attended more than one clinic visit were reviewed. In total, 48 unique genders were documented; gender evolved over time for some youth, as did desired gender-affirming care. At the most recent visit, 15 youth (12.9%) had a binary gender, and 101 youth (87.1%) had an NBGQ gender. At the initial visit, 56 youth (48.3%) were interested in gender-affirming hormone therapy, compared with 75 youth (65.6%) at the most recent visit. In addition, 21 (18.1%) and 49 (42.2%) youth were interested in surgery at the initial and most recent visits, respectively. In general, interest in interventions was higher than pursuit of interventions. Conclusion: There is vast diversity of gender and differences in desired gender-affirming care within the NBGQ youth population. Desires for gender-affirming care within the cohort changed over time, and not all those who expressed a desire for an intervention received it. The reasons are likely multifactorial, highlighting the need for expectation-free and patient-specific affirming care and research on the NBGQ youth population, while also considering barriers to care.

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.

Development of SkinTracker, an integrated dermatology mobile app and web portal enabling remote clinical research studies.

Introduction: In-person dermatology clinical research studies often face recruitment and participation challenges due to travel-, time-, and cost-associated barriers. Studies incorporating virtual/asynchronous formats can potentially enhance research subject participation and satisfaction, but few mobile health tools are available to enable remote study conduct. We developed SkinTracker, a patient-facing mobile app and researcher-facing web platform, that enables longitudinal collection of skin photos, patient reported outcomes, and biometric health and environmental data. Methods: Eight design thinking sessions including dermatologists, clinical research staff, software engineers, and graphic designers were held to create the components of SkinTracker. Following iterative prototyping, SkinTracker was piloted across six adult and four pediatric subjects with atopic dermatitis (AD) of varying severity levels to test and provide feedback on SkinTracker for six months. Results: The SkinTracker app enables collection of informed consent for study participation, baseline medical history, standardized skin photographs, patient-reported outcomes (e.g., Patient Oriented Eczema Measure (POEM), Pruritus Numerical Rating Scale (NRS), Dermatology Life Quality Index (DLQI)), medication use, adverse events, voice diary to document qualitative experiences, chat function for communication with research team, environmental and biometric data such as exercise and sleep metrics through integration with an Apple Watch. The researcher web portal allows for management and visualization of subject enrollment, skin photographs for examination and severity scoring, survey completion, and other patient modules. The pilot study requested that subjects complete surveys and photographs on a weekly to monthly basis via the SkinTracker app. Afterwards, participants rated their experience in a 7-item user experience survey covering app function, design, and desire for participation in future studies using SkinTracker. Almost all subjects agreed or strongly agreed that SkinTracker enabled more convenient participation in skin research studies compared to an in-person format. Discussion: To our knowledge, SkinTracker is one of the first integrated app- and web-based platforms allowing collection and management of data commonly obtained in clinical research studies. SkinTracker enables detailed, frequent capture of data that may better reflect the fluctuating course of conditions such as AD, and can be modularly customized for different skin conditions to improve dermatologic research participation and patient access.

Characteristics and complications of anogenital infantile hemangiomas: A multicenter retrospective analysis.

BACKGROUND: Infantile hemangiomas (IHs) of the anogenital region remain poorly characterized. OBJECTIVE: To examine the distribution, ulceration rate, and associated congenital anomalies of anogenital IHs. METHODS: Retrospective study at 8 tertiary referral centers. RESULTS: A total of 435 infants with an IH of the anogenital region were enrolled (of which, 319 [73%] were girls). Congenital anomalies were present in 6.4% (n = 28) of infants with an anogenital IH. Segmental or partial segmental anogenital IHs ulcerated in 72% (n = 99 of 138) of infants, whereas 45% (n = 133 of 297) of focal anogenital IHs experienced ulceration (P < .001). In a multivariable logistic regression analysis, segmental or partial segmental morphology (adjusted odds ratio [aOR], 2.70; 95% CI, 1.60-4.64), mixed type (aOR, 3.44; 95% CI, 2.01-6.07), and perianal (aOR, 3.01; 95% CI, 1.53-6.12) and buttocks location (aOR, 2.08; 95% CI, 1.17-3.76) had increased odds of ulceration. Segmental or partial segmental IHs of the genitalia were confined to distinct anatomic territories and were predominantly distributed unilaterally, with a linear demarcation at the perineal raphe. LIMITATIONS: Possible selection bias, given recruitment at tertiary referral centers. CONCLUSION: This study improves our understanding of high-risk features of anogenital IHs and demonstrates that genital segmental or partial segmental IHs develop within distinct anatomic territories.

Dengue: updates for dermatologists on the world's fastest-growing vector-borne disease.

Dengue is the world's fastest-growing vector borne disease and has significant epidemic potential in suitable climates. Recent disease models incorporating climate change scenarios predict geographic expansion across the globe, including parts of the United States and Europe. It will be increasingly important in the next decade for dermatologists to become familiar with dengue, as it commonly manifests with rashes, which can be used to aid diagnosis. In this review, we discuss dengue for general dermatologists, specifically focusing on its cutaneous manifestations, epidemiology, diagnosis, treatment, and prevention. As dengue continues to spread in both endemic and new locations, dermatologists may have a larger role in the timely diagnosis and management of this disease.

Nagashima-type palmoplantar keratoderma: Case series and two novel variants.

Nagashima-type palmoplantar keratoderma (PPK) is an autosomal recessive PPK. We report four patients, highlight two new genetic variants, and emphasize the possibility of misdiagnosing the condition. Concomitant atopic dermatitis, specifically, may make correct diagnosis challenging. Clinicians should consider the diagnosis of Nagashima-type PPK in patients presenting with mild PPK with transgrediens and understand the importance of individualized multimodal treatment regimens.

Long-pulsed neodymium-doped yttrium aluminum garnet for hair reduction in pediatric microtia repair.

Microtia is the term for congenital malformation of the ear in which the external and internal ear are absent or malformed. Surgical reconstruction is a common management approach and occasionally requires hair reduction of the newly constructed auricle. Few studies have investigated lasers for this purpose. We conducted a retrospective chart review of patients seen at a single institution between 2012 and 2021 who underwent laser hair reduction with long-pulsed neodymium-doped yttrium aluminum garnet laser (Nd:YAG). Efficacy ratings were done through review of clinical photographs. Twelve patients were identified with 14 total ears treated. The number of laser treatments varied from 1 to 9 sessions with an average of 5.1 treatments. The majority (8/12) had an "excellent" or "very good" response, one patient had a "good" response, and three were lost to follow-up. Other than pain, there were no side effects documented. Nd:YAG laser was both effective and safe in our pediatric cohort, without any cutaneous side effects in patients with darker skin.

Incidence and clinical factors associated with ulceration in infantile hemangiomas.

BACKGROUND: Ulceration is an important complication in infantile hemangiomas (IHs). Prior to the use of ß-blockers, the estimated incidence of this complication in a referral population was between 15% and 30%. The incidence and factors associated with ulceration have not been systematically studied since the emergence of ß-blocker therapy. OBJECTIVE: Examine the incidence and clinical predictors for ulceration in IHs. METHODS: Retrospective study at tertiary referral centers. RESULTS: Compared with a previous large pre-propranolol cohort study, ulceration occurred at a significantly lower incidence of 11.4%. Clinical factors associated with ulceration included partial segmental morphology, location in the diaper area, and size greater than 5 cm. Higher risk of ulceration in Black patients was observed, suggesting barriers to care including delayed diagnosis and referral to specialty care. LIMITATIONS: Retrospective design at tertiary referral centers. CONCLUSION: Compared with reports before the use of ß-blockers became widespread, the incidence of ulceration in IHs has decreased. However, it continues to be a relatively frequent complication of IH.

Solitary cutaneous infantile myofibroma as a hallmark of myofibromatosis: Two cases and review of the literature.

Infantile myofibroma (IM) commonly presents as a benign cutaneous fibrous tumor in infancy. Although the majority of solitary IM regress without any morbidity, some cases have underlying bone or visceral involvement that can lead to both morbidity and mortality. In this report with review of the literature, we present two cases of solitary cutaneous IM with internal involvement and discuss screening cases of solitary IM with full body imaging.

Skin and Mucosal Manifestations in NEMO Syndrome: A Case Series and Literature Review.

OBJECTIVES: To characterize the skin and mucosal findings of NEMO syndrome. METHODS: Retrospective review of clinical characteristics from a cohort of two families with mutations in IKBKG (the NEMO-encoding gene). A literature review identified 86 studies describing 192 patients with IKBKG mutations whose data were also included. SETTING: Single center with literature review. PARTICIPANTS: Patients with mutations in IKBKG from our center and reported in the literature. MAIN OUTCOMES AND MEASURES: Skin and mucosal characteristics of patients with NEMO syndrome. RESULTS: In addition to ectodermal dysplasia and recurrent infections, male patients had findings of ichthyosis, palmoplantar keratoderma, and inflammatory skin diseases. Both male and female patients had mucocutaneous ulcers and slow-to-heal chronic wounds. In combination with patients from the literature, 59% (85/144) of males had ectodermal dysplasia with anhidrosis (EDA) features, and 8% and 10% (12/144; 6/63) of males and females had dental findings, respectively. 4% (6/144) of males and 32% (20/63) of females had mucocutaneous ulcers. Ichthyosis/xerosis was present in 15% of males (21/144) but only 2% (1/63) females. Similarly, 13% (18/144) of male patients presented with dermatitis while this was reported in only 2% (1/63) of females. CONCLUSIONS: Our results both confirm and expand upon the known spectrum of mucocutaneous findings in NEMO syndrome. Further genetic studies are needed to correlate specific mutations to clinical and morphologic subtypes.

Posttraumatic onychoheterotopia: A case and review of the pediatric literature.

BACKGROUND: Onychoheterotopia, or ectopic nail, is a rare nail condition in which nail growth occurs in areas other than the distal phalanges. The majority of cases in the literature are noted to be congenital; however, acquired cases have less commonly been described following either acute or chronic trauma. METHODS: We present a case of acquired onychoheterotopia in a child, with a corresponding literature review of acquired pediatric onychoheterotopia cases for comparison. RESULTS: There were a total of 10 cases of acquired onychoheterotopia in pediatric patients in the literature. Including our patient, 81.8% (9/11) developed an ectopic nail on the fingers. Crush injury preceded the ectopic nails in 45.5 % (5/11) of cases. Infection occurred in 27.3% (3/11). CONCLUSIONS: Although the incidence and prevalence of acquired onychoheterotopia are unknown, it seems to be an uncommon phenomenon. From our case and others from the literature, there may be associations with crush injury specifically. Further research will be needed to fully elucidate the pathophysiology and risk factors for ectopic nail growth.

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.

WJMSC-derived small extracellular vesicle enhance T cell suppression through PD-L1.

Both mesenchymal stem cells (MSCs) and their corresponding small extracellular vesicles (sEVs, commonly referred to as exosomes) share similar immunomodulatory properties that are potentially beneficial for the treatment of acute graft versus host disease (aGvHD). We report that clinical grade Wharton's Jelly-derived MSCs (WJMSCs) secrete sEVs enriched in programmed death-ligand 1 (PD-L1), an essential ligand for an inhibitory immune checkpoint. A rapid increase in circulating sEV-associated PD-L1 was observed in patients with aGvHD and was directly associated with the infusion time of clinical grade WJMSCs. In addition, in vitro inhibitory antibody mediated blocking of sEV-associated PD-L1 restored T cell activation (TCA), suggesting a functional inhibitory role of sEVs-PD-L1. PD-L1-deficient sEVs isolated from WJMSCs following CRISPR-Cas9 gene editing fail to inhibit TCA. Furthermore, we found that PD-L1 is essential for WJMSC-derived sEVs to modulate T cell receptors (TCRs). Our study reveals an important mechanism by which therapeutic WJMSCs modulate TCR-mediated TCA through sEVs or sEV-carried immune checkpoints. In addition, our clinical data suggest that sEV-associated PD-L1 may be not only useful in predicting the outcomes from WJMSC clinical administration, but also in developing cell-independent therapy for aGvHD patients.

Adherent cell depletion promotes the expansion of renal cell carcinoma infiltrating T cells with optimal characteristics for adoptive transfer.

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy is a personalized cancer treatment which involves generating ex vivo cultures of tumor-reactive T cells from surgically resected tumors and administering the expanded TILs as a therapeutic infusion. Phase 1 of many TIL production protocols use aldesleukin (IL-2) alone to establish TIL cultures (termed "PreREP" (Pre-Rapid Expansion Protocol)); however, this fails to consistently produce TIL cultures from renal cell carcinoma (RCC) in a timely manner. Adding mitogenic stimulation via anti-CD3/anti-CD28 beads along with IL-2 to the fresh tumor digest (FTD) during TIL generation (termed "FTD+ beads") increases successful TIL culture rates; however, T cells produced by this method may be suboptimal for adoptive transfer. We hypothesize that adherent cell depletion (ACD) before TIL expansion will produce a superior TIL product by removing the immunosuppressive signals originating from adherent tumor and stromal cells. Here we investigate if "panning," a technique for ACD prior to TIL expansion, will impact the phenotype, functionality and/or clonality of ex vivo expanded RCC TILs. METHODS: Tumor specimens from 55 patients who underwent radical or partial nephrectomy at the University of Kansas Medical Center (KUMC) were used to develop the panning method and an additional 19 specimens were used to validate the protocol. Next-generation sequencing, immunohistochemistry/immunocytochemistry and flow cytometry were used during method development. The phenotype, functionality and clonality of autologous TILs generated in parallel by panning, PreREP, and FTD+ beads were assessed by flow cytometry, in vitro co-culture assays, and TCRB CDR3 sequencing. RESULTS: TIL cultures were successfully generated using the panning protocol from 15/16 clear cell, 0/1 chromophobe, and 0/2 papillary RCC samples. Significantly fewer regulatory (CD4+/CD25+/FOXP3+) (p=0.049, p=0.005), tissue-resident memory (CD8+/CD103+) (p=0.027, p=0.009), PD-1+/TIM-3+ double-positive (p=0.009, p=0.011) and TIGIT+ T cells (p=0.049, p=0.026) are generated by panning relative to PreREP and FTD+ beads respectively. Critically, a subset of TILs generated by panning were able to degranulate and/or produce interferon gamma in response to autologous tumor cells and the average tumor-reactive TIL yield was greatest when using the panning protocol. CONCLUSIONS: Removing immunosuppressive adherent cells within an RCC digest prior to TIL expansion allow for the rapid production of tumor-reactive T cells with optimal characteristics for adoptive transfer.

Regulation of cytotoxic T-cell responses by p53 in cancer.

An intriguing aspect of the tumor suppressor p53 is its ability to communicate to the adaptive immune system and control the cytotoxic T-lymphocyte (CTL) response to cancer cells. Wild-type p53 (wtp53) communicates with CTLs through proteins involved in the major histocompatibility complex (MHC) class I antigen presentation pathway [e.g., transporter associated with antigen processing 1 (TAP1) and endoplasmic reticulum amino peptidase 1 (ERAP1)], the apoptosis signal receptor Fas/APO-1, and the inhibitory immune-checkpoint programmed death-ligand 1 (PD-L1). The presence of wtp53 in cancer cells ultimately promotes effector CTL-induced tumor cell death. Analogously, wtp53 in tumors unleashes the CTL response via inhibition of PD-L1 and enhances their effectiveness by upregulating Fas/APO-1 and MHC I. Given that p53 is mutated in approximately 50% of human cancers and also impacts the immunoreactivity of cancer cells, a significant number of patients can be affected by the impaired CTL response that results from non-functional p53. An attenuated CTL response due to p53 mutations could decrease response rates to immunotherapeutic drugs, leading to poor patient prognoses. This review article will summarize how p53 can regulate the cell-mediated adaptive immune response to cancer.