Histological Assessment of the Effectiveness of Microneedling Device-Assisted Filler Delivery.

BACKGROUND: Microneedling is used to enhance transcutaneous drug delivery. However, the extent to which microneedling devices impact filler delivery and whether this varies by filler type, microneedling device type, and treatment sequence is not known. OBJECTIVE: To histologically assess and quantify the delivery of commonly used fillers through microneedling, using both a microneedling pen and a microneedling roller. In addition, the authors investigated whether there is a variation in filler delivery based on the sequence of microneedling in relation to topical filler application. METHODS: Ex vivo human abdominal skin samples were subjected to microneedling pen or microneedling roller treatment. Black tissue marking ink, hyaluronic acid, poly-l-lactic acid, or undiluted calcium hydroxyapatite was topically applied before or immediately after microneedling treatment. RESULTS: Histological evaluation revealed a notable presence of black ink within channels formed by both microneedling treatments (15.5%-98.1%), whereas there was limited presence of the various filler types tested (0%-6.6%) in all settings. Topical application before microneedling treatment led to relatively higher filler/ink deposition within the channels formed by the microneedling treatments compared with topical application after microneedling. CONCLUSION: Transcutaneous delivery of fillers was not significantly helped by microneedling treatment, whereas the microneedling devices demonstrated effective delivery of an aqueous solution.

Segmental basaloid follicular hamartomas derive from a post-zygotic SMO p.L412F pathogenic variant and express hair follicle development-related proteins in a pattern that distinguish them from basal cell carcinomas.

Basaloid follicular hamartomas (BFH) are benign small basaloid skin tumors that can present as solitary or multiple lesions. Congenital BFH lesions arranged in a segmental distribution have been described, suggesting they derive from a somatic post-zygotic mutational event. Previously, BFH were described in Happle-Tinschert syndrome, which results from a post-zygotic SMO variant and is characterized by segmental BFH with variable involvement of the teeth, skeleton, and central nervous system. Here, we describe two patients with isolated segmental BFH and no systemic involvement. Paired whole exome sequencing of BFH and normal tissue revealed a pathogenic SMO c.1234 C>T, p.L412F variant restricted to BFH tissue. We characterized the proliferation index and expression of Hedgehog and Wnt/beta-catenin pathway related proteins in segmental BFH compared to sporadic basal cell carcinomas (BCCs) and found that segmental BFH had a lower proliferation index. Although segmental BFH expressed a similar level of Gli-1 compared to BCCs, levels of LEF-1 and SOX-9 expression in BFH were weaker for both and patchier for LEF-1. Our results show that a somatic SMO activating variant causes segmental BFH. Since these patients are prone to developing BCCs, differences in SOX9, LEF1, and Ki-67 expression can help distinguish between these two basaloid lesions.

Trends in the Cost and Utilization of Omalizumab in the Medicare Population: 2013-2017.

Background: Omalizumab has been demonstrated to be effective in treating chronic spontaneous urticaria (CSU) and was FDA approved for this indication in 2014. Previous work has shown that access to injectable biologics varies across US counties. In the present study we evaluate geographic and temporal trends in the utilization of omalizumab in the Medicare population by dermatologists, with its use by allergists and pulmonologists as comparators. Methods: We analyzed year-over-year trends in omalizumab utilization across geographic regions using the Medicare Provider Utilization and Payment Data: Part D files. Results: Utilization of omalizumab by dermatologists increased rapidly after its FDA approval, from 0.08 claims/100,000 enrollees totaling $209/100,000 enrollees in 2014 to 1.45 claims/100,000 enrollees totaling $3115/100,000 enrollees in 2017. Nonetheless, prescribing dermatologists were present in only 2.8% (95% Confidence Interval (CI): 2.0%-3.9%) and 0.2% (95% CI: 0.0%-0.5%) of metropolitan and non-metropolitan counties, respectively, in 2017, demonstrating limited availability, especially in non-metropolitan counties. Similarly, prescribers of any specialty were available in 32.9% (95% CI: 30.2%-35.6%) and 3.8% (95% CI: 3.1%-4.8%) of metropolitan and non-metropolitan counties, respectively, in 2017. Conclusions: Our data suggest that despite increasing omalizumab utilization, there remains a lack of access across many counties, particularly in non-metropolitan regions. Efforts to expand omalizumab prescriber accessibility in these counties may improve outcomes for patients with CSU.

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.

Lack of association between pandemic chilblains and SARS-CoV-2 infection.

An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2-associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as "covid toes" during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.

Erratum: Cutaneous and hepatic vascular lesions due to a recurrent somatic GJA4 mutation reveal a pathway for vascular malformation.

[This corrects the article DOI: 10.1016/j.xhgg.2021.100028.].

Sentinel Lymph Node Biopsy Positivity in Patients With Acral Lentiginous and Other Subtypes of Cutaneous Melanoma.

IMPORTANCE: Acral lentiginous melanoma (ALM) is a rare subtype of malignant melanoma typically occurring on the palmar and plantar surfaces. Although it has distinctive genetic, prognostic, and behavioral characteristics relative to cutaneous melanomas overall, owing to its rarity, treatment is largely guided by data extrapolated from more common subtypes. Although sentinel lymph node (SLN) status has been shown to be a significant prognostic factor for ALM, the independent effect of ALM-subtype disease on the likelihood of SLN positivity and the stage-specific positivity rates for ALM are not well characterized. OBJECTIVE: To evaluate the association of ALM with SLN status as well as to characterize the clinical stage-specific rates of SLN positivity for ALM based on the AJCC Cancer Staging Manual, 8th edition (AJCC-8). DESIGN, SETTING, AND PARTICIPANTS: The National Cancer Database (NCDB) includes all reportable cases from Commission on Cancer accredited facilities and represents approximately 50% of all newly diagnosed melanoma cases in the US. This retrospective cohort study included cases of AJCC-8 clinical stage I to II melanomas from the NCDB diagnosed from 2012 to 2015. The analysis took place between April 2021 and September 2021. EXPOSURES: Melanoma histopathologic subtype. MAIN OUTCOMES AND MEASURES: Sentinel lymph node status. RESULTS: We identified 60 148 patients with malignant melanomas, 959 of whom had ALM-subtype disease. Among patients in the cohort, 25 550 (42.5%) were women and the mean (SD) age was 64 (16) years. Multivariable logistic regression controlling for demographic and histopathologic characteristics revealed that ALM was independently associated with the highest risk for SLN positivity among included subtypes (vs superficial spreading melanoma: odds ratio, 1.91; 95% CI, 1.59-2.28). Subgroup analysis by AJCC clinical stage demonstrated that ALM was independently associated with the highest risk for SLN positivity for both stage IB and II disease. The rate of SLN positivity for patients with stage IB and II ALM was 18.39% (95% CI, 13.82%-24.03%) and 39.53% (34.98%-44.26%), respectively. CONCLUSIONS AND RELEVANCE: In this cohort study ALM was independently associated with SLN positivity and had relatively high positivity rates at clinical stage IB and II. This suggests that SLNB should be encouraged for all patients with clinical stage IB and II ALM, and such patients should receive appropriate counseling about the higher regional metastatic risk of their cancers. Future work with a larger cohort is required to elucidate the risk of SLN positivity for stage IA ALM.

The Genetic Architecture of a Congenital Heart Defect Is Related to Its Fitness Cost.

In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000 Nkx2-5+/- mice from two inbred strain crosses illustrates the fundamental role of epistasis. Modifier genes raise or lower the risk of specific defects via pairwise (G×GNkx) and higher-order (G×G×GNkx) interactions with Nkx2-5. Their effect sizes correlate with the severity of a defect. The risk loci for mild, atrial septal defects exert predominantly small G×GNkx effects, while the loci for severe, atrioventricular septal defects exert large G×GNkx and G×G×GNkx effects. The loci for moderately severe ventricular septal defects have intermediate effects. Interestingly, G×G×GNkx effects are three times more likely to suppress risk when the genotypes at the first two loci are from the same rather than different parental inbred strains. This suggests the genetic coadaptation of interacting G×G×GNkx loci, a phenomenon that Dobzhansky first described in Drosophila. Thus, epistasis plays dual roles in the pathogenesis of congenital heart disease and the robustness of cardiac development. The empirical results suggest a relationship between the fitness cost and genetic architecture of a disease phenotype and a means for phenotypic robustness to have evolved.

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.

Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction.

The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Eight kindreds with familial AF and slow conduction, including a family affected by early-onset AF, heart block, and incompletely penetrant nonischemic dilated cardiomyopathy (DCM) underwent whole exome sequencing. A known pathogenic mutation in the desmin (DES) gene resulting in p.S13F substitution (NM_001927.3:c.38C>T) at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed DCM. Higher penetrance for AF and heart block prompted a genetic screening for DES modifier(s). A deleterious mutation in the phosphodiesterase-4D-interacting-protein (PDE4DIP) gene resulting in p.A123T substitution (NM_001002811:c.367G>A) was identified that segregated with early-onset AF, heart block, and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIPA123T in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the ß2-adrenergic-receptor, and decreased PKA phosphorylation of desmin after isoproterenol stimulation. Our findings identify PDE4DIP as a novel gene for slow AF and unravel its epistatic interaction with DES mutations in development of conduction disease and arrhythmia.

Cutaneous and hepatic vascular lesions due to a recurrent somatic GJA4 mutation reveal a pathway for vascular malformation.

The term "cavernous hemangioma" has been used to describe vascular anomalies with histology featuring dilated vascular spaces, vessel walls consisting mainly of fibrous stromal bands lined by a layer of flattened endothelial cells, and an irregular outer rim of interrupted smooth muscle cells. Hepatic hemangiomas (HHs) and cutaneous venous malformations (VMs) share this histologic pattern, and we examined lesions in both tissues to identify genetic drivers. Paired whole-exome sequencing (WES) of lesional tissue and normal liver in HH subjects revealed a recurrent GJA4 c.121G>T (p.Gly41Cys) somatic mutation in four of five unrelated individuals, and targeted sequencing in paired tissue from 9 additional HH individuals identified the same mutation in 8. In cutaneous lesions, paired targeted sequencing in 5 VMs and normal epidermis found the same GJA4 c.121G>T (p.Gly41Cys) somatic mutation in three. GJA4 encodes gap junction protein alpha 4, also called connexin 37 (Cx37), and the p.Gly41Cys mutation falls within the first transmembrane domain at a residue highly conserved among vertebrates. We interrogated the impact of the Cx37 mutant via lentiviral transduction of primary human endothelial cells. We found that the mutant induced changes in cell morphology and activated serum/glucocorticoid-regulated kinase 1 (SGK1), a serine/threonine kinase known to regulate cell proliferation and apoptosis, via non-canonical activation. Treatment with spironolactone, an inhibitor of angiogenesis, suppressed mutant SGK1 activation and reversed changes in cell morphology. These findings identify a recurrent somatic GJA4 c.121G>T mutation as a driver of hepatic and cutaneous VMs, revealing a new pathway for vascular anomalies, with spironolactone a potential pathogenesis-based therapy.