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.

Assessment of Mammalian Target of Rapamycin Pathway Activation in Basal Cell Carcinoma as a New Therapeutic Approach.

ABSTRACT: Targeting the mammalian target of rapamycin (mTOR) pathway represents a potentially novel approach to treat basal cell carcinoma (BCC), but activation of this pathway has not been well described in human BCCs. The purpose of this study was to assess whether mTOR pathway activation occurs in BCCs (both sporadic and syndromic) and report a case of a patient with Gorlin syndrome (GS) whose clinically suspicious BCCs responded to mTOR inhibition through topical sirolimus treatment. After Stanford Institutional Review Board Approval, archived BCCs from patients with GS (n = 25), sporadic BCCs (n = 35), and control tissues were subjected to immunohistochemical analysis for the activation of mTOR pathway, and immunohistochemical staining intensity was evaluated by a dermatopathologist. BCCs (compared with normal skin) had elevated levels of eIF4EBP1 (Padjusted = 0.0336), which is downstream of mTOR. a serine/threonine kinase Phospho-(AKT), which interacts with mTOR, was also significantly elevated (perinuclear: Padjusted < 0.0001; cytoplasmic: Padjusted = 0.0021). When off-label topical 1% sirolimus was used on a pediatric patient with GS, we noted reduction of new BCC development and decreased size of existing neoplasms clinically suspicious for BCCs. This treatment was well tolerated after 2 years of continuous use, with no other treatments needed during this period. Topical sirolimus is a promising therapeutic candidate against both sporadic and GS-associated BCC. Multicenter, prospective studies are needed to understand the efficacy and safety of topical mTOR inhibitors in BCC treatment, and ascertain whether the immunohistochemical markers downstream of mTOR could have predictive value in identifying BCCs most likely to respond to topical mTOR inhibitors, such as sirolimus.

Pachyonychia Congenita: A Research Agenda Leading to New Therapeutic Approaches.

Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles.

Diacerein 1% Ointment for the Treatment of Epidermolysis Bullosa Simplex: A Randomized, Controlled Trial.

BACKGROUND: In epidermolysis bullosa simplex (EBS), epithelial structural fragility results in blisters and erosions. Diacerein 1% ointment has been shown to reduce this blistering. OBJECTIVE: To evaluate the efficacy and safety of diacerein 1% ointment in the treatment of EBS. METHODS: A double-blind study of 54 patients with EBS were randomized to diacerein 1% or vehicle ointment once daily. The primary endpoint ( ≥60% reduction in body surface area of EBS) and the key secondary endpoint ( ≥2-point reduction in the Investigator’s Global Assessment) were evaluated at 8 weeks. RESULTS: There was no difference in the proportion of patients achieving either key efficacy endpoint between the diacerein 1% and vehicle groups (P>0.05). No difference in treatment emergent adverse events were noted between the groups. In post hoc analysis stratified by EBS subtypes, an IGA score of 0 or 1 was reported in 6 of 13 patients with severe EBS in the diacerein group (46.2%), compared with 2 of 13 patients with severe EBS in the vehicle group (15.4%); (relative risk= 3.08, 95% CI = 0.71, 13.4). CONCLUSIONS: Although there was no significant difference in outcomes between the groups, further study may elucidate the effects of diacerein on EBS lesions, especially in patients with severe EBS. Teng J, Paller AS, Bruckner AL, et al. Diacerein 1% ointment for the treatment of epidermolysis bullosa simplex: a randomized, controlled trial. J Drugs Dermatol. 2023;22(6):599-604. doi:10.36849/JDD.7108.

Topical Isotretinoin (TMB-001) Treatment for 12 Weeks Did Not Result in Clinically Relevant Laboratory Abnormalities in Participants with Congenital Ichthyosis in the Phase 2b CONTROL Study.

INTRODUCTION: Treatment with oral retinoids can be effective in patients with congenital ichthyosis (CI) but may be associated with clinically significant laboratory changes. In this Phase 2b CONTROL study analysis, we characterize the effects of TMB-001, a novel topical isotretinoin formulation, on laboratory values in participants with X-linked recessive (XLRI) and autosomal recessive lamellar (ARCI-LI) ichthyosis at 12 weeks. METHODS: A randomized, double-blind, vehicle-controlled, Phase 2b study was conducted with participants ≥ 9 years of age with confirmed XLRI and ARCI-LI. Participants were randomized 1:1:1 and stratified by CI subtype to receive TMB-001 0.05%:TMB-001 0.1%:vehicle twice daily for 12 weeks. Laboratory analyses were performed at screening and Week 12. RESULTS: Among 33 enrolled participants (TMB-001 0.05% n = 11, TMB-001 0.1% n = 10, and vehicle n = 12), 52% had ARCI-LI and 48% had XLRI. At 12 weeks, there were single reports of anemia, neutropenia, leukopenia, lymphocytosis, and leukocytosis after vehicle treatment; neutropenia was reported in one participant receiving TMB-001 0.1%. There were single reports of abnormal biochemistry values-liver enzymes, creatinine, urea nitrogen, hyperkalemia, and hyperproteinemia-across treatment cohorts. Non-fasting hyperglycemia was observed in three participants receiving TMB-001 0.1% and one participant receiving vehicle. Urinalysis abnormalities reported in > 1 participant included urobilinogen (TMB-001 0.1% n = 2, vehicle n = 2), protein (TMB-001 0.1% n = 3, vehicle n = 2), and leukocyte esterase (TMB-001 0.1% n = 2). Laboratory parameter changes were asymptomatic and did not require study discontinuation or drug withdrawal. CONCLUSION: There were no clinically significant laboratory changes in participants receiving TMB-001 isotretinoin ointment through 12 weeks of treatment, which differs from reported results for systemic isotretinoin. TRIAL REGISTRATION: NCT04154293.

Characteristics and outcomes for participants with congenital ichthyosis who responded to treatment with the topical isotretinoin formulation TMB-001: results from the Phase IIb CONTROL study.

BACKGROUND: Emollients and keratolytics are frequently used to manage symptoms of congenital ichthyosis (CI). Systemic retinoid treatment is complicated by teratogenicity and dose-limiting adverse effects. OBJECTIVES: This analysis from the randomized Phase IIb CONTROL study investigated the characteristics of participants who responded to treatment with TMB-001, a novel topical isotretinoin ointment formulation. METHODS: Participants ≥ 9 years of age with genetically confirmed CI and ≥ 2 (out of 4) Visual Index for Ichthyosis Severity (VIIS) assessment areas with ≥ 3 scaling score were randomized 1 : 1 : 1 to TMB-001 0.05%, TMB-001 0.1% or vehicle, twice daily for 12 weeks. Efficacy endpoints included the proportion of participants with ≥ 50% reduction in VIIS-scaling (VIIS-50) compared with baseline and ≥ 2-grade reduction in Investigator's Global Assessment (IGA)-scaling score compared with baseline. Changes in body surface area (BSA) involvement, Dermatology Life Quality Index (DLQI) scores and Itch-Numeric Rating Scale (I-NRS) scores were assessed. RESULTS: Among the 33 participants (11 randomized to TMB-001 0.05%, 10 to TMB-001 0.1% and 12 to vehicle), median age was 29 years (range 9-80), and most were male (64%) and White (79%). Baseline demographics were generally similar among participants who did or did not achieve TMB-001 treatment success. Participants who had lower mean BSA involvement and higher DLQI and I-NRS scores at baseline were more likely to achieve VIIS-50. Similarly, higher baseline DLQI and I-NRS scores were associated with IGA response; BSA involvement was similar for IGA responders vs. nonresponders. CONCLUSIONS: Higher DLQI and I-NRS scores at baseline were associated with participants achieving treatment success by VIIS-50 and IGA response. Lower BSA involvement was associated with VIIS-50 success.

Phase IIb randomized CONTROL study demonstrates a novel topical isotretinoin formulation, TMB-001, is safe and effective in participants with either recessive X-linked or autosomal recessive lamellar congenital ichthyosis.

BACKGROUND: In two severe congenital ichthyosis subtypes, autosomal recessive lamellar ichthyosis (ARCI-LI) and X-linked recessive ichthyosis (XLRI), cutaneous manifestations include widespread scaling. Approved topical treatment options are limited to emollients and keratolytics. AIM: This analysis from the randomized phase IIb CONTROL study assessed whether the efficacy and safety of TMB-001, a novel topical isotretinoin ointment formulation, differed between ARCI-LI and XLRI subtypes. METHODS: Participants ≥ 9 years with genetically confirmed XLRI or ARCI-LI and ≥ 2 (of 4) Visual Index for Ichthyosis Severity (VIIS) assessment areas with ≥ 3 scaling score were randomized 1 : 1 : 1 to TMB-001 0.05%/TMB-001 0.1%/vehicle, twice daily for 12 weeks. The proportion of participants with ≥ 50% reduction vs. baseline in VIIS scaling (VIIS 50; primary endpoint) and ≥ 2-grade reduction in Investigator's Global Assessment (IGA)-scaling score vs. baseline (key secondary endpoint) were evaluated. Adverse events (AEs) were monitored. RESULTS: Among enrolled participants (TMB-001 0.05%, n = 11; 0.1%, n = 10; and vehicle, n = 12), 52% had ARCI-LI and 48% XLRI subtypes. Mean age was 33.6 and 35.4 years for participants with ARCI-LI and XLRI, respectively. Overall, 33%, 50% and 17% of participants with ARCI-LI and 100%, 33% and 75% of participants with XLRI achieved VIIS 50 in the TMB-001 0.05%, TMB-001 0.1% and vehicle groups, respectively (nominal P = 0.24 for 0.05% vs. vehicle, intent-to-treat population). Improvement of ≥ 2-grade IGA score was observed in 33%, 50% and 0% of participants with ARCI-LI and 83%, 33% and 25% of participants with XLRI in the TMB-001 0.05%, TMB-001 0.1% and vehicle groups, respectively (nominal P = 0.03 for 0.05% vs. vehicle, intention-to-treat population). Most AEs were application-site reactions. CONCLUSION: Regardless of congenital ichthyosis subtype, TMB-001 demonstrated greater proportions of participants achieving VIIS 50 and ≥ 2-grade IGA improvement vs. vehicle.

Assessment of Hormonal Contraceptive Utilization and Associated Odds of Hypercoagulopathy in Patients with Venous Malformations Using a National Claims Database.

BACKGROUND: Vascular anomalies that exhibit a slow velocity of blood flow, specifically venous malformations (VM), are associated with hypercoagulability. There is limited literature on the utilization of hormonal contraceptives (HCs) and the development of clotting events in female individuals diagnosed with VM. OBJECTIVE: We aimed to characterize HC utilization and associated odds of hypercoagulopathy in patients with VM of child-bearing age. METHODS: Using a national administrative claims database, we identified female patients with VM aged 15-49 years and a control population, matched for age and length of insurance enrollment, from 2016 to 2021. Multivariable logistic regression was used to estimate the odds of hypercoagulation events associated with HC use. RESULTS: Two hundred and sixty-seven (47.2%) patients with VM and 1284 (45.4%) control patients utilized HCs during the study period. Oral contraceptives were the most common HC for patients with and without VM (73.8% and 76.9% of those taking HCs, respectively), and estrogen-containing combination HCs (70.4% in patients with VM and 75.9% in controls) were more prevalent than progestin-only HCs in both populations. Despite a heightened baseline odds of hypercoagulopathy in patients with VM relative to patients without VM (odds ratio = 12.54; 95% confidence interval 7.73-20.3), HC use was not associated with an increased odds of hypercoagulation in the VM subpopulation (odds ratio = 0.82; 95% confidence interval 0.46-1.46). In contrast, tobacco use (odds ratio = 2.12; 95% confidence interval 1.09-4.12) and a history of coagulopathy (odds ratio = 3.92; 95% confidence interval 1.48-10.36) were predictive of thromboembolic events in the VM cohort. CONCLUSIONS: These findings suggest that patients with VM may safely use HCs with careful consideration of other risk factors for thromboses.

Ichthyosis, cataracts, and motor delay in an infant: A case of Chanarin-Dorfman syndrome.

Chanarin-Dorfman syndrome (CDS) is a rare, autosomal recessive disorder of impaired triacylglycerol catabolism leading to cytoplasmic deposition of triglycerides in various cell types. We describe the case of an 8-month-old boy with cataracts, strabismus, motor delays, and an ichthyosiform rash since birth. Genetic testing revealed a pathogenic variant of the ABHD5 gene, suggestive of CDS, and further workup demonstrated hepatic steatosis and myopathy. His ichthyosis improved with initiation of a diet low in very long-chain fatty acids and medium-chain fatty acid supplementation.

Sirolimus in the Treatment of Microcystic Lymphatic Malformations: A Systematic Review.

Background: Genetic alterations in lymphatic development can lead to microcystic lymphatic malformations (micro LMs). LMs can have both microcystic and macrocytic components or be exclusively one or the other. LMs can result in serious, sometimes life-threatening, sequelae. Absent consensus guidelines, treatment has been largely empiric. Recent advances in our understanding of the pathogenesis of micro LMs have provided a foundation for novel therapeutic approaches. This review examines clinical data over the last 10 years on the role of sirolimus, an inhibitor of the PI3K/AKT/mTOR signaling pathway implicated in micro LM development, in the treatment of micro LM. Methods and Results: Systematic review of published clinical studies from January 1, 2011, to July 15, 2021, using the PubMed, Google Scholar, and Cochrane Reviews databases, and utilizing delimiters to focus specifically on sirolimus in the treatment of micro LM. A total of 16 studies were identified (13 case studies or case reviews; 3 prospective) that included 52 subjects treated with topical (n = 15) or oral (n = 37) sirolimus for micro LM. Clinically meaningful, long-term improvement (up to 3 years) was noted in 92% (46/50), mostly previously treated subjects. Sirolimus yielded improvements in key manifestations such as lymphatic leakage, bleeding, vesicle bulk, pain, and skin discoloration. Some subjects experienced a rapid onset of effect (within 2 weeks). No unexpected adverse events were seen. Conclusion: Sirolimus appears to be an effective and safe option in the management of cutaneous and complex micro LM. However, prospective, controlled trials are clearly needed to accurately elucidate the benefits and risks of sirolimus in the management of micro LM. ClinicalTrials.gov Identifier: NCT05050149.

Evidence-Based Clinical Practice Guidelines for Laser-Assisted Drug Delivery.

Importance: Laser-assisted drug delivery (LADD) is used for various medical and cosmetic applications. However, there is insufficient evidence-based guidance to assist clinicians performing LADD. Objective: To develop recommendations for the safe and effective use of LADD. Evidence Review: A systematic literature review of Cochrane Central Register of Controlled Trials, Embase, and MEDLINE was conducted in December 2019 to identify publications reporting research on LADD. A multidisciplinary panel was convened to draft recommendations informed by the systematic review; they were refined through 2 rounds of Delphi survey, 2 consensus meetings, and iterative review by all panelists until unanimous consensus was achieved. Findings: Of the 48 published studies of ablative fractional LADD that met inclusion criteria, 4 were cosmetic studies; 21, oncologic; and 23, medical (not cosmetic/oncologic), and 6 publications of nonablative fractional LADD were included at the request of the expert panel, producing a total of 54 studies. Thirty-four studies (63.0%) were deemed to have low risk of bias, 17 studies (31.5%) had moderate risk, and 3 (5.5%) had serious risk. The key findings that informed the guidelines developed by the expert panel were as follows: LADD is safe in adults and adolescents (≥12 years) with all Fitzpatrick skin types and in patients with immunosuppression; it is an effective treatment for actinic keratosis, cutaneous squamous cell carcinoma in situ, actinic cheilitis, hypertrophic scars, and keloids; it is useful for epidermal and dermal analgesia; drug delivery may be increased through the application of heat, pressure, or occlusion, or by using an aqueous drug solution; laser settings should be selected to ensure that channel diameter is greater than the delivered molecule; antibiotic prophylaxis is not recommended, except with impaired wound healing; antiviral prophylaxis is recommended when treating the face and genitalia; and antifungal prophylaxis is not recommended. The guideline's 15 recommendations address 5 areas of LADD use: (I) indications and contraindications; (II) parameters to report; (III) optimization of drug delivery; (IV) safety considerations; and (V) prophylaxis for bacterial, viral, and fungal infections. Conclusions and Relevance: This systematic review and Delphi consensus approach culminated in an evidence-based clinical practice guideline for safe and effective use of LADD in a variety of applications. Future research will further improve our understanding of this novel treatment technique.

A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex.

BACKGROUND: Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses. Prior work has been limited by small sample sizes, and much remains unexplored about the disease burden and health-related quality of life (QOL) of patients with EBS. The aim of this study was to characterize the most common patient-reported clinical manifestations and the health-related impact of QOL in EBS, and to examine differences in disease burden by age. METHODS: Patients with a diagnosis of epidermolysis bullosa (EB) or their caregivers completed a one-time online survey administered by EBCare, an international online EB registry. Survey data from respondents self-reporting a diagnosis of EBS were analyzed for clinical and wound manifestations, medication use, and QOL (using Quality of Life in Epidermolysis Bullosa [QOLEB] scores). Differences across age groups were assessed using Kruskal-Wallis and Fisher's exact tests. RESULTS: There were 214 survey respondents with EBS. The mean age was 32.8 years (standard deviation = 19.2). Many respondents reported blisters (93%), recurrent wounds (89%), pain (74%), chronic wounds (59%), itch (55%), and difficulty walking (44%). Mean QOLEB score was 14.7 (standard deviation = 7.5) indicating a "moderate" impact on QOL, and 12% of respondents required regular use of opiates. Findings were consistent in subgroup analyses restricted to respondents with diagnostic confirmation via genetic testing or skin biopsy (n = 63 of 214). Age-stratified analyses revealed differences in disease burden: younger respondents were more likely to self-report severe disease (24% vs. 19% vs. 5% for respondents aged 0-9 vs. 10-17 vs. 18 + , p = 0.001), failure to thrive (9% vs. 15% vs. 3%, p = 0.02), and use of gastrostomy tubes (15% vs. 12% vs. 1%, p < 0.001) and topical antibiotics (67% vs. 69% vs. 34%, p < 0.001), while older respondents were more likely to be overweight or obese (6% vs. 0% vs. 51%, p < 0.001) and have difficulty walking (24% vs. 46% vs. 48%, p = 0.04). CONCLUSIONS: In the largest international cross-sectional survey of EBS patients conducted, respondents reported extensive disease burden including significant wounding, pain, itch, difficulty walking, and impact on QOL. Age stratified disease manifestations. These findings suggest significant unmet need, and treatment and counseling for EBS patients should consider age-specific differences.

Gorlin Syndrome: Assessing Genotype-Phenotype Correlations and Analysis of Early Clinical Characteristics as Risk Factors for Disease Severity.

PURPOSE: Gorlin syndrome (GS) is a rare genetic disorder characterized by lifetime risk of basal cell carcinomas (BCCs), skeletal anomalies (SAs), and other extracutaneous neoplasms. There is great variation in disease severity, and a genotype-phenotype correlation has not been well established. Here, we investigate whether patients' clinical characteristics predict disease severity to inform clinical decision making. METHODS: Data of 248 patients with GS were collected between 2014 and 2021 from three institutions. Multivariable regression analyses were performed to investigate whether clinical characteristics predicted disease burden. Genotype-phenotype correlations were investigated in 40 patients. RESULTS: Patients with SAs had a mean increase of 120 lifetime BCCs (95% CI, 27.1 to 213) relative to patients without SAs. Those with ≥ 2 SAs had 2.45 increased odds (95% CI, 1.01 to 5.91) of advanced or metastatic BCCs. Moreover, the presence of multiple SAs was associated with 5.00 increased odds of having a keratocystic odontogenic tumor (95% CI, 2.22 to 11.3) and 2.79 increased odds of an ovarian fibroma (95% CI, 1.05 to 7.40). Genotype-phenotype analyses showed that missense/in-frame mutations were more likely to be hereditary compared with severe deleterious mutation types (100% v 27%; P = .004). In addition, heat map visualization illustrated that those with more deleterious variants, like large deletions, trended toward increased burden of SAs and BCCs per year. CONCLUSION: GS patients with SAs may be at greater risk for developing more numerous and severe BCCs and other neoplastic growths including keratocystic odontogenic tumors and ovarian fibromas. Current clinical guidelines suggest yearly follow-up in individuals with GS. Since SAs are usually recognized at the time of diagnosis, our results suggest that more vigilant lifetime multidisciplinary surveillance should be considered for these patients starting in childhood.

Spitz nevus with EHBP1-ALK fusion and distinctive membranous localization of ALK.

ALK rearrangements define a histopathologically distinctive yet diverse subset of Spitz tumors characterized by fusiform to epithelioid melanocytes with frequent fascicular growth and ALK overexpression. Molecularly, these tumors are characterized by fusions between ALK and a variety of gene partners, most commonly TPM3 and DCTN1. We describe an unusual case of a Spitz nevus occurring in a 13-year-old female that manifested ALK immunopositivity with cell membrane localization. The proliferation was polypoid and composed of elongated nests of epithelioid melanocytes with enlarged nuclei, prominent nucleoli, and abundant cytoplasm without significant atypia and lacking mitotic figures. The nevus exhibited strong and diffuse expression of p16. Targeted next-generation RNA sequencing revealed an in-frame EHBP1-ALK fusion, which has been reported only once in the literature. EHBP1 encodes an adaptor protein with plasma membrane targeting potential. Together, these findings suggest that the 5' ALK fusion partner in Spitz tumors may dictate the subcellular localization of the ALK chimeric oncoprotein. In summary, this case highlights a rare ALK fusion associated with a distinct immunohistochemical staining pattern and further expands the spectrum of ALK-rearranged melanocytic tumors.

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.