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.

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.

Early intervention and prevention of allergic diseases.

Food allergy (FA) is now one of the most common chronic diseases of childhood often lasting throughout life and leading to significant worldwide healthcare burden. The precise mechanisms responsible for the development of this inflammatory condition are largely unknown; however, a multifactorial aetiology involving both environmental and genetic contributions is well accepted. A precise understanding of the pathogenesis of FA is an essential first step to developing comprehensive prevention strategies that could mitigate this epidemic. As it is frequently preceded by atopic dermatitis and can be prevented by early antigen introduction, the development of FA is likely facilitated by the improper initial presentation of antigen to the developing immune system. Primary oral exposure of antigens allowing for presentation via a well-developed mucosal immune system, rather than through a disrupted skin epidermal barrier, is essential to prevent FA. In this review, we present the data supporting the necessity of (1) an intact epidermal barrier to prevent epicutaneous antigen presentation, (2) the presence of specific commensal bacteria to maintain an intact mucosal immune system and (3) maternal/infant diet diversity, including vitamins and minerals, and appropriately timed allergenic food introduction to prevent FA.

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.

Next-generation sequencing confirms T-cell clonality in a subset of pediatric pityriasis lichenoides.

BACKGROUND: Pityriasis lichenoides (PL) is a papulosquamous disease that affects both adults and children. Previous studies have shown a subset of this entity to have clonal T-cell populations via PCR-based assays. In this study, we sought to implement next-generation sequencing (NGS) as a more sensitive and specific test to examine for T-cell clonality within the pediatric population. METHODS: We identified 18 biopsy specimens from 12 pediatric patients with clinical and histopathologic findings compatible with PL. Patient demographics, clinical features, management, and histopathologic findings were reviewed. All specimens were analyzed for clonality with NGS of T-cell receptor beta (TRB) and gamma (TRG) genes. RESULTS: Of the 12 patients, 9 (75%) had complete resolution of lesions at the time of data collection (mean follow-up 31 months). The remaining three patients significantly improved with methotrexate (with or without acitretin). Interestingly, 7 of 12 patients (58%) and 9 of 17 biopsy specimens (53%) showed evidence of T-cell clonality. Two patients showed matching TRB clones from different anatomic sites. CONCLUSIONS: T-cell clonality is a common finding in PL, probably representing a "reactive clonality" rather than a true lymphoproliferative disorder. Clonality alone cannot be used as a means to distinguish PL from lymphomatoid papulosis or cutaneous lymphoma.

Eruptive nevi in a patient with constitutional mismatch repair deficiency (CMMRD).

Biallelic mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2 result in one of the most aggressive genetic cancer conditions, constitutional mismatch repair syndrome (CMMRD). We present a case of a 10-year-old boy with biallelic MSH6 mutation and systemic lupus erythematosus with eruptive melanocytic nevi after receiving chemotherapy for mediastinal T-cell lymphoblastic lymphoma.

Dermatologic toxicities of targeted antineoplastic agents and immune checkpoint inhibitor therapy in pediatric patients: A systematic review.

Cutaneous adverse events (cAEs) from targeted antineoplastic agents and immune checkpoint inhibitors are common in children with cancer and may lead to dose reduction or cessation of critical oncologic treatment. Timely diagnosis and proper management of cAEs in pediatric oncology patients is essential to optimize ongoing cancer-directed therapy and improve quality of life. This systematic review of published studies summarizes dermatologic toxicities to targeted anticancer treatments and immune checkpoint inhibitors.

Psoriasiform dermatitis during dupilumab treatment for moderate-to-severe atopic dermatitis in children.

BACKGROUND/OBJECTIVES: Psoriasiform eruptions after initiation of dupilumab have been previously described in adults. This report details the risk of developing or unmasking psoriasiform eruptions after initiation of dupilumab in children. METHODS: Records of patients ≤18 years of age with atopic dermatitis who developed psoriasiform dermatitis during treatment with dupilumab were reviewed retrospectively. RESULTS: Six children, 4-18 years of age, on dupilumab for severe atopic dermatitis developed new-onset psoriasiform dermatitis at a median duration of 8 months (range, 6-12 months) after dupilumab initiation. Typical locations of psoriasis were involved (face, scalp, trunk, and extensor extremities). The majority showed clearance or near clearance with the use of medium-strength to potent topical corticosteroid ointments and 83% continued use of the dupilumab. A 7th patient had psoriasis, in addition to severe atopic dermatitis, and the psoriasis was unmasked by its failure to respond to dupilumab. CONCLUSION: Although unusual, psoriasiform lesions can appear during effective treatment with dupilumab for atopic dermatitis, potentially reflecting a shift toward cutaneous IL-23/TH 17 pathway activation with dupilumab-induced suppression of type 2 immunity.

Imatinib as a potentially effective therapeutic alternative in corticosteroid-resistant eosinophilic fasciitis.

Eosinophilic fasciitis (EF) is a rare condition in children that is typically treated with systemic corticosteroids. We present the case of a 9-year-old boy with biopsy-proven EF, refractory to systemic corticosteroids and methotrexate. The tyrosine kinase inhibitor imatinib was added as adjuvant therapy, leading to improvement in joint function and skin laxity. Our case is the first to suggest the anti-fibrotic properties of imatinib may benefit EF patients.

Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review.

Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p = .0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.

Genetics of vascular malformation and therapeutic implications.

PURPOSE OF REVIEW: Vascular malformations (VaMs) are a consequence of disrupted morphogenesis that may involve arterial, capillary, venous, or lymphatic endothelium alone or in a combination. VaMs can have serious health impacts, leading to life-threatening conditions sometimes. Genetic mutations affecting proliferation, migration, adhesion, differentiation, and survival of endothelial cells, as well as integrity of extracellular matrix are believed to be the pathogenesis of these disorders. Here, we present an updated review of genetic mutations and potential therapeutic targets for VaMs. RECENT FINDINGS: Increased number of genetic mutations have been discovered in vascular anomalies via targeted deep sequencing. When a genetic defect is identified, it often presents in only a small percentage of cells within the malformation. In addition, mutations within the same gene may result in different clinical phenotypes. Management of VaMs can be challenging depending on the severity and functional impairment associated. There are no standard treatment algorithms available to date for VaMs, therefore the disorder has significant unmet clinical needs. Currently, the focus of therapeutic development is to target constitutively activated intracellular signaling pathways resulted from genetic mutations. SUMMARY: Knowledge about the genetic mutations and altered signaling pathways related to VaMs have improved our understanding about the pathogenesis of vascular anomalies and provided insights to the development of new targeted therapies.

Successful treatment of spindle cell hemangiomas in a patient with Maffucci syndrome and review of literatures.

Maffucci syndrome is a rare genetic disease due to somatic mutation of IDH1 gene. Currently there is no medical treatment available for spindle cell hemangioma associated with this disorder. Here we report successful management of these hemangiomas using sirolimus in combination with surgery.

Atypical presentations of congenital hemangiomas: Extending the clinical phenotype.

BACKGROUND/OBJECTIVES: Congenital hemangiomas (CH) are a group of benign vascular tumors that are present at birth and exhibit variable involution during infancy. Congenital hemangiomas that do not involute are typically solitary patch or plaque-type tumors that grow proportionally with somatic growth. We report a case series of 9 patients with persistent CH, which exhibited uncommon features including segmental involvement, recurrent or severe pain, or growth via volumetric increase in size or apparent increased extent of anatomic involvement over time. METHODS: Via retrospective chart review, we included patients with persistent CH and atypical presentations. Available data regarding clinical characteristics, natural history, histopathology, imaging, and genetic tests were collected. RESULTS: Data on 9 patients were collected, including 7 noninvoluting CH and 2 partially involuting CH. Three of the 9 cases had segmental distribution, 6 had apparent growth or clinical evolution, and 4 were symptomatic with pain. One also had marked localized intravascular coagulopathy. CONCLUSIONS: Ongoing or recurrent pain and large extent of anatomic involvement can be features of CH, albeit uncommon ones, and can pose both diagnostic and management challenges. Tissue genomic studies can offer a novel tool for CH diagnosis.

Cutaneous manifestations of nutritional deficiency.

PURPOSE OF REVIEW: Childhood malnutrition is a major global health issue. It is often thought of as a developing world problem and therefore, underdiagnosed or misdiagnosed in developed countries. The delay in diagnosis and treatment can lead to increased morbidity and mortality. Cutaneous manifestations are often the initial presenting signs of nutritional deficiency. Early recognition is essential in timely initiation of the necessary interventions. This article will review pertinent cutaneous findings and systemic manifestations associated with common nutritional deficiencies. RECENT FINDINGS: Malnutrition has historically been associated with poverty in developing countries. However, recent literatures suggest that the incidence of nutritional deficiencies continuous to rise among infants from developed countries, as a result of dietary restrictions because of perceived food allergies or intolerance. It is also an emerging finding in children with complicated medical problems. SUMMARY: It is very important to raise awareness about cutaneous manifestations of nutritional deficiency as early and appropriate treatment results in excellent prognosis.

Self-initiated use of topical cannabidiol oil for epidermolysis bullosa.

Epidermolysis bullosa is a rare blistering skin disorder that is challenging to manage because skin fragility and repeated wound healing cause itching, pain, limited mobility, and recurrent infections. Cannabidiol, an active cannabinoid found in cannabis, is postulated to have antiinflammatory and analgesic effects. We report 3 cases of self-initiated topical cannabidiol use in patients with epidermolysis bullosa in an observational study. One patient was weaned completely off oral opioid analgesics. All 3 reported faster wound healing, less blistering, and amelioration of pain with cannabidiol use. Although these results demonstrate promise, further randomized, double-blind clinical trials are necessary to provide scientific evidence of our observed benefits of cannabidiol for the treatment of epidermolysis bullosa.

Genetic diseases associated with an increased risk of skin cancer development in childhood.

PURPOSE OF REVIEW: Childhood skin cancers are relatively rare and may indicate an underlying genetic disorder. The increasing elucidation of genetic pathways is changing the diagnosis and management of genetic skin cancer susceptibility syndromes. In this review, we provide an overview of genetic conditions that predispose to skin cancer development in childhood and signs that providers should assess when evaluating affected individuals. RECENT FINDINGS: In basal cell nevus syndrome (BCNS), the patched2 (PTCH2) and suppressor of fused (SUFU) genes have been implicated in disease pathogenesis. The sonic hedgehog (SHH) pathway inhibitor vismodegib was shown in a placebo-controlled phase III randomized trial to reduce the tumor burden in patients with BCNS. Epidermolysis bullosa (EB) has been classified into four major types and more than 30 subtypes based partly on specific mutations, and best clinical practice guidelines for the management of cutaneous squamous cell carcinoma in EB have been developed. Oculocutaneous albinism (OCA) has been associated with new mutations in genes named OCA5, OCA6, and OCA7, bringing to the total number of culprit genes to seven (OCA1-OCA7). SUMMARY: Advances in our understanding of genetic conditions that predispose to childhood skin cancer include new disease classification systems, management guidelines, and treatment options.

Use of topical sirolimus in the management of multiple familial trichoepitheliomas.

The management of trichoepitheliomas is challenging, especially in children. This challenge is exemplified in patients with multiple trichoepitheliomas who present with progression of lesion count and size despite treatment with current strategies, including CO2 laser and surgery. We present the novel use of topical 1% sirolimus cream in two siblings with multiple facial trichoepitheliomas; one was treated with a combination of CO2 laser ablation and topical sirolimus, and the other was treated with topical sirolimus alone. Both siblings had a reduction in the growth of new lesions with no reported side effects. This is the first report demonstrating that topical sirolimus, either in combination with CO2 laser or alone, can be a promising treatment for trichoepitheliomas.

Long-Term Follow-Up of Lymphatic Malformations in Children Treated with Sildenafil.

BACKGROUND/OBJECTIVES: Lymphatic malformations (LMs) are challenging to treat. Reports on the benefits of sildenafil for LM management have been mixed. This study evaluated long-term clinical outcomes of pediatric LM patients after sildenafil treatment. METHODS: A retrospective chart review was performed on pediatric LM patients treated with sildenafil in the past 5 years. Patients were also contacted to complete a survey of comprehensive questions about their LM after sildenafil and subsequent interventions. RESULTS: Of 12 patients identified, 10 (83.3%) participated in the follow-up survey. The average age was 8 years (range 4-16 yrs), median treatment duration was 9 months, and the average time of follow-up after sildenafil was 4 years; one patient is still taking sildenafil. Ten patients surveyed (83.3%) reported positive therapeutic response, with improvement in the size and compressibility of their LM during posttreatment clinical visits. Six received additional interventions (four sirolimus, one sclerotherapy, one surgery) after sildenafil was discontinued, with all but one reporting a positive response to subsequent interventions. Minor side effects at the time of sildenafil treatment included mild flushing, dizziness, and transient nausea, but no adverse effects were reported at the long-term follow-up. CONCLUSION: This is the first report of long-term follow-up of pediatric LM patients treated with sildenafil. Our findings suggest that sildenafil is beneficial for the symptomatic treatment of LMs. Additional analysis on the role of sildenafil as adjuvant therapy is necessary to optimize the use of this medication in the management of complex LMs.

An Atopic Dermatitis Management Algorithm for Primary Care Providers and Assessment of Its Usefulness as a Clinical Tool.

BACKGROUND/OBJECTIVES: There is a lack of primary care provider (PCP) understanding of atopic dermatitis (AD) treatments and topical steroid use. We designed an AD management algorithm for pediatric PCPs. We hypothesized that the algorithm would improve pediatric PCPs' knowledge of AD diagnosis and management. METHODS: Pediatric primary care resident and attending physicians at three residency programs were invited to participate in an electronic AD algorithm survey that contained demographic and 19 knowledge-based questions. Participants were randomized to intervention and control groups, with the intervention group receiving a short lecture and copy of our algorithm to use in an inpatient or outpatient setting for 2 months. Changes in scores between preintervention and postintervention surveys were compared. RESULTS: Of the 54 participants, those in the intervention group (n = 26) performed significantly better than those in the control group (n = 28) after controlling for pretest scores (ß = 1.19 [95% confidence interval 0.07, 2.32], p = 0.04). The intervention group had a higher average score on the posttest knowledge questions (71% correct) than the control group (65% correct) (p = 0.06). The majority of physicians who received the algorithm agreed or strongly agreed that they liked using the algorithm. CONCLUSION: The use of a management algorithm improved physician knowledge about the diagnosis and treatment of AD and was well accepted by physicians. Use of this management algorithm may lead to better recognition and management of AD, particularly earlier recognition of and therapy for superinfection, improving treatment outcomes and quality of life for patients and families.