Management of Atopy with Dupilumab and Omalizumab in CADINS Disease.

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity. We assessed the response of dupilumab in five patients and omalizumab in one patient with CADINS for the treatment of severe atopic symptoms. CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB. Three children and three adults with dominant-negative CARD11 LOF mutations were included. All developed atopic disease in infancy or early childhood. In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria. Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria. All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued. In conclusion, treatment with dupilumab and omalizumab for severe, refractory atopic disease in patients with CADINS appears to be effective and well tolerated in patients with CADINS with severe atopy.

Risk factors and outcomes of melanoma in children and adolescents: A retrospective multicenter study.

BACKGROUND: Pediatric melanoma presents with distinct clinical features compared to adult disease. OBJECTIVE: Characterize risk factors and negative outcomes in pediatric melanoma. METHODS: Multicenter retrospective study of patients under 20 years diagnosed with melanoma between January 1, 1995 and June 30, 2015 from 11 academic medical centers. RESULTS: Melanoma was diagnosed in 317 patients, 73% of whom were diagnosed in adolescence (age ≥11). Spitzoid (31%) and superficial spreading (26%) subtypes were most common and 11% of cases arose from congenital nevi. Sentinel lymph node biopsy was performed in 68% of cases and positive in 46%. Fatality was observed in 7% of cases. Adolescent patients with melanoma were more likely to have family history of melanoma (P = .046) compared to controls. LIMITATIONS: Retrospective nature, cohort size, control selection, and potential referral bias. CONCLUSION: Pediatric melanoma has diverse clinical presentations. Better understanding of these cases and outcomes may facilitate improved risk stratification of pediatric melanoma.

A comparative analysis of RAS variants in patients with disorders of somatic mosaicism.

PURPOSE: RAS genes (HRAS, KRAS, and NRAS) are commonly found to be mutated in cancers, and activating RAS variants are also found in disorders of somatic mosaicism (DoSM). A survey of the mutational spectrum of RAS variants in DoSM has not been performed. METHODS: A total of 938 individuals with suspected DoSM underwent high-sensitivity clinical next-generation sequencing-based testing. We investigated the mutational spectrum and genotype-phenotype associations of mosaic RAS variants. RESULTS: In this article, we present a series of individuals with DoSM with RAS variants. Classic hotspots, including Gly12, Gly13, and Gln61 constituted the majority of RAS variants observed in DoSM. Furthermore, we present 12 individuals with HRAS and KRAS in-frame duplication/insertion (dup/ins) variants in the switch II domain. Among the 18.3% individuals with RAS in-frame dup/ins variants, clinical findings were mainly associated with vascular malformations. Hotspots were associated with a broad phenotypic spectrum, including vascular tumors, vascular malformations, nevoid proliferations, segmental overgrowth, digital anomalies, and combinations of these. The median age at testing was higher and the variant allelic fraction was lower in individuals with in-frame dup/ins variants than those in individuals with mosaic RAS hotspots. CONCLUSION: Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.

Health literacy in pediatric dermatology: challenges and opportunities.

PURPOSE OF REVIEW: Health literacy influences how children and families participate in their medical care, use health services, and overall health outcomes. Health literacy is underexplored in pediatric dermatology. In this scoping review, we provide examples of how limited health literacy can be a barrier to patient care in pediatric dermatology and how to mitigate its effects. RECENT FINDINGS: Limited health literacy is associated with worse health outcomes, decreased medication adherence, and decreased use of the healthcare system versus those with adequate health literacy. Materials created to help patients understand their medical conditions and treatment options often are written at a reading level far above that of the average patient and caregiver. Given the reading level of patient-facing materials, those with limited health literacy are more susceptible to medication administration errors, with omissions or incorrect dosing being most frequent to occur. There is limited research about how skills related to health literacy, including numeracy and electronic health literacy, can be addressed in pediatric dermatology. SUMMARY: Health literacy impacts patient care, treatment, and adherence in pediatric dermatology. This article gives examples of how to address common challenges in the pediatric dermatology clinic and presents areas for further research and improvement.

Tumor predisposition: what's the skin got to do with it?

PURPOSE OF REVIEW: Recognition of skin findings associated with tumor predisposition syndromes can prompt early evaluation and surveillance and improve management. Additionally, knowing when to test and when to defer performing genetic testing can streamline management. This article reviews tumor predisposition syndromes with recently characterized skin findings and disorders for which early recognition and counseling can impact the course of disease. RECENT FINDINGS: Café au lait macules (CALMs) are important in many tumor predisposition syndromes, and 'atypical' CALMs are associated with constitutional mismatch repair deficiency and Fanconi anemia. Melanoma predisposition syndromes caused by pathogenic variants in POT1 and BAP1 are more recently described, and both are associated with Spitzoid tumors. Somatic pathogenic variants can cause segmental nevoid basal cell carcinoma syndrome and a mosaic form of Peutz-Jeghers syndrome. Patients with PTEN hamartoma syndrome have increased risk for melanoma but this might not occur until adulthood. SUMMARY: The cutaneous manifestations of tumor predisposition syndromes can aid diagnosis. Early photoprotection is key to modifying a main risk factor for skin cancer in many of these syndromes. Implementing surveillance guidelines facilitates early detection of tumors.

Immunosuppressant-associated eruptions in pediatric inflammatory bowel disease: A case-control study.

Paradoxically, immunosuppressive therapy for inflammatory bowel disease (IBD) can induce psoriasiform or eczematous eruptions. This case-control study identified infliximab exposure, Crohn's disease, and history of inflammatory skin conditions as significant risk factors for these eruptions in children with IBD. Our results also showed possible trends in age and race.

Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth.

PURPOSE: Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1. METHODS: Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity. RESULTS: The phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone. CONCLUSION: Somatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway.

Shared decision making in pediatric dermatology: context, opportunities, and practical examples.

PURPOSE OF REVIEW: Shared decision making (SDM) is an important part of patient-centered care. However, it is neither widely practiced nor researched in pediatric dermatology. In this article, we provide practical examples of how to engage in SDM in pediatric dermatology, and identify future areas of research. RECENT FINDINGS: Children and parents/guardians desire SDM in clinical encounters. The process is applicable to discussions of medical as well as surgical care. Additionally, SDM can help prepare children for the transition from pediatric to adult/general providers. Clinicians often want more guidance on its implementation, and there is a dearth of research on SDM or decision tools specific to pediatric dermatology. SUMMARY: SDM is underused and understudied in pediatric dermatology. This article highlights how to engage in SDM and presents opportunities for research and implementation in pediatric dermatology.

Post-transplant malignancies in pediatric organ transplant recipients.

The majority of cancer diagnoses in pediatric solid organ transplant recipients (SOTRs) are post-transplantation lymphoproliferative disorders (PTLD) or skin cancers. However, pediatric SOTRs are also at significantly elevated risk for multiple other solid and hematological cancers. The risks of specific cancers vary by transplanted organ, underlying disease, and immunosuppression factors. More than one-quarter of pediatric SOTRs develop cancer within 30 years of transplantation and their risk of solid cancer is 14 times greater than the general population. Pediatric SOTRs are at significantly higher risk of cancer-associated death. Improving patient survival among pediatric SOTRs puts them at risk of adult epithelial cancers associated with environmental carcinogenic exposures. Vaccination against oncogenic viruses and avoidance of excessive immunosuppression may reduce the risk of solid cancers following transplantation. Patient and family education regarding photoprotection is an essential component of skin cancer prevention. There is significant variability in cancer screening recommendations for SOTRs and general population approaches are typically not validated for transplant populations. An individualized approach to cancer screening should be developed based on estimated cancer risk, patient life expectancy, and screening test performance.

Cutaneous reactions to pediatric cancer treatment: Part I. Conventional chemotherapy.

Chemotherapies often cause side effects of the skin, nails, and mucosal surfaces. These mucocutaneous toxicities contribute to morbidity and affect quality of life. Identification and management of these drug-induced eruptions is vital to allow for continuation of essential therapies. This review demonstrates the wide range of chemotherapy-induced cutaneous toxicities in children and includes clues for diagnosis as well as tips for counseling and management.

Cutaneous reactions to pediatric cancer treatment part II: Targeted therapy.

Cancer remains a leading cause of morbidity and mortality among children. Targeted therapies may improve survivorship; however, unique side-effect profiles have also emerged with these novel therapies. Changes in hair, skin, and nails-termed dermatologic adverse events (AEs)-are among the most common sequelae and may result in interruption or discontinuation of therapy. Though dermatologic AEs have been detailed in adults, these findings are not well described in the pediatric population. We reviewed the literature to characterize dermatologic AEs to anticancer targeted therapies available as of July 2020 and summarized the spectrum of clinical findings as well as treatment recommendations for children. Dermatologic AEs are among the most common AEs reported in pediatric patients receiving targeted therapy, but morphologic and histologic descriptions are often lacking in current publications. Pediatric dermatologists are uniquely poised to recognize specific morphology of dermatologic AEs and make recommendations for prevention and treatment that may improve quality of life and enable ongoing cancer therapy.

Risk Factors and Outcomes of Nonmelanoma Skin Cancer in Children and Young Adults.

OBJECTIVE: To identify risk factors associated with nonmelanoma skin cancer (NMSC) occurrence and survival in children. STUDY DESIGN: This was a multicenter, retrospective, case-control study of patients <20 years of age diagnosed with NMSC between 1995 and 2015 from 11 academic medical centers. The primary outcome measure was frequency of cases and controls with predisposing genetic conditions and/or iatrogenic exposures, including chemotherapy, radiation, systemic immunosuppression, and voriconazole. RESULTS: Of the 124 children with NMSC (40 with basal cell carcinoma, 90 with squamous cell carcinoma), 70% had at least 1 identifiable risk factor. Forty-four percent of the cases had a predisposing genetic condition or skin lesion, and 29% had 1 or more iatrogenic exposures of prolonged immunosuppression, radiation therapy, chemotherapy, and/or voriconazole use. Prolonged immunosuppression and voriconazole use were associated with squamous cell carcinoma occurrence (cases vs controls; 30% vs 0%, P = .0002, and 15% vs 0%, P = .03, respectively), and radiation therapy and chemotherapy were associated with basal cell carcinoma occurrence (both 20% vs 1%, P < .0001). Forty-eight percent of initial skin cancers had been present for >12 months prior to diagnosis and 49% of patients were diagnosed with ≥2 skin cancers. At last follow-up, 5% (6 of 124) of patients with NMSC died. Voriconazole exposure was noted in 7 cases and associated with worse 3-year overall survival (P = .001). CONCLUSIONS: NMSC in children and young adults is often associated with a predisposing condition or iatrogenic exposure. High-risk patients should be identified early to provide appropriate counseling and management.

Staphylococcus aureus antibiotic susceptibility patterns in pediatric atopic dermatitis.

BACKGROUND/OBJECTIVES: Staphylococcus aureus is the most prevalent bacterial pathogen in atopic dermatitis (AD) patients presenting with skin infections. Despite the known association between S aureus and AD, guidance on empiric antibiotics for skin infections in pediatric AD patients is limited. METHODS: We conducted a retrospective study over a five-year period to characterize the S aureus strains recovered from pediatric AD patients with clinically apparent bacterial skin infections treated in an academic medical center. We assessed patient demographics and dilute bleach bath usage to determine whether these factors were correlated with methicillin resistance. Culture results from our AD cohort were also compared to those from pediatric patients presenting to the Saint Louis Children's Hospital emergency department (ED) with S aureus skin abscesses from 2013 to 2015. RESULTS: Methicillin-sensitive S aureus (MSSA) was more prevalent (77.8%) than methicillin-resistant S aureus (MRSA) (22.2%). There was no correlation between MRSA and age, sex, race, or dilute bleach bath use. In comparison with pediatric patients presenting to the ED, AD patients had lower rates of MSSA susceptibility to doxycycline and MRSA susceptibility to trimethoprim-sulfamethoxazole (TMP-SMX). CONCLUSIONS: First-generation cephalosporins remain appropriate empiric therapy for most pediatric AD patients. In patients with a history of MRSA, empiric doxycycline or TMP-SMX could be considered, given their high MRSA susceptibility rates.

Pediatric leukemia cutis: A case series.

BACKGROUND: Pediatric leukemia cutis (LC) is often difficult to diagnose due to similarity in appearance to other dermatologic diseases. Several case reports and smaller case series have been published in the medical literature, but studies on larger cohorts of children with LC are lacking. OBJECTIVE: This study aimed to better characterize the clinical features, course, and prognosis of LC in the pediatric population. METHODS: We performed a retrospective case series of 31 patients diagnosed with LC at Boston Children's Hospital and the Children's Hospital of Philadelphia. RESULTS: The number and morphology of LC lesions varied among patients, with the head and lower extremities being the most common sites of involvement. Leukemia cutis presented concomitantly with systemic leukemia in the majority of cases. Most cases of LC arose during initial leukemia episodes, rather than with relapsed leukemia. Acute myeloid leukemia was the subtype most frequently associated with LC, followed by acute lymphoblastic leukemia. Diagnosis altered treatment timing and therapeutic decisions. CONCLUSION: Children most often present concomitantly with LC and systemic leukemia. Since the morphology and distribution of LC varies, physicians must maintain a high index of suspicion for this diagnosis, as the presence of LC may change the management of systemic leukemia.

Dermatologic considerations in pediatric transplant recipients.

PURPOSE OF REVIEW: The pediatric transplant patient population is growing as the number of solid organ transplants and indications for hematopoietic stem cell transplant increase. Understanding cutaneous sequelae of pediatric transplant and treatment strategies to manage these outcomes is vital to the care of these patients. RECENT FINDINGS: Important work in the past year enhances our understanding of the cutaneous implications of pediatric transplantation, including further work in areas of malignancy, infection, and graft versus host disease as well as newly reported risks. SUMMARY: This review highlights recent developments in the recognition and management of dermatological complications of pediatric transplant that will be useful for the practicing pediatrician or dermatologist.

Mood changes with methotrexate therapy for dermatologic disease.

Neurotoxicity and cognitive effects of low-dose methotrexate for rheumatologic disease have often been described, but the neuropsychiatric effects of low-dose methotrexate for cutaneous disease have been underreported in the dermatology literature. We describe two children who experienced mood changes with methotrexate treatment for lichen sclerosus with morphea overlap and psoriasis, with rapid resolution of these symptoms after methotrexate cessation. We also detail possible mechanisms underlying psychiatric changes with methotrexate therapy.

Granulomatous dermatitis secondary to vemurafenib in a child with Langerhans cell histiocytosis.

We present a 3-year-old boy with Langerhans cell histiocytosis who developed granulomatous dermatitis while taking vemurafenib. Vemurafenib currently has Food and Drug Administration approval for the treatment of BRAF V600E+ metastatic melanoma in adults, but recent discoveries of BRAF V600E in more than half of tested Langerhans cell histiocytosis lesions have prompted clinical trials of vemurafenib therapy for children with refractory, multisystem Langerhans cell histiocytosis. This report contributes to the knowledge of its potential side effects when used in children.

Skin cancer risk education in pediatric solid organ transplant patients: an evaluation of knowledge, behavior, and perceptions over time.

Skin cancer risk is elevated in solid OTRs. Studies of skin cancer awareness and sun-protection behaviors in pOTRs have not been reported. We measured effects over time of a multimodal educational intervention on knowledge of sun-protection practices and skin cancer risk, engagement in sun-protection behaviors, and self-efficacy and perceived barriers to photoprotection in pOTRs, their guardians, and a comparison group of children and guardians. Knowledge about skin cancer risk increased in pOTRs and their guardians (P≤.01) and frequency of pOTRs' sun-protection behaviors reported by pOTRs and their guardians also improved.

The preadolescent acne microbiome: A prospective, randomized, pilot study investigating characterization and effects of acne therapy.

BACKGROUND/OBJECTIVES: Acne, a common pediatric disease, tends to be more comedonal in preadolescents, whereas older individuals are more likely to have inflammatory lesions in addition to comedones. Thus the microbiome of preadolescents may be different. In this pilot study we aimed to characterize the preadolescent acne microbiome, compare the microbiome in preadolescents with and without acne, and investigate changes in the microbiome after topical treatment with benzoyl peroxide or a retinoid in a small cohort of preadolescents. METHODS: Participants were 7-10 years of age with (intervention group) or without (control group) acne and were recruited during routine outpatient dermatology visits. Baseline questionnaires, physical examination, and pore strip application were performed for all participants. Intervention group participants were randomized to receive topical therapy with benzoyl peroxide 5% gel or cream or tretinoin 0.025% cream. Participants with acne were followed up 8-10 weeks later and pore strip application was repeated. RESULTS: Preadolescents with acne were colonized with a greater diversity of cutaneous bacteria than controls and the most commonly identified bacterium was Streptococcus. The number of bacterial species and phylogenetic diversity decreased after treatment with benzoyl peroxide and tretinoin. CONCLUSION: The predominant bacteria in microbiome studies of adult acne is Propionibacterium, whereas in this pediatric population we saw a lot of Streptococcus bacteria. After treatment, the microbiomes of intervention group participants more closely resembled those of control group participants.

Severe Mucha-Habermann-Like Ulceronecrotic Skin Disease in T-Cell Acute Lymphoblastic Leukemia Responsive to Basiliximab and Stem Cell Transplant.

A 5-year-old girl with T-cell acute lymphoblastic leukemia (T-ALL) developed a progressive eruption of crusted papules and ulcerative plaques involving 80% of her body surface area with histopathology consistent with febrile ulceronecrotic Mucha-Habermann disease (FUMHD), although multiple specimens also contained clonal leukemic cells. Her skin disease was refractory to many classic treatments for FUMHD, including methotrexate, and became so severe that concern about superinfection prevented intensification of chemotherapy for her malignancy. The addition of basiliximab promoted gradual improvement of the skin, allowing for chemotherapy intensification and subsequent bone marrow transplantation, after which the eruption resolved completely. This report describes a severe case of FUMHD-like eruption associated with clonal leukemic cells that improved with basiliximab, suggesting anti-CD25 therapy as a novel treatment for ulceronecrotic skin disease in the setting of high interleukin-2 levels.