Jeffrey L. Sugarman

Whole-Exome Sequencing Reveals Somatic Mutations in HRAS and KRAS, which Cause Nevus Sebaceus

ACKNOWLEDGMENTS We thank the patients and their families for taking part in this project. We also thank S Aasi, R Khosla, and P Lorenz for their valuable assistance. Bryan K. Sun, Andrea Saggini, Kavita Y. Sarin, Jinah Kim, Latanya Benjamin, Philip E. LeBoit and Paul A. Khavari Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA and Department of Dermatology, University of Rome Tor Vergata, Rome, Italy E-mail: bryansun@stanford.edu

Prescribing practices for systemic agents in the treatment of severe pediatric atopic dermatitis in the US and Canada: The PeDRA TREAT survey

Background: There is a paucity of literature to direct physicians in the prescribing of immunomodulators for patients with severe atopic dermatitis (AD). Objective: To survey systemic agent prescribing practices for severe childhood AD among clinicians in the United States and Canada. Methods: The TREatment of severe Atopic dermatitis in children Taskforce (TREAT), US&CANADA, a project of the Pediatric Dermatology Research Alliance (PeDRA), developed an online multiple‐response survey to assess clinical practice, gather demographic information and details of systemic agent selection, and identify barriers to their use in patients with recalcitrant pediatric AD. Results: In total, 133 of 290 members (45.9%) of the Society for Pediatric Dermatology completed the survey, and 115 of 133 (86.5%) used systemic treatment for severe pediatric AD. First‐line drugs of choice were cyclosporine (45.2%), methotrexate (29.6%), and mycophenolate mofetil (13.0%). The most commonly used second‐line agents were methotrexate (31.3%) and mycophenolate mofetil (30.4%); azathioprine was the most commonly cited third‐line agent. The main factors that discouraged use of systemic agents were side‐effect profiles (82.6%) and perceived risks of long‐term toxicity (81.7%). Limitations: Investigation of the sequence of systemic medications or combination systemic therapy was limited. Recall bias may have affected the results. Conclusion: Great variation exists in prescribing practices among American and Canadian physicians using systemic agents for treatment of pediatric AD.

Somatic V600E BRAF Mutation in Linear and Sporadic Syringocystadenoma Papilliferum

Jonathan L. Levinsohn(1),(2),(3), Jeffrey L. Sugarman(4), Kaya Bilguvar(1),(5), Jennifer M. McNiff(2),(3), The Yale Center for Mendelian Genomics, and Keith A. Choate(1),(2),(3) (1)Department of Genetics, Yale University, New Haven, Connecticut (2)Department of Pathology, Yale University, New Haven, Connecticut (3)Department of Dermatology, Yale University, New Haven, Connecticut (4)Departments of Dermatology and Family Medicine, University of California, San Francisco, San Francisco, California

Somatic Mutations in NEK9 Cause Nevus Comedonicus

Acne vulgaris (AV) affects most adolescents, and of those affected, moderate to severe disease occurs in 20%. Comedones, follicular plugs consisting of desquamated keratinocytes and sebum, are central to its pathogenesis. Despite high heritability in first-degree relatives, AV genetic determinants remain incompletely understood. We therefore employed whole-exome sequencing (WES) in nevus comedonicus (NC), a rare disorder that features comedones and inflammatory acne cysts in localized, linear configurations. WES identified somatic NEK9 mutations, each affecting highly conserved residues within its kinase or RCC1 domains, in affected tissue of three out of three NC-affected subjects. All mutations are gain of function, resulting in increased phosphorylation at Thr210, a hallmark of NEK9 kinase activation. We found that comedo formation in NC is marked by loss of follicular differentiation markers, expansion of keratin-15-positive cells from localization within the bulge to the entire sub-bulge follicle and cyst, and ectopic expression of keratin 10, a marker of interfollicular differentiation not present in normal follicles. These findings suggest that NEK9 mutations in NC disrupt normal follicular differentiation and identify NEK9 as a potential regulator of follicular homeostasis.

Impediments to Research in Pediatric Dermatology: The Results of a Survey of the Members of the Society for Pediatric Dermatology

Abstract:  A research task force of the Society for Pediatric Dermatology (SPD) was established to investigate the barriers to expanding research in the field of pediatric dermatology. A survey was designed to address constraints limiting research activities among members of the SPD. A nine‐question survey was distributed to SPD members at the annual meeting in 2007. Of the 70 respondents, 99% reported limitations to research activities. Of those, 90% (62/69) cited time constraints as a cause, 71% lack of funding, 38% lack of training, 35% lack of research infrastructure, 10% (7/69) lack of mentoring, and 25% (17/69) cited other reasons. SPD members face many challenges that curtail their bench and clinical research, although time constraints are most common. The high demand for clinic‐directed activity and continuing workforce issues in the specialty likely contribute to the time constraints.

Epidermal nevus syndromes: New insights into whorls and swirls

Knowledge of the molecular underpinnings of many epidermal nevi and epidermal nevus syndrome has expanded rapidly in recent years. In this review and update on epidermal nevus syndrome, we will cover recent genetic discoveries involving epidermal nevi, including nevus sebaceus, keratinocytic epidermal nevus, nevus comedonicus, congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome, phakomatosis pigmentokeratotica, Beckers nevus, porokeratotic adnexal ostial nevus, inflammatory linear verrucous epidermal nevi, and cutaneous‐skeletal hypophosphatemia syndrome. We will discuss how newly defined mutations relate to the biology reflected in the cutaneous patterns seen in these mosaic disorders and how new molecular data has informed our understanding of these diseases and shaped management decisions.

Sebaceous Gland, Hair Shaft, and Epidermal Barrier Abnormalities in Keratosis Pilaris with and without Filaggrin Deficiency

Although keratosis pilaris (KP) is common, its etiopathogenesis remains unknown. KP is associated clinically with ichthyosis vulgaris and atopic dermatitis and molecular genetically with filaggrin-null mutations. In 20 KP patients and 20 matched controls, we assessed the filaggrin and claudin 1 genotypes, the phenotypes by dermatoscopy, and the morphology by light and transmission electron microscopy. Thirty-five percent of KP patients displayed filaggrin mutations, demonstrating that filaggrin mutations only partially account for the KP phenotype. Major histologic and dermatoscopic findings of KP were hyperkeratosis, hypergranulosis, mild T helper cell type 1-dominant lymphocytic inflammation, plugging of follicular orifices, striking absence of sebaceous glands, and hair shaft abnormalities in KP lesions but not in unaffected skin sites. Changes in barrier function and abnormal paracellular permeability were found in both interfollicular and follicular stratum corneum of lesional KP, which correlated ultrastructurally with impaired extracellular lamellar bilayer maturation and organization. All these features were independent of filaggrin genotype. Moreover, ultrastructure of corneodesmosomes and tight junctions appeared normal, immunohistochemistry for claudin 1 showed no reduction in protein amounts, and molecular analysis of claudin 1 was unremarkable. Our findings suggest that absence of sebaceous glands is an early step in KP pathogenesis, resulting in downstream hair shaft and epithelial barrier abnormalities.

A Retrospective Review of Streptococcal Infections in Pediatric Atopic Dermatitis

Abstract:  In order to assess the clinical characteristics and impact of group A streptococcal infection in children with atopic dermatitis, a retrospective review was performed in children diagnosed with atopic dermatitis who had a skin culture. Culture results and clinical characteristics of those with group A streptococcus were compared with those with Staphlococcus aureus. Infection with group A streptococcus was present in 16%; infection with Staphlococcus aureus was present in 72%, and 14% had mixed cultures. Patients infected with group A streptococcus were more likely to be febrile, to have facial and periorbital involvement, and to be hospitalized compared with those infected with Staphlococcus aureus alone (p ≤ 0.01 for all comparisons). Bacteremia and cellulitis were significantly more common in those infected with group A streptococcus than in those infected with Staphlococcus aureus. Retrospective design and review of only those patients receiving bacterial cultures may select for greater severity than in the general atopic dermatitis population. Group A streptococcus appears to be a significant skin pathogen infecting children with atopic dermatitis. Children with atopic dermatitis and group A streptococcal infection are more likely to have invasive disease and complications than those infected with Staphlococcus aureus alone.

Skin-infiltrating, interleukin-22–producing T cells differentiate pediatric psoriasis from adult psoriasis

Background: Evidence from adult psoriasis studies implicates an imbalance between regulatory and effector T cells, particularly TH‐17–producing T cells, in the pathogenesis of psoriasis. Little is known about the immunopathology of psoriasis in children. Objective: We sought to functionally characterize the inflammatory cell profiles of psoriatic plaques from pediatric patients and compare them with healthy, age‐matched controls and adult psoriasis patients. Methods: Skin samples from pediatric psoriasis patients and healthy controls were analyzed by multiparameter flow cytometry to determine the dominant immune cell subsets present and cytokines produced. Results: Lesional tissue from pediatric psoriasis patients had significantly increased interleukin (IL) 22 derived from CD4+ and CD8+ cells compared with the tissues from healthy pediatric controls and adult psoriasis patients. Tissue from pediatric psoriasis patients had significantly less elevation of IL‐17 derived from CD4+ and CD8+ cells compared with the tissue from adult psoriasis patients. In contrast with the lesions from adult patients, lesional skin in pediatric patients with psoriasis did not have increases in regulatory T cells. Limitations: This is a pilot study, thus the sample size is small. Conclusion: Significant differences in IL‐17 and IL‐22 expression were observed in the pediatric psoriasis patients compared with pediatric healthy controls and adult psoriasis patients. IL‐22 might be relevant in the pathogenesis of pediatric psoriasis and represents a potential treatment target unique to pediatric psoriasis.

Pediatric psoriasis: Evolving perspectives

Childhood‐onset psoriasis is a common skin disorder that has recently received increasing attention, particularly because of its significant medical, social, financial, and psychological burdens and its associated comorbidities. With limited data available and lack of standardized management guidelines for pediatric psoriasis, an expert panel desired to provide an updated critical overview and practical guidance for management of the affected population.