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Background In 2015, a major achievement in vitiligo research was the development of an internationally agreed upon core outcome domain set for randomized clinical trials (RCTs). Three outcomes were identified as being essential: repigmentation, side-effects/harms and maintenance of gained repigmentation. Four items were further recommended for inclusion. The following recommendations then followed: repigmentation should be assessed by measuring the percentage of repigmentation in quartiles (0–25%, 26–50%, 51–79%, 80–100%) and cosmetic acceptability of the results should be assessed using the Vitiligo Noticeability Scale. Objectives The primary objective of this study was to assess uptake of the core outcome domain set for RCTs in vitiligo. Secondary objectives were to update the systematic review on outcomes reported in vitiligo RCTs, and to assess whether repigmentation and cosmetic acceptability of the results were measured using the above-mentioned recommended scales. Methods We searched PubMed, Cochrane Library (CENTRAL and Systematic Reviews) and ClinicalTrials.gov for vitiligo RCTs between November 2009 and March 2021. Screening and data extraction were independently performed on title and summary by two researchers. All outcomes and outcome measures reported in eligible RCTs were retrieved and collated. Results In total, 174 RCTs were identified: 62 were published between 2009 and 2015, and 112 were published between 2016 and 2021.Thirty-eight different outcomes were reported. Repigmentation was the primary outcome in 89% of trials (150 of 169). Forty-nine different tools were used to measure repigmentation. Side-effects and harms were reported in 78% of trials (136 of 174). Maintenance of gained repigmentation was reported in only 11% of trials (20 of 174) and duration of follow-up varied greatly from 1 to 14 months. Cosmetic acceptability of the results and cessation of disease activity were assessed in only 2% of trials (four of 174). Quality of life of patients with vitiligo was assessed in 13% of trials (22 of 174). Finally, only 11 of 112 RCTs (10%) published between 2016 and 2021 reported all three essential core outcome domains (repigmentation, side-effects and maintenance of gained repigmentation) and none of the trials reported both essential and recommended core outcome domains. Conclusions Efforts are still needed to close the gap between set recommendations and RCT outcome reporting.

International audience; Objective: To investigate whether the initiation of treatment with an interleukin-17 inhibitor (IL-17i) in real life is associated with a higher risk of inflammatory bowel disease (IBD) in patients who had both psoriasis (PsO) and psoriatic arthritis (PsA)/ankylosing spondylitis (AS). Methods: This nationwide cohort study was conducted using the French National Health Data System database. All adult patients with PsO and PsA/AS who were identified as having newly initiated treatment with an IL-17i during 2016–2019 were included. As controls, patients with PsO and PsA/AS who had newly initiated either 1) apremilast or 2) etanercept (ETN) during this period but had not received IL-17i were included. The follow-up end date was September 30, 2019. The primary end point was the risk of occurrence of IBD associated with exposure to an IL-17i compared to exposure to the other treatments, as determined in a time-to-event analysis with propensity score–weighted Cox and Fine-Gray proportional hazards models. Results: The study included a total of 16,793 new IL-17i users (mean ± SD age 48.4 ± 13 years, 45% men), 20,556 new apremilast users (age 52.6 ± 15 years, 54% men), and 10,294 new ETN users (age 46.3 ± 15 years, 44% men). New IL-17i users and new ETN users had received more biologics for their underlying disease compared to new apremilast users. IBD occurred in 132 patients: 72 new IL-17i users (0.43%), 11 new apremilast users (0.05%), and 49 new ETN users (0.48%). Most IBD cases occurred after 6 months of exposure (82%, 55%, and 76%, respectively). After propensity score weighting, the risk of IBD was significantly greater among patients initiating an IL-17i compared to those initiating apremilast (weighted hazard ratio [HR] 3.8 [95% confidence interval (95% CI) 2.1–6.8]). No difference in the risk of IBD between new IL-17i users and new ETN users was observed (weighted HR 0.8 [95% CI 0.5–1.2]). Conclusion: Patients with PsO and PsA/AS who initiate treatment with an IL-17i do not have a higher risk of developing IBD when compared to patients initiating ETN who display the same severity of underlying disease. These results need to be confirmed in other large studies of patients with PsO and PsA/AS.

Cutaneous lichen planus is a highly pruritic dermatosis with an unmet need in its management. The aim of this study was to evaluate the short-term effect and tolerance of high doses of clobetasol propionate 0.05% in cutaneous lichen planus. We conducted a single-center retrospective cohort study from 2017 to 2021. All adults treated with high-dose (5 g/day) clobetasol propionate 0.05% for cutaneous lichen planus were included. Patients with less than 10% affected body surface area at initial presentation or who received concomitant systemic therapy were excluded. The primary endpoint was the rate of complete remission by week 16. Secondary endpoints included maximum daily and median cumulative doses, reduction in pruritus and occurrence of adverse events. Fifty-seven patients, 60% female, with a mean age of 48 years (min-max,18-83) were included. Cutaneous lichen planus had been present for a median duration of 2 months at initial presentation (min-max, 1-4) and involved a median body surface area of 27%. Pruritus was reported by 55/57 (96%) patients. At week 16, 41/57 (72%) patients had achieved complete remission without treatment modification, among whom 25/41 (61%) had achieved it at week 6. The median daily and cumulative doses were, respectively, 20 g/day (IQR, 10-20) and 560 g (IQR, 320-925). Three patients experienced mild adverse events. No statistical association was demonstrated between the duration of the disease before treatment initiation and clinical response. In conclusion, high-dose clobetasol propionate 0.05% seems to be an effective, well-tolerated, and easy-to-implement treatment for cutaneous lichen planus.

Quantitative analysis of continuous electroencephalography (QEEG) is increasingly being used to augment seizure detection in critically ill patients. Typically, seizures manifest on QEEG as abrupt increases in power and frequency, a visual pattern often called "flames." Here, we present a case of a 16-year-old patient with intractable Lennox-Gastaut syndrome secondary to a pathogenic variant in the SCN2A gene who had tonic seizures that manifest as abrupt decreases in power on QEEG, a visual pattern we term "icicles." Recognition of QEEG patterns representative of different seizure types is important as QEEG use becomes more widespread including in pediatric populations.

Neurofibromatosis 1 (NF1) is an inherited, autosomal-dominant, tumor predisposition syndrome with a birth incidence as high as 1:2000. A patient with NF1 is four to five times more likely to develop a malignancy as compared to the general population. The number of epidemiologic studies on lymphoproliferative malignancies in patients with NF1 is limited. The aim of this study was to determine the incidence rate of lymphoproliferative malignancies (lymphoma and leukemia) in NF1 patients followed in our referral center for neurofibromatoses. We used the Informatics for Integrated Biology and the Bedside (i2b2) platform to extract information from the hospital’s electronic health records. We performed a keyword search on clinical notes generated between Jan/01/2014 and May/11/2020 for patients aged 18 years or older. A total of 1507 patients with confirmed NF1 patients aged 18 years and above were identified (mean age 39.2 years; 57% women). The total number of person-years in follow-up was 57,736 (men, 24,327 years; women, 33,409 years). Mean length of follow-up was 38.3 years (median, 36 years). A total of 13 patients had a medical history of either lymphoma or leukemia, yielding an overall incidence rate of 22.5 per 100,000 (0.000225, 95% confidence interval (CI) 0.000223–0.000227). This incidence is similar to that of the general population in France (standardized incidence ratio 1.07, 95% CI 0.60–1.79). Four patients had a medical history leukemia and 9 patients had a medical history of lymphoma of which 7 had non-Hodgkin lymphoma, and 2 had Hodgkin lymphoma. Our results show that adults with NF1 do not have an increased tendency to develop lymphoproliferative malignancies, in contrast to the general increased risk of malignancy. While our results are consistent with the recent population-based study in Finland, they are in contrast with the larger population-based study in England whereby NF1 individuals were found to be 3 times more likely to develop both non-Hodgkin lymphoma and lymphocytic leukemia. Large-scale epidemiological studies based on nationwide data sets are thus needed to confirm our findings.

Purpose of review An early understanding of the role of the Ras/Raf/MEK/ERK signalling pathway in regulating cell proliferation has set the stage for the development of several potent and selective MEK inhibitors (MEKi). MEKi represent promising therapies for RAS-driven neoplasias and RASopathies associated with increased Ras/MAPK activity. Recent findings Neurofibromatosis 1 (NF1) is a prototypic RASopathy in which early-phase clinical trials with MEKi have been successful in the treatment of plexiform neurofibromas (pNF) and low-grade gliomas (LGGs). The phase 2 trial (SPRINT) of selumetinib in pNF resulted in at least 20% reduction in the size of pNF from baseline in 71% of patients and was associated with clinically meaningful improvements. On the basis of this trial, selumetinib (Koselugo) received FDA approval for children 2 years of age and older with inoperable, symptomatic pNF. The phase 2 trial of selumetinib in LGG resulted in 40% partial response and 96% of patients had 2 years of progression-free survival. Summary Given the potential of MEK inhibition as an effective and overall well tolerated medical treatment, the use of targeted agents in the NF1 population is likely to increase considerably. Future work on non-NF1 RASopathies should focus on developing preclinical models and defining endpoints for measurement of efficacy in order to conduct clinical trials.

The skin plays an important role in establishing interpersonal relationships, and thus visible skin disorders, which have a significant impact on physical appearance, influence other people's behaviours and attitudes.To develop and validate a dermatologic-specific questionnaire to evaluate stigmatization in individuals with visible skin conditions.Items were generated by a verbatim report based on qualitative interviews with patients with various dermatologic conditions. Subsequently, a study was implemented for psychometric analysis. A dermatology-specific stigmatization questionnaire (PUSH-D) was refined via item reduction according to inter-question correlations, consensus among experts and exploratory factor analysis. Internal consistency was determined by calculating Cronbach's α. Concurrent validity was determined by calculating the correlation between PUSH-D and the Dermatology Life Quality Index (DLQI) and the Rosenberg Self-Esteem Scale (RSES).From a primary list of 22 items, PUSH-D was reduced to a 17-item questionnaire, covering two pertinent dimensions based on the exploratory factor analysis. Construct validity was demonstrated, and PUSH-D showed good internal consistency (Cronbach's α = 0.9). PUSH-D correlated strongly with the DLQI 0.72 (p 0.001) and moderately with the RSES 0.49 (p 0.001).PUSH-D allows a comprehensive view of the degree of stigmatization in visible skin disorders, as well as the comparability of stigmatization levels across various skin conditions.

The ketogenic diet (KD) is initiated emergently in the intensive care unit (ICU) for patients with super refractory status epilepticus (SRSE) and epileptic encephalopathies (EE). However, few data are available regarding safety, effectiveness, and long-term outcomes.We performed a retrospective cohort study of consecutive patients with KD initiated in the ICU from 2010 to 2018 for SRSE and EE. We characterized time to ketosis, adverse effects, and seizure outcomes. Responders were defined as having ≥50 % reduction in seizure frequency compared to prior to KD initiation.We identified 29 patients. KD was initiated for SRSE in 12 patients, EE in 8 patients, and EE with SRSE in 9 patients. KD was initiated after a median of 9 days. Ketosis was achieved 2 days faster in fasted patients (p0.0001). All patients had at least 1 KD-related adverse effect, most often hypoglycemia, constipation, or acidosis. There was ≥50 % reduction in seizure frequency compared to prior to KD initiation by 1 week in 17/28 patients, seizure-freedom by 2 weeks in 7/28 patients, and weaned off anesthetics in 11/17 patients. All KD-responders at 1 month had continued response at 6 months. Mortality at 1 year was 24 %. There was no difference in KD response or mortality between KD indication groups.Emergent KD initiation in the ICU is feasible, safe, and often effective for SRSE and EE. Expected adverse effects were common but treatable. Morbidity and mortality in this group was high. A ≥ 50 % reduction in seizure is achieved in most responders by 1-2 weeks.

Neurofibromatosis 1 (NF1) is one of the most common autosomal dominant genetic disorders with a birth incidence as high as 1:2000. It is caused by mutations in the NF1 gene on chromosome 17 which encodes neurofibromin, a regulator of neuronal differentiation. While NF1 individuals are predisposed to develop benign and malignant nervous system tumors, various non-tumoral neurological conditions including multiple sclerosis (MS) have also been reported to occur more frequently in NF1. The number of epidemiologic studies on MS in NF1 individuals is very limited. The aim of this study was to determine the estimated population proportion of MS in NF1 patients followed in our Referral Centre for Neurofibromatosis using the Informatics for Integrated Biology and the Bedside (i2b2) platform to extract information from the hospital’s electronic health records. We found a total 1507 patients with confirmed NF1, aged 18 years (y) and above (mean age 39.2y, range 18-88y; 57% women). Five NF1 individuals were found to have MS, yielding an estimated population proportion of 3.3 per 1000 (0.0033, 95% Confidence Interval 0.0014–0.0077). The median age at diagnosis was 45 y (range 28–49 y). Three patients had relapsing-remitting MS and two patients had secondary progressive MS. Patients with NF1 were found to be twice more likely to develop MS than the general population in France (odds ratio 2.2), however this result was not statistically significant (95% Confidence Interval 0.91–5.29). Our results show that patients with NF1 might have a slight increased tendency to develop MS; however, due to the small sample size of our study, the results may not be sufficiently powered to detect this rare association. Large-scale epidemiological studies based on nationwide datasets are needed to confirm our findings. These findings further emphasize the need for a focused follow-up of patients with NF1, as early detection and management of MS can prevent further neurological disability.

Summary Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre‐KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow‐up, side events, and KDT discontinuation. It has been helpful in outlining a state‐of‐the‐art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

BackgroundDietary changes impact human physiology and immune function and have potential as therapeutic strategies.ObjectiveAssess the tolerability of a ketogenic diet (KD) in patients with relapsing multiple sclerosis (MS) and define the impact on laboratory and clinical outcome metrics.MethodsSixty-five subjects with relapsing MS enrolled into a 6-month prospective, intention-to-treat KD intervention. Adherence was monitored with daily urine ketone testing. At baseline, fatigue, depression and quality of life (QoL) scores were obtained in addition to fasting adipokines and MS-related clinical outcome metrics. Baseline metrics were repeated at 3 and/or 6 months on-diet.ResultsEighty-three percent of participants adhered to the KD for the study duration. Subjects exhibited significant reductions in fat mass and showed a nearly 50% decline in self-reported fatigue and depression scores. MS QoL physical health (67±16 vs 79±12, pConclusionKDs are safe and tolerable over a 6-month study period and yield improvements in body composition, fatigue, depression, QoL, neurological disability and adipose-related inflammation in persons living with relapsing MS.Trial registration informationRegistered on ClinicalTrials.gov under registration numberNCT03718247, posted on 24 October 2018. First patient enrolment date: 1 November 2018. Link:https://clinicaltrials.gov/ct2/show/NCT03718247?term=NCT03718247&draw=2&rank=1.

Concomitant disseminated herpes simplex virus (HSV) and varicella zoster virus (VZV) infection is a rare event. We describe a case of disseminated HSV and VZV infection in an 80-year-old patient many years after splenectomy for idiopathic thrombocytopenic purpura (ITP). This is the first case of disseminated HSV-1 and VZV infection with molecular evidence of the simultaneous presence of both viruses in two different body sites (the skin and cerebrospinal fluid). This adds to the three reports of patients developing cutaneous disseminated herpes zoster multiple years after splenectomy for ITP. Keywords: Disseminated herpes simplex virus, Disseminated varicella zoster virus, Idiopathic thrombocytopenic purpura, Splenectomy

Introduction Le psoriasis (PsO), le rhumatisme psoriasique (PsA) et la spondylarthrite ankylosante (AS) sont associes a un surrisque de maladie inflammatoire chronique de l’intestin (MICI). Lors des essais cliniques evaluant l’efficacite des anti-IL17 dans le PsO/PsA/AS, des cas d’aggravation ou des MICI de novo ont ete rapportes. L’objectif de l’etude a ete d’estimer le risque de MICI en vie reelle des patients atteints de PsO/PsA/AS, debutant un traitement anti-IL17 par rapport a : – ceux debutant l’apremilast et ; – ceux debutant l’etanercept. Materiel et methodes L’etude de cohorte exposes/non exposes a ete realisee a partir des donnees de remboursement et d’hospitalisation du Systeme national des donnees de sante (SNDS). Tous les adultes PsO/PsA/AS, nouveaux utilisateurs d’anti-IL17 entre 2016 et 2019 etaient inclus. Les nouveaux utilisateurs d’(i) apremilast et (ii) etanercept etaient les 2 populations « non exposes ». La date de point etait le 30 septembre 2019. Les patients prevalents MICI pendant les 5 ans precedant la date index etaient exclus. Le critere de jugement principal etait la survenue d’une MICI (definie par 2 hospitalisations pour MICI ou 1 ALD) evaluee par un modele Cox pondere par l’inverse du score de propension (IPTW). Resultats (si adapte) Au total 16 793 nouveaux utilisateurs (NU) d’anti-IL17 (âge moyen 48 ± 13 ans ; 46 % d’hommes) ; 20 556 NU d’apremilast (53 ± 15 ans ; 53 %) ; et 10 245 NU d’etanercept (46 ± 15 ans ; 44 %) ont ete inclus. Les caracteristiques des patients sont precisees. Les patients sous anti-IL17 avaient recu plus de biologiques (74 %) vs 5 % pour l’apremilast et 27 % pour l’etanercept. Un total de 132 cas de MICI sont survenus au cours du suivi, respectivement : 72 (0,43 %), 11 (0,05 %) et 49 (0,48 %). La majorite des cas survenaient apres 6 mois d’exposition (82 %, 55 % et 76 % respectivement). Apres ajustement par ponderation, le risque de survenue de MICI etait significativement plus eleve chez les NU d’anti-IL17 en comparaison au NU d’apremilast (hazard ratio pondere 3,8, intervalle de confiance a 95 % 2,1–6,8). Aucune difference n’etait observee entre les NU d’anti-IL17 et les NU d’etanercept (0,8 : IC 0,5–1,2). Discussion Les patients initiant un anti-IL17 presentaient un surrisque de developper une MICI par rapport a ceux sous apremilast. Cependant aucun surrisque n’etait mis en evidence quand ils etaient compares a l’etanercept. La difference entre les 2 comparateurs s’explique probablement par une severite moindre de la maladie inflammatoire des patients sous apremilast par rapport a ceux sous etanercept. Ainsi, en tenant compte de la severite de la maladie, notre etude n’a pas montre de surrisque de MICI chez les patients debutant un anti-IL17. Ces resultats necessitent d’etre confirmes par d’autres etudes a large echelle.

Introduction Le lichen plan cutane (LPC) est une dermatose inflammatoire affichante et prurigineuse alterant la qualite de vie des patients. Regulierement resolutive en 9 a 12 mois, l’efficacite des traitements est incertaine et la prise en charge mal codifiee. Le but de cette etude etait d’evaluer l’interet a court terme de fortes doses de propionate de clobetasol 0,05 %. Materiel et methodes Cohorte historique monocentrique, (accord IRB) de 2017 a 2021 ayant inclus tous les patients de plus de 18 ans suivis dans le service de dermatologie d’un hopital universitaire pour un LPC traite par propionate de clobetasol 0,05 % a des doses > 5 g/jour. Les patients presentant une surface corporelle atteinte (SCA) initiale inferieure a 5 % ou recevant un traitement systemique concomitant etaient exclus. Le critere de jugement principal etait le taux de remission complete avant 16 semaines de traitement, defini par une SCA Resultats Cinquante-deux patients, 62 % de femmes, d’un âge median de 49 ans [18–83], ont ete inclus. La poussee de LPC, confirmee par l’examen histologique chez 47/52, evoluait depuis une duree mediane de 3 mois (EI 1,1–4,8) et concernait une SCA mediane de 26,5 % (EI 15–40). Tous les patients sauf un rapportaient un prurit. La quantite mediane de propionate de clobetasol 0,05 % journaliere etait de 20 g [5–30], pour une duree mediane de 3 semaines (EI 2–4). A 16 semaines : 37/52 patients, soit 71,2 % (IC 95 % = [56,9 %–82,9 %]), etaient en reponse complete sans modification ou ajout de traitement, dont 50 % dans les 6 premieres semaines. Le prurit avait disparu chez 32 patients, soit 61,5 % (IC 95 % = [47,0 %–74,7 %]), et aucun evenement indesirable n’a ete signale. Enfin, aucune association statistique n’a ete demontree entre la duree de la poussee avant la mise sous traitement et la reponse clinique. Discussion Cette etude met en evidence une reponse complete a 16 semaines chez 71 % des patients ayant un LPC. La principale limite de cette etude est sa nature retrospective pour une maladie dont la resolution spontanee est la regle. Neanmoins, la reponse obtenue des 1 mois et demi pour la moitie des patients et la courte duree d’evolution du LPC a l’inclusion sont en faveur d’un role du traitement plutot que de l’evolution naturelle de la maladie. La balance benefice/risque de ce schema therapeutique semble interessant comparativement aux autres traitements disponibles (corticosteroides, methotrexate, acitretine, phototherapie) dont le niveau de preuve d’efficacite est egalement faible. Ces resultats plaident pour la realisation d’une etude prospective multicentrique.

Disorders of carbohydrate metabolism resulting in accumulation of polyols in body fluids were first described in the early 1990s by van der Knapp et al, but this diagnosis remains rare with very few patients reported with primary neurological phenotypes. We present a child with a presumed polyol disorder whose clinical course was similar to two of the original five patients and who had similar findings in quantification of urinary polyols. In addition, we document details of central nervous system pathology in this rare metabolic disorder. The basic pathology is that of a neurodegenerative disorder with hypomyelination leukodystrophy consequent to a defect of oligodendroglia and resultant axonal and neuronal loss.

Neurofibromatosis 1 (NF1) is one of the most common inherited disorders and affects one in 3000 people worldwide. It is a multisystem genetic disorder that is primarily associated with cutaneous, neurologic, and orthopedic manifestations. People with NF1 may also develop cardiac disease, however their prevalence, natural history, and pathogenesis have only recently received medical and scientific attention. Solid data demonstrate a higher than expected frequency of congenital heart defects among patients with NF1, warranting early diagnosis in NF1 children to prevent potential long-term hemodynamic consequences. Although no straightforward genotype–phenotype correlations have been clearly described in NF1, a few exceptions have been identified, all of which involve cardiac malformations. NF1 patients also display abnormal cardiac functions, some of which are intrinsic to the disease, and others secondary to an associated hypertension. On the molecularlevel, the role of haploinsufficiency for neurofibromin in heart development and function has been the subject of many studies. All of these studies have shown that complex developmental mechanisms are involved in cardiac development.

Vitiligo is the most common depigmenting disorder affecting 0.1%-2% of the population worldwide. The characteristic white patches result from the selective loss of melanocytes. Sustained recent efforts have resulted in a detailed understanding of the genetic architecture of vitiligo. About 80% of vitiligo risk is attributable to genetic factors; and the rest (20%) is attributable to the environment. Over the past decade, substantial progress has been made in our understanding of the pathogenesis of vitiligo which is now clearly classified as an autoimmune disease. Melanocytes from patients with vitiligo are more susceptible to oxidative stress which begets the release of exosomes and inflammatory cytokines that will lead to activation of the innate immune response and subsequently to adaptive immune response through activation of autoreactive cytotoxic CD8+ T cells. These produce interferon-γ (IFN-γ) which promotes disease progression through IFN-γ-induced chemokine secretion from surrounding keratinocytes to further recruit T cells to the skin through a positive feedback loop. CD8 tissue-resident memory T cells are in turn responsible for long-term maintenance and potential relapse of vitiligo in human patients through cytokine-mediated recruitment of T cells from the circulation. This review summarizes the current knowledge on vitiligo and attempt to give an overview of the future in vitiligo treatment.

Neurofibromatosis type 1 (NF1) is a relatively common inherited disorder which affects one in 3000 people worldwide. It is a multisystem genetic disorder that is primarily associated with cutaneous, neurologic, and orthopedic manifestations; some of which are progressive and result in substantial morbidity or mortality. The mainstay of management of patients with NF1 is a longitudinal care with age specific monitoring of disease manifestations, aiming at the early detection and symptomatic treatment of complications as they arise. Given the complexity of this disorder, the management of children and adults with NF1 requires access to the full complement health care providers and coordination among the multiple specialties is crucial. This chapter focuses on the major clinical manifestations and complications that appear throughout the lifetime of individuals with NF1 and provides recommendations for disease surveillance and intervention to optimize the management of individuals with NF1.

Vitiligo, a common depigmenting skin disorder, has an estimated prevalence of 0.5–2% of the population worldwide. The disease is characterized by the selective loss of melanocytes which results in typical nonscaly, chalky-white macules. In recent years, considerable progress has been made in our understanding of the pathogenesis of vitiligo which is now clearly classified as an autoimmune disease. Vitiligo is often dismissed as a cosmetic problem, although its effects can be psychologically devastating, often with a considerable burden on daily life. In 2011, an international consensus classified segmental vitiligo separately from all other forms of vitiligo, and the term vitiligo was defined to designate all forms of nonsegmental vitiligo. This review summarizes the current knowledge on vitiligo and attempts to give an overview of the future in vitiligo treatment.

Although first discovered in 1931, vitamin D has seen an increased interest in the scientific community over the past decades, including the dermatology field. Vitamin D promotes calcium and phosphorus absorption; however, the actions of vitamin D are not confined to bone. Indeed, there is now overwhelming and compelling scientific data that vitamin D plays a crucial role in a plethora of cellular function and in extra-skeletal health. Except for fatty fish livers, very few foods naturally contain vitamin D; and the major source of vitamin D comes from skin exposure to sunlight via ultraviolet B. Keratinocytes are unique in the body as not only do they provide the primary source of vitamin D for the body, but they also possess both the enzymatic machinery to metabolize the vitamin D produced to active metabolites. This has been referred to as the photoendocrine vitamin D system. Vitamin D regulates keratinocytes proliferation and differentiation; and plays a role in the defense against opportunistic infections. Multiple factors are linked to vitamin D status; and a growing number of dermatologic diseases has been linked to vitamin D status such as atopic dermatitis, psoriasis, vitiligo, and cutaneous cancers. In this article, we reviewed the potential determinants of vitamin D status, as its implications in dermatologic diseases.

Objective Voltage-gated sodium (Na+) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β1, are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of four patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in two cases, p.Pro1333Leu, and p.Val1769Ala).

Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD syndrome) is a rare X-linked dominant genodermatosis caused by mutations in the NAD(P) dependent steroid dehydrogenase-like protein gene. Its defect leads to accumulation of toxic metabolic intermediates upstream from the pathway block and to the deficiency of bulk cholesterol, probably leading to altered keratinocyte membrane function, resulting in the phenotype seen in CHILD syndrome. Symptomatic treatment using emollients and retinoids to reduce scaling has long been used until recently, whereby new therapeutic means based on the pathogenesis-targeted therapy have been developed. We subsequently chose to use the same pathogenesis-based therapy using a 2% cholesterol and 2% lovastatin cream with or without glycolic acid in two of our patients. Improvement in CHILD skin lesions was seen as early as 4 weeks after initiation. The addition of glycolic acid helped improve the penetrance of the cholesterol and lovastatin cream into the thick waxy scales. Our study confirms the efficacy of the pathogenesis-targeted therapy and introduces the possibility of modifying its formula by adding glycolic acid in order to improve the treatment.

Ichthyosis Follicularis, Atrichia, and Photophobia (IFAP) is a severe rare genetic disorder caused by mutations in the gene encoding the Membrane-Bound Transcription Factor Peptidase, Site 2 (MBTPS2). Olmsted syndrome is another rare genetic disease with overlapping clinical features caused by mutations in the gene encoding the Transient Receptor Potential Cation Channel, subfamily V (TRPV3). Mutations in MBTPS2 have been recently reported in Olmsted syndrome, underscoring the overlap and the confusion in separating Olmsted from IFAP syndrome. We studied a Lebanese family with IFAP syndrome both, clinically and molecularly, and investigated whether there is a cross relation between TRPV3 and MBTPS2. We identified a recurrent mutation designated p.F475S in MBTPS2 in the affected individuals. This mutation was not found in 100 control individuals from the same population. We determined that TRPV3 regulatory region is a target for MBTPS2. In addition, there was an increased cell death in the cells transfected with the mutant versus the wild-type MBTPS2. In conclusion, we identified a direct regulatory effect of MBTPS2 on TRPV3 which can partially contribute to the overlapping clinical features of IFAP and Olmsted syndromes under a common signaling pathway.

This article addresses the question of why male politicians continue to be relatively unlikely to act in favor of gender-equality policy change, despite the advances in gender equality in recent decades. Drawing together literature on men and masculinities, feminist institutionalism and women’s substantive representation, we present a theoretical argument in which we distinguish between an internal and an external mandate to push for genderequality policy change. We argue that both these mandates apply to female politicians but not to their male colleagues. As a consequence, a gendered leeway exists: men have more leeway than women in political maneuvering. We illustrate this argument by analyzing high-ranked party representatives within the selflabelled feminist Swedish Social Democratic Party. This article contributes theoretically to the launching of a research agenda on the role of men in processes of gender-equality policy adoption. “So far, no further? Gender equality initiatives on the Swedish labor market”

Treatment-resistant epilepsy affects 30% of children with epilepsy and results in significantly reduced quality of life. The ketogenic diets offer a chance for significant seizure reduction and seizure freedom. Compliance is strongly linked to the effectiveness of these treatments. The high-fat and low-carbohydrate content of the ketogenic diets makes creating and cooking palatable meals challenging. Keto centers typically support caretakers with recipes, but do not have a kitchen to provide hands-on education. Hence, our program built a ketogenic kitchen in 2013. The purpose of this study was to assess the effects of the kitchen on the quality of our education and confidence of caretakers during both initiation and ongoing outpatient support of the ketogenic diets. An anonymous survey of 37 questions was created using Survey Monkey, with a 5-point scale or yes-no responses. Families whose children have been a part of our dietary treatment program from 2014 to 2016, reachable by e-mail, were asked to take the survey. The data were analyzed using descriptive statistics. Seventy-seven families completed our survey. The overall quality of the classes taught by the dietitians improved with the use of the Ketogenic Teaching Kitchen. Hands-on cooking classes enhanced the learning experience, making our new ketogenic diet families noticeably more confident preparing meals at the time of discharge. The Keto Teaching Kitchen has greatly enhanced our dietary treatment program. We believe that all keto centers would benefit from access to a teaching kitchen.

Formation of neutrophil extracellular traps has been implicated in autoimmunity. However, the presence and clinical relevance of neutrophil extracellular traps in immune-complex-mediated cutaneous small and medium vessel vasculitides has not been investigated. This study retrospectively analysed 72 patients with histology-proven hypersensitivity vasculitis (n = 21), IgA vasculitis (n = 22), urticarial vasculitis (n = 22), erythema elevatum diutinum (n = 3) and polyarteritis nodosa (n = 4). Neutrophil extracellular traps were detected in hypersensitivity vasculitis, IgA vasculitis, urticarial vasculitis and erythema elevatum diutinum, but not in polyarteritis nodosa lesions. Neutrophil extracellular traps were found around inflamed vessels, and their formation was highest early after the onset of vasculitis and decreased progressively thereafter. Neutrophil extracellular traps were strongly correlated with the histological severity of vasculitis and the production of reactive oxygen species. Both hypersensitivity vasculitis and IgA vasculitis showed significantly more neutrophil extracellular traps than did urticarial vasculitis, independent of the histological severity and duration of vasculitis. These results provide evidence on the implication of neutrophil extracellular traps in the early phases of immune-complex-mediated small vessel vasculitis.

ObjectiveTo assess the safety and tolerability of a modified Atkins diet (KDMAD), a type of ketogenic diet (KD), in subjects with relapsing MS while exploring potential benefits of KDs in MS.MethodsTwenty subjects with relapsing MS enrolled into a 6-month, single-arm, open-label study of the KDMAD. Adherence to KDMAD was objectively monitored by daily urine ketone testing. Fatigue and depression scores and fasting adipokines were obtained at baseline and on diet. Brain MRI was obtained at baseline and 6 months. Intention to treat was used for primary data analysis, and a per-protocol approach was used for secondary analysis.ResultsNo subject experienced worsening disease on diet. Nineteen subjects (95%) adhered to KDMAD for 3 months and 15 (75%) adhered for 6 months. Anthropometric improvements were noted on KDMAD, with reductions in body mass index and total fat mass (p < 0.0001). Fatigue (p = 0.002) and depression scores (p = 0.003) were improved. Serologic leptin was significantly lower at 3 months (p < 0.0001) on diet.ConclusionsKDMAD is safe, feasible to study, and well tolerated in subjects with relapsing MS. KDMAD improves fatigue and depression while also promoting weight loss and reducing serologic proinflammatory adipokines.Classification of evidenceThe study is rated Class IV because of the absence of a non-KD control group.

The nail is a unique epithelial skin appendage made up of a fully keratinized nail plate. The nail can be affected in several systemic illnesses, dermatological diseases, and inherited nail disorders. Nail dystrophies can present as isolated disorders or as a part of syndromes. Substantial progress has been achieved in the management and diagnosis of nail diseases; however, not much is known about the underlying molecular controls of nail growth. The homeostasis and development of the nail appendage depend on the intricate interactions between the epidermis and underlying mesenchyme, and comprise different signaling pathways such as the WNT signaling pathway. Digit-tip regeneration in mice and humans has been a known fact for the past six decades; however, only recently the underlying biological mechanisms by which the nail organ achieves digit regeneration have been elucidated. Moreover, significant progress has been made in identifying nail stem cells and localizing stem cell niches in the nail unit. More fascinating, however, is the role they play in orchestrating the processes that lead to the regeneration of the digit. Further elucidating the role of nail stem cells and the signaling pathways driving epithelial-mesenchymal interactions in the nail unit might contribute to the development of novel therapeutic tools for amputees.

The rise of the adult worker family norm across countries of the Organisation for Economic Co-operation and Development has created challenges for reconciling work and family life as the unpaid work of the female caregiver can no longer be assumed. The article compares childcare arrangements and maternity/parental leave programmes in Sweden, Australia and Canada that attempt to address these challenges. Sweden was an early innovator, establishing the ‘gold standard’ for such arrangements in the form of publicly funded, universally accessible, centre-based childcare and generously paid parental leave, including a ‘daddy quota’. Yet policy development remains open to contestation and change even here. Australia and Canada have shown a preference for market-based solutions although each has taken steps towards Swedish style solutions. In particular, Canadian federalism has left space for such experiments at the provincial scale. The broader institutional arrangements embedded in each country have helped to shape the responses. Yet political contestation, enlivened by the transnational flow of ideas (and ideals), has played an important role in shaping the direction and velocity of change. In the first section we develop this argument, beginning with reflections on how to identify the significance of changes, then moving on to explore the role of institutions, actors and ideas in accounting for these developments. Subsequent sections examine developments first in Sweden then Australia and Canada.

A Feminist Opposition to Gender Equality? : Making Sense of the Social Democratic Party's Internal Struggle over Extending Parental-Leave Quotas in Sweden

Breastfeeding continues to be the recommended mode of infant feeding with numerous nutritive and nonnutritive benefits to both mothers and babies. The ketogenic diet (KD) is a high-fat, adequate protein, and very low carbohydrate diet prescribed for infants and children with treatment-resistant epilepsy. Due to the high carbohydrate content of breast milk (BM) and the extremely low carbohydrate allowance of the KD, these 2 modes of feeding are typically not used together. We report our experience to demonstrate that BM can be part of a successful KD treatment. A retrospective chart review was performed and 4 patients met criteria. They were younger than 2 years and were fed BM before KD initiation. All achieved ketosis at low (2-3:1) ratios and remained ketotic while using BM. The average amount of BM consumed was 139 ± 50 mL/day, equivalent to 11 ± 4.5 grams of carbohydrates per day. Three patients achieved >50% reduction in seizure frequency within 2 months of treatment. Patients continued using BM for an average of 105 ± 50 days. For all cases, BM was discontinued due to maternal preference. BM is a viable, preferred, carbohydrate source for infants prescribed the KD.

Objective. The ketogenic diet (KD) can result in hyperlipidemias. We report improvements in the lipid profiles of 3 children who were switched from KetoCal 4:1 powder (formulation prior to fall 2013) to KetoCal 4:1 Liquid formula. Compared with the KetoCal 4:1 powder formulation prior to fall 2013, KetoCal 4:1 Liquid has no trans-fatty acids, reduced saturated fatty acids, added omega-3 fatty acids, and added fiber. Methods. A retrospective chart review revealed 3 patients in our KD program with elevated lipid profiles while receiving 100% of their nutritional needs from KetoCal 4:1 powder. The patients were switched to KetoCal 4:1 Liquid and treated for >3 months. Fasting lipid profiles were obtained before and 2 to 3 months after the formula switch. All patients were on ≥4:1 ratio KD formula. Results. After changing formulas, the lipid profiles of all 3 patients improved. Mean total cholesterol, triglycerides, and low-density lipoprotein were reduced by 29%, 33%, and 58%, respectively. High-density lipoprotein increased by 10% on average. Conclusion. A decrease in lipid levels was observed with the transition to KetoCal 4:1 Liquid after an average of 2.1 months. Changes in dietary fat profile (including addition of omega-3 fatty acids) and the addition of fiber in enteral formulas can positively affect lipid profiles of tube-fed KD patients.

International audience; A peptide ending with RFamide (Arg-Phe-amide) was discovered independently by three different laboratories in 2003 and named 26RFa or QRFP. In mammals, a longer version of the peptide, 43 amino acids, was identified and found to bind to the orphan G protein-coupled receptor GPR103. We searched the genome database of Branchiostoma floridae (Bfl) for receptor sequences related to those that bind peptides ending with RFa or RYa (including receptors for NPFF, PRLH, GnIH, and NPY). One receptor clustered in phylogenetic analyses with mammalian QRFP receptors. The gene has 3 introns in Bfl and 5 in human, but all intron positions differ, implying that the introns were inserted independently. A QRFP-like peptide consisting of 25 amino acids and ending with RFa was identified in the amphioxus genome. Eight of the ten last amino acids are identical between Bfl and human. The prepro-QRFP gene in Bfl has one intron in the propeptide whereas the human gene lacks introns. The Bfl QRFP peptide was synthesized and the receptor was functionally expressed in human cells. The response was measured as inositol phosphate (IP) turnover. The Bfl QRFP peptide was found to potently stimulate the receptor's ability to induce IP turnover with an EC50 of 0.28nM. Also the human QRFP peptides with 26 and 43 amino acids were found to stimulate the receptor (1.9 and 5.1nM, respectively). Human QRFP with 26 amino acids without the carboxyterminal amide had dramatically lower potency at 1.3μM. Thus, we have identified an amphioxus QRFP-related peptide and a corresponding receptor and shown that they interact to give a functional response.