Dermatological manifestations in Costello syndrome: A prospective multicentric study of 31 HRAS-positive variant patients.

BACKGROUND: Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description. OBJECTIVES: To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype-genotype correlations. METHODS: We performed a 10-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Thirty-one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and 'cobblestone' papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype-genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S). CONCLUSIONS AND RELEVANCE: This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.

cLFM-Qol: A specific quality of life measurement tool for children from 11 to 15 years with low-flow malformations.

BACKGROUND: Low-flow malformations (LFMs) are rare diseases with a significant impact on health-related quality of life (HRQoL), especially in children. No disease-specific questionnaire is available for children with LFMs. OBJECTIVE: To develop and validate a specific HRQoL questionnaire for children from 11 to 15 years old suffering from LFMs. METHODS: A preliminary questionnaire based on a verbatim from focus groups was created and sent to children from 11 to 15 years old suffering from LFMs, together with a dermatology-specific and a generic HRQoL questionnaire (cDLQI and EQ-5D-Y). RESULTS: A total of 75 from 201 included children responded to the questionnaires. The final version of the questionnaire (cLFM-QoL) included 15 questions and was not divisible into subscales. It demonstrated excellent internal consistency (cronbach 0.89), convergent validity and readability (SMOG 6.04). cLFM-QoL mean score (± SD) was 12.9/45 (8.03) for all grades of severity, for mild 8.22/45 (7.5), moderate 14.03/45 (8.35), severe 12.35/45 (6.59) or very severe patients 20.7/45 (3.39) (p 0.006). CONCLUSION: cLFM-QoL is a validated short and easy to use specific questionnaire with excellent psychometric capacities. It will be suitable for any children aged 11-15 with LFMs, in daily practice or clinical trials.

IL-4/IL-13 Inhibitors for Atopic Dermatitis Induce Psoriatic Rash Transcriptionally Close to Pustular Psoriasis.

Dupilumab is a therapeutic antibody targeting IL-4 and IL-13 receptor subunit alpha used for the treatment of patients with atopic dermatitis (AD). Cases of psoriasis-like reactions induced under dupilumab treatment (dupilumab-induced psoriatic eruption [DI-Pso]) for AD were recently reported. To understand the pathogenesis of DI-Pso, we performed gene expression profiling studies on skin biopsies of DI-Pso (n = 7) compared with those of plaque psoriasis, AD, and healthy controls (n = 4 each). Differential gene expression was performed using enrichment and Gene Ontology analysis. Gene expression was validated by qPCR, and protein levels were assessed by immunohistochemistry. Transcriptomic and protein analysis of DI-Pso compared with that of healthy controls, plaque psoriasis, and AD skins revealed activation of T helper 17/IL-23 pathways associated with a significant expression of IL-36, surrogate marker of pustular psoriasis. By contrast, T helper 2 representative genes' expression was strongly decreased in DI-Pso across comparison. Matching analysis with public data of pustular psoriasis skin corroborated that DI-Pso and pustular psoriasis upstream regulators overlap, greater than the overlap with plaque psoriasis. Furthermore, DI-Pso showed strongly decreased expression of many barrier skin genes compared with healthy controls, plaque psoriasis, and AD. Our data indicate that the pathogenesis of DI-Pso relied on a shift of skin immune responses from a T helper 2 to an IL-36 and T helper 17 polarization and on intensified skin barrier alterations.

Risk of melanoma in congenital melanocytic nevi of all sizes: A systematic review.

Congenital melanocytic nevi (CMN) are commonly encountered benign skin lesions in newborns. Larger CMN is associated with a higher lifetime risk of developing melanoma. However, the level of risk is unclear when CMN are small or medium-sized. Our objective was to assess melanoma risk in patients with CMN of all size categories. A literature review with meta-analysis was performed. Prevalence and incidence densities of melanoma at onset were calculated in the entire study population and according to CMN size, type of treatment and location of the CMN. A total of 91 melanomas were reported in 7915 patients (1.15%, 95% CI, 0.93-1.41). The overall incidence density was 0.057% person-years (95% CI, 0.044-0.071). The risk ratio of melanoma incidence densities was 21.9 (95% CI, 8.55-56.3) in large to giant CMN compared with small to medium CMN at 15 years of age. The incidence density was higher in CMN located on the trunk and as well as in those which were untreated or partially treated versus complete excision. Our review suggests patients with CMN of medium, large and giant size are at risk of melanoma, whereas the risk remains unknown for small CMN.

Biologics combined with conventional systemic agents for the treatment of children with severe psoriasis. Real-life data from the BiPe cohorts and a practice survey among French and Italian pediatric dermatologists.

Combined therapies involve the use of multiple drugs to increase efficacy and reduce the toxicity of individual treatments. We evaluated the use of combinations of conventional systemic therapies and biologics in children with psoriasis in daily practice. This two-part study used data from the 170 children in the Franco-Italian BiPe cohorts to evaluate the use, efficacy, and safety of combined conventional systemic-biologic therapies, and from a survey carried out among French and Italian dermatologists to better understand the reasons for using or avoiding these combinations. In total, 33 children (19.4%) from 13 dermatology centers received 48 combined conventional systemic-biologic therapies (cumulative duration: 43.6 years), including three triple combination therapies (acitretin-methotrexate, with a TNF-alpha inhibitor). A total of 14 different combinations were used, most frequently etanercept-acitretin (n = 10), adalimumab-acitretin (n = 7), adalimumab-methotrexate (n = 5), and ustekinumab-methotrexate (n = 5). The combined therapies were started at biologic initiation in 41 cases (85.4%), and after a period of biologic monotherapy in the remaining 7 cases. Mean PGA and PASI scores decreased between baseline and M3 with all the combinations used. Four serious adverse events were reported, all with favorable outcomes. The survey was completed by 61 dermatologists: 39 (63.9%) had previously used or planned to use the combined therapies, most commonly TNF-alpha inhibitors with acitretin or methotrexate. The main reason for using these treatments was to improve the outcome of biologic therapies in cases of partial efficacy or loss of efficacy. Combined therapies have been used frequently in the treatment of childhood psoriasis, in a range of clinical situations and in variable drug combinations, without significant toxicity. Although the use of these combined therapies needs to be clarified in future management guidelines, these combined therapies should be considered for the treatment of children with severe psoriasis, psoriatic arthritis, and recalcitrant disease.

Effectiveness and Safety of Adalimumab, Etanercept and Ustekinumab for Severe Psoriasis in Children Under 12 Years of Age: A French-Italian Daily Practice Cohort (BiPe Jr).

INTRODUCTION: Biological therapies are valuable treatments for severe psoriasis. Children aged under 12 years are underrepresented in therapeutic trials for these drugs. The objective of the 'BiPe Jr' cohort study was to evaluate the drug survival, effectiveness, tolerance and switching patterns of biological therapies in children under 12 years of age with psoriasis. METHODS: We conducted a multicentre retrospective study of children with psoriasis who received at least one injection of a biological agent, even off-licence, before the age of 12 years in France and Italy, collecting the data between April and August 2021. The data collected were from March 2012 up to August 2021. RESULTS: In total, 82 children (mean age: 9.1 years; females: 61.0%) received 106 treatments. The drugs administered were adalimumab (n = 49), etanercept (n = 37), ustekinumab (n = 15), anakinra (n = 2), infliximab (n = 2) and secukinumab (n = 1). The most common form of psoriasis was plaque psoriasis (62.9%). The Physician Global Assessment and the Psoriasis Area Severity Index (PASI) scores decreased significantly from baseline to 3 months after treatment initiation for the three main biological drugs; PASI went from 14.1 ± 9.4 to 4.1 ± 11.3 for adalimumab (p = 0.001), 14.9 ± 9.3 to 5.1 ± 4.0 for etanercept (p = 0.002) and 11.6 ± 8.3 to 2.6 ± 2.2 for ustekinumab (p = 0.007). A trend towards higher 2-year maintenance rates was observed for ustekinumab and adalimumab, compared with etanercept (p = 0.06). 52 children discontinued their biological therapy, most frequently due to inefficacy (n = 28) and remission (n = 14). Seven serious adverse events (SAEs) were reported, including four severe infections. DISCUSSION: Our analyses of drug survival and treatment patterns, combined with those of previous studies conducted in older children, indicate that there is a trend towards higher 2-year survival rates of ustekinumab and adalimumab. The SAEs identified were rare, but highlight the need for increased vigilance concerning infections. Overall, the biological therapies showed good effectiveness and safety profiles when used in daily practice for the treatment of young children with psoriasis.

Treatment of two infants with PIK3CA-related overgrowth spectrum by alpelisib.

PIK3CA-related overgrowth spectrum (PROS) includes rare genetic conditions due to gain-of-function mutations in the PIK3CA gene. There is no approved medical therapy for patients with PROS, and alpelisib, an approved PIK3CA inhibitor in oncology, showed promising results in preclinical models and in patients. Here, we report for the first time the outcome of two infants with PROS having life-threatening conditions treated with alpelisib (25 mg) and monitored with pharmacokinetics. Patient 1 was an 8-mo-old girl with voluminous vascular malformation. Patient 2 was a 9-mo-old boy presenting with asymmetrical body overgrowth and right hemimegalencephaly with West syndrome. After 12 mo of follow-up, alpelisib treatment was associated with improvement in signs and symptoms, morphological lesions and vascular anomalies in the two patients. No adverse events were reported during the study. In this case series, pharmacological inhibition of PIK3CA with low-dose alpelisib was feasible and associated with clinical improvements, including a smaller size of associated complex tissue malformations and good tolerability.

Chilblains during lockdown are associated with household exposure to SARS-CoV-2: a multicentre case-control study.

OBJECTIVES: During the COVID-19 pandemic, numerous cases of chilblains have been reported. However, in most cases, RT-PCR or serology did not confirm SARS-CoV-2 infection. Hypotheses have been raised about an interferon-mediated immunological response to SARS-CoV-2, leading to effective clearance of the SARS-CoV-2 without the involvement of humoral immunity. Our objective was to explore the association between chilblains and exposure to SARS-CoV-2. METHODS: In this multicentre case-control study, cases were the 102 individuals referred to five referral hospitals for chilblains occurring during the first lockdown (March to May 2020). Controls were recruited from healthy volunteers' files held by the same hospitals. All members of their households were included, resulting in 77 case households (262 individuals) and 74 control households (230 individuals). Household exposure to SARS-CoV-2 during the first lockdown was categorized as high, intermediate or low, using a pre-established algorithm based on individual data on symptoms, high-risk contacts, activities outside the home and RT-PCR testing. Participants were offered a SARS-CoV-2 serological test. RESULTS: After adjustment for age, the association between chilblains and viral exposure was estimated at OR 3.3, 95% CI (1.4-7.3) for an intermediate household exposure, and 6.9 (2.5-19.5) for a high household exposure to SARS-CoV-2. Out of 57 case households tested, six (11%) had positive serology for SARS-CoV-2, whereas all control households tested (n = 50) were seronegative (p = 0.03). The effect of potential misclassification on exposure has been assessed in a bias analysis. DISCUSSION: This case-control study demonstrates the association between chilblains occurring during the lockdown and household exposure to SARS-CoV-2.

Long-term Outcome of Chilblains Associated with SARS-CoV-2.

Numerous cases of chilblains have been observed in the course if the COVID-19 pandemic. The aims of this study were to provide comprehensive follow-up data for patients reporting chilblains, and to determine the risk factors for incomplete recovery. Patients referred to 5 hospitals in France between March and May 2020 for chilblains were surveyed on December 2020. A teleconsultation was offered. Among 82 patients reporting chilblains, 27 (33%) reported complete recovery, 33 (40%) had recurrences of chilblains after their hands and feet had returned to normal, and 22 (27%) developed persistent acral manifestations, mostly acrocyanosis, with or without further recurrences of chilblains. Most recurrences of chilblains occurred during the following autumn and winter. A past history of chilblains was not associated with recurrences or persistent acral manifestations. Women had a significantly higher risk of developing recurrences or persistent acral manifestations (odds ratio 1.30; 95% confidence interval 1.06-1.59). In conclusion, two-thirds of patients reporting chilblains at the start of the COVID-19 pandemic experienced persistent or recurrent acral manifestations after a 10-month follow-up.

Transient abdominal telangiectasia of the newborn.

We report 20 newborns who developed, at a median age of 7 days, large abdominal patches of radially arranged purplish telangiectasia in a bilateral and symmetrical pattern in relation to the midline, creating a "butterfly wing" pattern. Clinical examination was normal in 13 newborns, six newborns had abdominal distention, and one newborn had poor weight gain due to inadequate breastfeeding. Most lesions spontaneously resolved within 3 months and did not reoccur for 19 newborns. Transient abdominal telangiectasia of the newborn (TATN) appears to be a distinctive entity that has not been previously described.

Rheumatic involvement and bone scan features in Schnitzler syndrome: initial and follow-up data from a single-center cohort of 25 patients.

OBJECTIVE: To report on the characteristics and long-term course of rheumatic manifestations in Schnitzler syndrome (SchS). METHODS: A retrospective cohort study of patients with SchS followed between 2000 and 2020. Inclusion criteria included a diagnosis of SchS (Strasbourg criteria). All available bone scans were reviewed and scored according to the intensity and number of pathological sites. The scintigraphic score was compared with the clinical activity score, CRP level, and treatments. RESULTS: Twenty-five patients were included. Median age at diagnosis was 68 years. Eighty patients (72%) had SchS-related rheumatic pain. Most patients had a long-standing isolated rash before constitutional and/or rheumatic symptoms appeared. The monoclonal component level was usually very low (IgMκ in 22/25). Rheumatic pain predominated around the knees. Bone scans revealed abnormal tracer uptake in 15/18 (85%). The scintigraphic score correlated with clinical activity (r = 0.4, p < 0.02) and CRP level (r = 0.47, p < 0.01). The scintigraphic score was lower in patients receiving corticosteroids or IL1Ra (interleukin 1 receptor antagonist) than in untreated patients (median scores:2, 0, and 13, respectively; p < 0.05). Two patients developed Waldenström macroglobulinemia. Of the 22 surviving patients, median age at follow-up was 76 years. IL1Ra was used in 13 patients, with dramatic efficacy on both symptoms and bone scan features. CONCLUSIONS: Rheumatic manifestations are very prevalent in SchS. However, bone pain can be misleading and contribute to misdiagnosis. Bone scan abnormalities are very prevalent and correlate with disease activity and treatments. IL1-Ra has a dramatic and durable efficacy but may not be required in every patient early on.

Management of Congenital Melanocytic Naevi in Children: A French National Survey Using Clinical Vignettes.

Management of congenital melanocytic naevi in childhood may vary depending on the habits and experience of the treating clinician. The aim of this study was to assess current practice and determinants of surgical excision decision-making among French physicians. A national survey was conducted among dermatologists, paediatricians and surgeons, using clinical vignettes illustrating 29 scenarios. The primary outcome was the decision to perform surgical excision in each vignette. Of the 11,310 decisions made by the 390 participants (257 dermatologists, 35 surgeons, and 98 paediatricians) surgical excision was chosen in 33% of cases. The stated motivations for performing surgical excision were: melanoma risk, aesthetic/psychosocial risk, or both, in 39%, 34% and 27% of cases, respectively. Physicians with a higher level of experience in oncodermatology were more likely to opt for surgical excision. The age of the child, the size of the congenital melanocytic naevi, and the visibility of the lesion had no influence on the decision to perform surgical excision.

Effectiveness of an antenatal maternal supplementation with prebiotics for preventing atopic dermatitis in high-risk children (the PREGRALL study): protocol for a randomised controlled trial.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory disease affecting 10%-15% of children in Europe. There is a need for new primary preventive therapeutic strategies in at-risk populations. Recent research has indicated that atopic diseases are associated with a disrupted gut microbial 'balance' in early life raising the possibility that interventions which yield optimal patterns of microflora could improve host's health. Prebiotics, sugars with immunomodulatory properties that stimulate the diversity of the digestive microbiota, are ideal candidates for such research. So far, most clinical trials have focused on improving infant gut colonisation postnatally. However, prenatal life is a crucial period during which different tolerance mechanisms are put in place. We aim to determine whether antenatal prebiotics supplementation prevents AD in high-risk children. METHODS AND ANALYSIS: This is a randomised, multicentre, double-blind, trial to evaluate the effectiveness of antenatal prebiotic maternal supplementation (galacto-oligosaccharide/inulin) in pregnant women versus placebo on the occurrence of AD at 1 year of age in at-risk children (defined as having a maternal history of atopic disease). Participating women will be randomised to daily ingestion of a prebiotics or placebo (maltodextrin) from 20 weeks' gestation until delivery. The primary outcome is the prevalence of AD at 1 year of age, using the version of the UK Working Party Diagnostic Criteria optimised for preventive studies. Key secondary endpoints are AD severity, quality of life and prebiotics tolerance. The target sample size is 376 women (188 patients per group) which will provide 80% power to detect a 33% reduction of the risk of AD in the verum group (α=0.05). The primary analysis will be based on the intention-to-treat principle. ETHICS AND DISSEMINATION: Results will be presented in peer-reviewed journals and at international conferences. Ethics approval for the study was obtained from the institutional ethical review board of 'Comité de Protection des Personnes Sud Ouest-Outre-Mer III' of the University Hospital Centre of Bordeaux (2017/13). TRIAL REGISTRATION NUMBER: NCT03183440; Pre-results.

Clinical Profile of Methotrexate-resistant Juvenile Localised Scleroderma.

Methotrexate has demonstrated its efficiency for the treatment of juvenile localized scleroderma but some patients may be resistant. The aim of our study was to define the profile of such patients. We performed an observational retrospective multicenter study between 2007 and 2016 and included all children seen in the French Paediatric Dermatology and Rheumatology departments with active localized scleroderma treated by methotrexate for a minimum of 4 months. Metho-trexate efficacy was assessed clinically and/or by imaging between the fourth to twelfth months of treatment. A total of 57 patients were included. Metho-trexate dosage ranged from 7 to 15 mg/m2/week. Only 4 patients were resistant. No common features could be identified between these 4 patients. Children with localized scleroderma are rarely resistant to metho-trexate and we did not identify a clinical profile for those resistant patients.

Acanthosis nigricans, hypochondroplasia, and FGFR3 mutations: Findings with five new patients, and a review of the literature.

Early development of extensive acanthosis nigricans (AN) is a key feature in some patients who have hypochondroplasia (HCH) in association with FGFR3 mutations. We here report regarding five new patients with HCH who exhibited AN, and we compare their characteristics to the eight patients previously described in the literature. In these patients, the AN lesions began in childhood, and they were extensive. These lesions were located on the torso, the abdomen, and the face, in addition to the typical skin fold sites. Other skin lesions were frequently reported: café-au-lait macules, melanocytic nevi, lentigines, and seborrheic keratosis. The Lys650Thr mutation was the predominant reported mutation of FGFR3.