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.

Low risk of embryonic and other cancers in PIK3CA-related overgrowth spectrum: Impact on screening recommendations.

The PIK3CA-related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%-21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long-term follow-up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.

Accurate diagnosis of acute hemorrhagic edema of infancy: a French multicenter observational study.

The purpose of the study is to highlight clinical signs that are either suggestive of or against the diagnosis of AHEI to improve diagnosis and management. The medical records of children under 3 years old diagnosed with AHEI were retrospectively reviewed. Clinical data and photographs were reviewed by three independent experts, and the cases were classified as probable, doubtful, or unclear AHEI. Of the 69 cases of children diagnosed with AHEI included in 22 centers, 40 were classified as probable, 22 as doubtful, and 7 as unclear. The median age of patients with probable AHEI was 11 months [IQR 9-15], and they were in overall good condition (n = 33/40, 82.5%). The morphology of the purpura was targetoid in 75% of cases (n = 30/40) and ecchymotic in 70% of cases (n = 28/40) and affected mostly the legs (n = 39/40, 97%), the arms (n = 34/40, 85%), and the face (n = 33/40, 82.5%). Edema was observed in 95% of cases and affected mostly the hands (n = 36/38, 95%) and feet (n = 28/38, 74%). Pruritus was absent in all patients with probable AHEI and described for 6/21 with doubtful AHEI (29%). AHEI was the original diagnosis in only 24 patients (n = 24/40, 60%). The major differential diagnoses were purpura fulminans and urticaria multiforme.  Conclusion: AHEI, which the diagnosis is made on clinical findings, is often misdiagnosed. Purpuric lesions localized on the face/ears, arms/forearms, and thighs/legs with edema of the hands without pruritus in a young child with a good overall condition are highly suggestive of AHEI. What is Known: •Acute hemorrhagic edema of infancy (AHEI) is a cutaneous leukocytoclastic vasculitis affecting children under 3 years old. •Appropriate diagnosis is important to distinguish this benign disease from more serious diseases to avoid investigations and treatments, iatrogenic harm and unnecessary follow-up. What is New: •AHEI is an uncommon disorder often misdiagnosed by pediatricians and dermatologists. •Purpuric lesions localized on the face/ears, arms/forearms, and thighs/legs with edema of the hands without pruritus in an infant with a good overall condition are highly suggestive of AHEI.

Effectiveness of biologic therapies in children with palmoplantar plaque psoriasis: An analysis of real-life data from the BiPe cohorts.

BACKGROUND: Palmoplantar plaque psoriasis is a frequent clinical subtype of childhood psoriasis. This study evaluated the effectiveness of biologic therapies in children with palmoplantar plaque psoriasis using data from the two Biological treatments for Pediatric Psoriasis (BiPe) cohorts. METHODS: Data for all 170 patients included in the BiPe cohorts were analyzed. Data on the effectiveness (PGA, PASI between baseline and 3 months of treatment) of biologic therapies were then compared between children with palmoplantar plaque psoriasis (n = 20) and those with generalized plaque psoriasis (n = 136). Clinical and demographic data were also analyzed. RESULTS: Children in the palmoplantar group were more likely to be male (p = .04), with an earlier age of psoriasis onset (p < .001), and more frequent nail involvement (p < .001). After 3 months of biologic treatment, mean PGA scores were higher in the palmoplantar group than in the generalized plaque psoriasis group (p = .004). In the palmoplantar group, continuation rates were higher for adalimumab than for etanercept or ustekinumab (p = .01). Primary inefficacy was a more frequent reason for stopping biologic therapies in the palmoplantar group (p = .01), and disease remission was less frequent (p = .05). Combined systemic and biologic therapies were more frequently used in palmoplantar plaque psoriasis (p < .001). CONCLUSIONS: This study demonstrated the treatment-resistant nature of palmoplantar plaque psoriasis and indicated that adalimumab could be the most effective biologic treatment. Larger studies are needed to allow therapeutic algorithms for palmoplantar plaque psoriasis to be proposed in pediatric psoriasis management guidelines.

Ichthyosis: presentation and management.

PURPOSE OF REVIEW: This review focuses on the presentation and management of ichthyoses and highlights recent advances in treatment that hold promise for better targeted therapy. RECENT FINDINGS: The ichthyoses are a group of rare genetic diseases with a wide phenotypic spectrum, characterized most often by generalized hyperkeratosis and scaling with variable erythema. The highly visible scaling and frequent itch contribute to decreased quality of life. Management for ichthyosis focuses on symptomatic relief and scale reduction with emollients, keratolytics, and retinoids. Recent advances in immune profiling and genotype-phenotype mapping have increased understanding of ichthyosis and shifted focus to pathogenesis-based targeted therapies with emerging biologics, small molecular inhibitors, and gene therapy. SUMMARY: This article discusses clinical assessment and genotyping to make the diagnosis of specific forms of ichthyosis, provides guidance for management, and reviews new treatment options with systemic agents.

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.

Ichthyosis.

The ichthyoses are a large, heterogeneous group of skin cornification disorders. They can be inherited or acquired, and result in defective keratinocyte differentiation and abnormal epidermal barrier formation. The resultant skin barrier dysfunction leads to increased transepidermal water loss and inflammation. Disordered cornification is clinically characterized by skin scaling with various degrees of thickening, desquamation (peeling) and erythema (redness). Regardless of the type of ichthyosis, many patients suffer from itching, recurrent infections, sweating impairment (hypohidrosis) with heat intolerance, and diverse ocular, hearing and nutritional complications that should be monitored periodically. The characteristic clinical features are considered to be a homeostatic attempt to repair the skin barrier, but heterogeneous clinical presentation and imperfect phenotype-genotype correlation hinder diagnosis. An accurate molecular diagnosis is, however, crucial for predicting prognosis and providing appropriate genetic counselling. Most ichthyoses severely affect patient quality of life and, in severe forms, may cause considerable disability and even death. So far, treatment provides only symptomatic relief. It is lifelong, expensive, time-consuming, and often provides disappointing results. A better understanding of the molecular mechanisms that underlie these conditions is essential for designing pathogenesis-driven and patient-tailored innovative therapeutic solutions.

Clinical Features, Histological Characteristics, and Disease Outcomes of Mycosis Fungoides in Children and Adolescents: A Nationwide Multicentre Cohort of 46 Patients.

BACKGROUND: Our objective was to describe the clinical, histological characteristics, and disease outcome of a cohort of mycosis fungoides (MF) diagnosed during childhood including disease status at adulthood. METHODS: This is a retrospective multicentre survey of patients aged under 18 years at diagnosis with histologically confirmed MF. Patients' clinical and histological characteristics, treatments, and disease outcome (for patients followed for more than 12 months) were analysed. RESULTS: Forty-six patients were included (median age at diagnosis: 11 years; M:F sex ratio: 3:1) with 39 (85%) followed for at least 12 months. Thirty-nine patients (85%) had stage I MF. Hypopigmented patches were observed in 48% and folliculotropism in 43% patients. Immunophenotype of the skin infiltrate was predominantly CD8+ in 17% of patients. Initial management included a wait-and-see strategy in 6/39 (15%), skin-directed treatment in 27 (69%), and systemic treatment in 6 (15%) patients, respectively, with partial or complete clinical response (PR or CR) observed in 28 patients (72%). 14/39 patients (36%) relapsed after initial response. After a median follow-up period of 54 months, disease status at last news was PR or CR in 31/39 (79%), stable disease in 6 (15%), and progression in 2 (5%) patients. Histological transformation was observed in 3/39 (8%). Of the 15 patients followed until adulthood, 13 (87%) had persistent MF. DISCUSSION: This survey confirms the high frequency of hypopigmented and folliculotropic lesions and of CD8+ immunophenotype compared to adult MF patients. The long-term course is usually indolent but transformation may occur sometimes long after disease onset and the disease may persist during adulthood.

Oral health status in patients with inherited epidermolysis bullosa: a comparative multicenter study.

OBJECTIVE: Epidermolysis bullosa (EB) is a rare genetic mucocutaneous disorder characterized by epithelial fragility leading to blister formation on skin and mucous membranes with even minor mechanical trauma. Most EB oral health publications give fragmented information, focusing on only one oral health aspect or one EB type. The aim of this study was to expand the knowledge of the overall oral health status of individuals with dystrophic, junctional, and simplex EB. METHOD AND MATERIALS: A comparative multicenter study, including a control group, and based on questionnaires and clinical examinations, was undertaken in three EB expert centers. RESULTS: Most EB (90.2%) participants brushed their teeth at least once a day despite the pain. The prevalence of enamel defects and caries experience did not differ between the 42 EB participants and the 42 age-/sex-matched healthy controls. Gingival inflammation unrelated to dental plaque accumulation was found in EB participants. Blisters, erythema, and erosion/ulceration mainly involved gingiva, buccal mucosa, lips, and palate, with different topographic patterns according to EB type. EB patients whatever the age showed a similar lesion distribution. Simplex and dystrophic EB patients under 12 years old displayed higher lesion severity than junctional EB ones. Only dystrophic type exhibited microstomia and ankyloglossia. CONCLUSION: Oral health status seemed to benefit from a close collaboration between dental practitioner and dermatologist, and from regular dental examination, starting at a young age and with a focus on prevention. The new appreciation of oral health involvement highlighted by this study is essential for EB patients care, regarding comorbidities and quality of life.

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.

Perialar intertrigo in children and adolescents: A multicenter prospective study of 41 cases.

BACKGROUND/OBJECTIVES: We observed isolated cases of perialar intertrigo in children and teenagers that did not appear to correspond to any known clinical entity. The objective of this study was to describe the clinical features of this dermatosis and the clinical characteristics of the patients. METHODS: We conducted a prospective, multicenter cohort study in France from August 2017 to November 2019. All the patients under 18 years of age with chronic perinasal intertrigo were included. A standardized questionnaire detailing the clinical characteristics of the patients and the description of the intertrigo. If possible, a Wood's lamp examination of the intertrigo was done. RESULTS: Forty-one patients were included (25 boys and 16 girls, average age: 12.1 years). Intertrigo was bilateral in 38 patients (93%). The majority of patients had no symptoms (54%). Pruritus was present in 39% of cases. Orange red follicular fluorescence was present in the perialar region on Wood's light examination in 78% of cases with active fluorescence. The presumptive diagnoses suggested by the investigators were acne (24.4%), seborrheic dermatitis (19.5%), rosacea (9.8%), psoriasis (9.8%) and perioral dermatitis (7.3%). No diagnosis was proposed in 22% of the cases. CONCLUSIONS: We describe a previously undescribed clinical sign which is characterized by a chronic bilateral erythematous intertrigo located in the perialar region. It can be isolated or associated with various facial dermatoses.

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.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Series of 49 French Pediatric Cases.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and potentially fatal adverse reaction. It can be difficult to diagnose, even more so among children, because symptoms may mimic other commonly encountered pediatric conditions. OBJECTIVE: To describe clinical and laboratory features of DRESS syndrome in the pediatric population (age ≤18 years) and establish causative agents and treatment modalities. METHODS: This was a multicenter retrospective study of probable and definite DRESS cases (Registry of Sever Cutaneous Adverse Reaction score ≥ 4) in children hospitalized in 15 French university hospitals between 2000 and 2020. RESULTS: We included 49 cases. All children had fever and rash, 69.4% had lymphadenopathy, and 65.3% had facial edema. The most common organ affected was the liver (83.7%). Treatment consisted of topical corticosteroid in only 30.6% and systemic corticosteroid in 55.1%; 12.2% received intravenous immunoglobulin. Among probable and likely culprit drugs, 65% were antibiotics and 27.5% were antiepileptics, median time to DRESS symptom onset after initiation of 15 days (13 days with antibiotics and 21 days with antiepileptics). Twenty-seven children had allergy assessment for causative agents, 65.4% of whom had positive tests. CONCLUSIONS: Culprit drugs are frequently antibiotics and antiepileptic drugs, and onset is often less than 2 weeks after treatment starts, especially with antibiotics. Treatment with topical corticosteroids appears to be sufficient in the least severe cases. Treatment by systemic corticosteroid therapy remains the reference treatment in case of severe organ damage.

Crusted scabies in children in France: a series of 20 cases.

To evaluate the risk factors for crusted scabies in children in France. The retrospective multicenter study, conducted in France, of children (aged < 18 years) with profuse and/or crusted scabies confirmed by dermoscopy and/or microscopy. Data were obtained using a standardized questionnaire. We included 20 children. The mean age was 4.5 years, and 70% of the patients were girls. Their medical history revealed a neurological pathology (agenesis of the corpus callosum; n = 1, 5.0%), prematurity (n = 1, 5.0%), Down syndrome (n = 1, 5.0%), atopic dermatitis (n = 2, 10%), and asthma (n = 2, 10.0%). Fifteen (75.0%) children were treated with steroids before being diagnosed with scabies: 12 (60.0%) with topical steroids, one (5.0%) with a systemic steroid, and two (10.0%) with inhaled steroids. One child (5.0%) lived in a precarious environment. The mean duration of pruritus was 3.4 months, and that of the skin lesions was 3.1 months. The most commonly affected areas for crusted scabies were the palms/hands (66.7%) and the armpits (33.3%). Thirteen children (65.0%) were hospitalized, 14 (70.0%) were treated with ivermectin and all received topical treatments; 85.7% were cured within an average of 38 days, but one child had a relapse 3 months later in the form of common scabies.Conclusion: The main risk factor for developing crusted scabies in France was the misdiagnosis and the use of corticosteroids, especially topical forms typically used in "healthy" children. Management of the children was effective and similar to that used in adults. What is Known: • Crusted scabies is an extremely contagious disease which is rarely reported in infancy, especially in healthy children. • The main risk factors include immunosuppression, physical debilitation, and intellectual disability. What is New: • The main risk factor of severe scabies in this study was delayed diagnosis associated with the use of topical or systemic corticosteroids. • The treatment was successful in 85.7% of cases, and 65% of children needed to be hospitalized.

Switching biologics in children with psoriasis: Results from the BiPe cohort.

BACKGROUND: There is currently little information on switching biologics in pediatric psoriasis. OBJECTIVE: To evaluate the real-world clinical practice and safety of switching biologics in the "Biological Treatments for Pediatric Psoriasis" (BiPe) cohort. METHODS: Data for all 134 patients included in the BiPe cohort were analyzed. A further evaluation of the subpopulation of patients who switched from a first-line biologic to a second-line biologic was then conducted. Drug survival rates were also compared between biologics given as first-line or second-line agents. RESULTS: Overall, 29 patients (female: 55%; mean age: 16.6 ± 3.0 years) switched between two biologics. Etanercept (ETN) was the first-line biologic used in 23 patients: 16 (69.6%) switched to adalimumab (ADA) and seven (30.4%) to ustekinumab (UST). Six patients received first-line ADA and switched to UST. Loss of efficacy (62.1%), primary inefficacy (20.7%), and parental choice (6.9%) were the main reasons for switching biologics. One (3.4%) of the switches was performed because of adverse events or intolerance. For UST and ADA, the 18-month drug survival rate did not differ according to whether the agent was given as a first-line or second-line biologic (UST: P = .24; ADA: P = .68). No significant differences in drug survival rates were observed between the three different switches (ADA to UST, ETN to ADA, and ETN to UST). CONCLUSION: Our study provided key insights into the real-life clinical practice of switching biologics in pediatric psoriasis patients. However, more information and guidance on switching biologics in pediatric psoriasis are needed to improve real-life practice and outcomes.