Successful treatment of congenital erythropoietic porphyria using matched unrelated hematopoietic stem cell transplantation in an adult: A case report.

Congenital erythropoietic porphyria (CEP), or Gunther disease, is a rare genetic disease responsible for severe dermatologic, hepatic and/or haematological damages related to the deficient activity of the uroporphyrinogen III synthase. Allogeneic stem cell transplantation (Allo-SCT) represents the only curative treatment and few allotransplanted cases have been reported in children but not in adults. Here we report for the first time the successful cure of a 46-year old man with CEP with a 5-year follow-up after Allo-SCT.

Social cognition in children with neurofibromatosis type 1.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is a genetic pathology that can lead to impaired social functioning that has a negative impact on patients' quality of life. To date, although the hypothesis of impaired social cognition has been proposed as a potential explanation for these difficulties, very few studies have focused on theory of mind in children with NF1. Furthermore, other complex sociocognitive abilities have never been investigated. The aim of the present study was to assess theory of mind, moral reasoning, and social information processing in children with NF1 compared with a control group. METHOD: We administered the Paediatric Evaluation of Emotions, Relationships and Socialization® to 38 children with NF1 aged between 8 years and 16 years 11 months (mean = 11.4, SD = 2.3) and 43 control children with comparable sociodemographic characteristics. RESULTS: Patients performed significantly worse than controls on moral reasoning and social information processing tests, but there was no significant difference on theory of mind. CONCLUSIONS: These results seem to confirm the presence of social cognition difficulties in NF1 that could explain, at least in part, their social difficulties, although not all dimensions are concerned. The differences between the processes we assessed are discussed in relation to the methodologies used to measure them, and raises questions about the complementarity of traditional tools and more ecological assessments.

Perception and recognition of primary and secondary emotions by children with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a genetic disease that can lead to impaired social adaptation and functioning, thus affecting quality of life. To date, studies of these children's social cognition abilities have been scant and far from exhaustive. Therefore, the purpose of the present study was to assess the ability of children with NF1, compared with controls, to process facial expressions of emotions - not only including the usual primary emotions (happiness, anger, surprise, fear, sadness and disgust), but secondary emotions, too. To do so, the links between this ability and the characteristics of the disease (mode of transmission, visibility, and severity) were examined. A total of 38 children with NF1 aged 8-16 years 11 months (mean = 11.4, SD = 2.3) and 43 sociodemographically comparable control children performed the emotion perception and recognition tests of a social cognition battery. Results confirmed that the processing of primary and secondary emotions is impaired in children with NF1, but there were no significant links with either mode of transmission, severity, or visibility. These results encourage further comprehensive assessments of emotions in NF1, and suggest that investigations should be extended to higher level social cognition skills, such as theory of mind and moral judgments.

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.

French cohort of children and adolescents with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas: CASSIOPEA study.

Surgery is a treatment option for neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN), but complete resection is often not feasible. Real-world studies are warranted to understand disease burden, progression, and need for medical treatment in patients with inoperable PN. CASSIOPEA was a retrospective study of French pediatric patients (aged ≥3 to <18 years) presenting at a national multidisciplinary team (MDT) review with NF1 and ≥1 symptomatic, inoperable PN. Medical records were reviewed from the time of MDT review and over a follow-up period of up to 2 years. Primary objectives were to describe patient characteristics and target PN-associated therapy patterns. A secondary objective was evolution of target PN-related morbidities. Patients with prior, ongoing, or MDT recommendation of mitogen-activated protein kinase kinase (MEK) inhibitor treatment were excluded. Overall, 78 target PN were identified in 76 patients. At MDT review, median age was 8.4 years, with approximately 30% of patients aged 3-6 years. Target PN were primarily internal (77.3%), and 43.2% were progressive. Target PN location was evenly distributed. 34 target PN had documented MDT recommendations; of these, a majority (76.5%) were for non-medication management, including surveillance. At least one follow-up visit was recorded for 74 target PN. Despite initially being considered inoperable, 12.3% of patients underwent surgery for target PN. At MDT review, most (98.7%) target PN were associated with ≥1 morbidity, primarily pain (61.5%) and deformity (24.4%); severe morbidities were identified in 10.3%. Of 74 target PN with follow-up data, 89.2% were associated with ≥1 morbidity, primarily pain (60.8%) and deformity (25.7%). Of 45 target PN associated with pain, pain improved in 26.7%, was stable in 44.4%, and deteriorated in 28.9%. Deformity improved in 15.8% and remained stable in 84.2% of 19 target PN associated with deformity. None deteriorated. In this real-world study in France, NF1-PN disease burden was considerable, and a considerable proportion of patients were very young. Most patients received only supportive care without medication for target PN management. Target PN-related morbidities were frequent, heterogeneous, and generally did not improve during follow-up. These data highlight the importance of effective treatments that target PN progression and improve disease burden.

PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma.

Phakomatosis pigmentovascularis is a diagnosis that denotes the coexistence of pigmentary and vascular birthmarks of specific types, accompanied by variable multisystem involvement, including CNS disease, asymmetrical growth, and a predisposition to malignancy. Using a tight phenotypic group and high-depth next-generation sequencing of affected tissues, we discover here clonal mosaic variants in gene PTPN11 encoding SHP2 phosphatase as a cause of phakomatosis pigmentovascularis type III or spilorosea. Within an individual, the same variant is found in distinct pigmentary and vascular birthmarks and is undetectable in blood. We go on to show that the same variants can cause either the pigmentary or vascular phenotypes alone, and drive melanoma development within pigmentary lesions. Protein structure modeling highlights that although variants lead to loss of function at the level of the phosphatase domain, resultant conformational changes promote longer ligand binding. In vitro modeling of the missense variants confirms downstream MAPK pathway overactivation and widespread disruption of human endothelial cell angiogenesis. Importantly, patients with PTPN11 mosaicism theoretically risk passing on the variant to their children as the germline RASopathy Noonan syndrome with lentigines. These findings improve our understanding of the pathogenesis and biology of nevus spilus and capillary malformation syndromes, paving the way for better clinical management.

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.

New-onset inflammatory bowel diseases among IL-17 inhibitor-treated patients: results from the case-control MISSIL study.

OBJECTIVES: To describe new-onset IBD (new IBD) in patients treated with IL-17 inhibitors (IL-17i), to assess their incidence and to identify their risk factors in real life. METHODS: A French national registry (MISSIL) aimed to report all cases of new IBD in patients treated with IL-17i from January 2016 to December 2019. Using the estimated number of patients treated by IL-17 in France during the study period, the annual incidence rates of new IBD was reported in IL-17i-treated patients. A case-control study was performed with two controls per new IBD case matched by gender, age and underlying inflammatory disease. RESULTS: Thirty-one cases of new IBD under IL-17i were collected: 27 patients treated for spondyloarthritis and four patients for psoriasis. All were observed with secukinumab (SEK). The median time to onset of new IBD symptoms was 4.0 (1.5-7.5) months. SEK was discontinued in all patients. The evolution was favourable with complete resolution (17/31), improvement (7/31) or stabilization (5/31). Two patients died: one due to a massive myocardial infarction and one due to post-colectomy complications. The incidence of new IBD decreased from 0.69/100 patient-years [PY] (7/1010) in 2016 to 0.08/100 PY (6/7951) in 2019. No previous treatment with etanercept (odds ratio [OR] = 0.33, 95% CI: 0.14-0.80, P = 0.014) and low number of previous biologic therapies (OR = 0.67, 95% CI: 0.47, 0.94, P = 0.021) were significantly associated with new IBD. CONCLUSION: The incidence of new IBD was low and decreased from 2016 to 2019. The outcome was favourable in 24 out of 31 patients, but two patients died.

Executive functions and quality of life in children with neurofibromatosis type 1.

BACKGROUND: To examine the impact of executive function disorders on health-related quality of life (QoL) in children with neurofibromatosis type 1 (NF1), we conducted a prospective single-center study among 40 children with NF1 aged 8-12 years (mean = 9.7, SD = 1.4) and their parents, comparing them with 56 healthy control children matched for age, sex, parental education level, and handedness. We collected children's self-reports and parents' proxy reports of QoL with the Kidscreen-52 questionnaire, and measured executive functions by combining seven performance-based tests and a daily life questionnaire completed by parents and teachers. RESULTS: Several QoL domains were significantly impaired in the children with NF1, compared with healthy controls, mainly according to their parents' reports (3 out of 9 scales; Cohen's d: 0.57-0.76), with particularly low scores in the social support and peers and school environment domains. Executive function difficulties (Cohen's d: 0.64-1.72) significantly predicted the impairment of QoL domains as perceived by the children or their parents, regardless of the indirect indicators of learning disabilities. CONCLUSIONS: Both performance-based executive function scores and behavioral ratings of executive functions in daily life by parents and teachers were associated with low QoL levels in the children with NF1. The school environment and social integration appear to be particularly affected and should therefore be targeted in the management of the disease.

Sirolimus (Rapamycin) for Slow-Flow Malformations in Children: The Observational-Phase Randomized Clinical PERFORMUS Trial.

IMPORTANCE: Sirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking. OBJECTIVE: To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment. DESIGN, SETTING AND PARTICIPANTS: This multicenter, open-label, observational-phase randomized clinical trial included 59 children aged 6 to 18 years with a slow-flow vascular malformation who were recruited between September 28, 2015, and March 22, 2018, in 11 French tertiary hospital centers. Statistical analysis was performed on an intent-to-treat basis from December 4, 2019, to November 10, 2020. INTERVENTIONS: Patients underwent an observational period, then switched to an interventional period when they received oral sirolimus (target serum levels, 4-12 ng/mL). The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient. MAIN OUTCOMES AND MEASURES: The primary outcome was change in the volume of vascular malformations detected on magnetic resonance imaging scan (with centralized interpretation) per unit of time (ie, between the interventional period and the observational period). Secondary outcomes included subjective end points: pain, bleeding, oozing, quality of life, and safety. RESULTS: Among the participants (35 girls [59.3%]; mean [SD] age, 11.6 [3.8] years), 22 (37.3%) had a pure venous malformation, 18 (30.5%) had a cystic lymphatic malformation, and 19 (32.2%) had a combined malformation, including syndromic forms. Variations in the volume of vascular malformations detected on magnetic resonance imaging scans associated with the duration period were not overall significantly different between the interventional period and the observational period (all vascular malformations: mean [SD] difference, -0.001 [0.007]; venous malformations: mean [SD] difference, 0.001 [0.004]; combined malformations: mean [SD] difference, 0.001 [0.009]). However, a significant decrease in volume was observed for children with pure lymphatic malformations (mean [SD] difference, -0.005 [0.005]). Overall, sirolimus had positive effects on pain, especially for combined malformations, and on bleeding, oozing, self-assessed efficacy, and quality of life. During sirolimus treatment, 56 patients experienced 231 adverse events (5 serious adverse events, none life-threatening). The most frequent adverse event was an oral ulcer (29 patients [49.2%]). CONCLUSIONS AND RELEVANCE: This observational-phase randomized clinical trial allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Pure lymphatic malformations seem to be the best indication for sirolimus therapy because evidence of decreasing lymphatic malformation volume per unit of time, oozing, and bleeding and increasing quality of life was found. In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02509468; clinicaltrialsregister.eu Identifier: 2015-001096-43.

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.

Prebiotic Supplementation During Pregnancy Modifies the Gut Microbiota and Increases Metabolites in Amniotic Fluid, Driving a Tolerogenic Environment In Utero.

The gut microbiota is influenced by environmental factors such as food. Maternal diet during pregnancy modifies the gut microbiota composition and function, leading to the production of specific compounds that are transferred to the fetus and enhance the ontogeny and maturation of the immune system. Prebiotics are fermented by gut bacteria, leading to the release of short-chain fatty acids that can specifically interact with the immune system, inducing a switch toward tolerogenic populations and therefore conferring health benefits. In this study, pregnant BALB/cJRj mice were fed either a control diet or a diet enriched in prebiotics (Galacto-oligosaccharides/Inulin). We hypothesized that galacto-oligosaccharides/inulin supplementation during gestation could modify the maternal microbiota, favoring healthy immune imprinting in the fetus. Galacto-oligosaccharides/inulin supplementation during gestation increases the abundance of Bacteroidetes and decreases that of Firmicutes in the gut microbiota, leading to increased production of fecal acetate, which was found for the first time in amniotic fluid. Prebiotic supplementation increased the abundance of regulatory B and T cells in gestational tissues and in the fetus. Interestingly, these regulatory cells remained later in life. In conclusion, prebiotic supplementation during pregnancy leads to the transmission of specific microbial and immune factors from mother to child, allowing the establishment of tolerogenic immune imprinting in the fetus that may be beneficial for infant health outcomes.

Executive functions in preschool-aged children with neurofibromatosis type 1: Value for early assessment.

Introduction: Executive functions (EFs) impairment is common in children with neurofibromatosis type 1 (NF1), and could be a significant vulnerability associated with this medical disorder. However, we still know little about EFs in preschool NF1. Our study assessed EFs in NF1 children using performance-based tests and daily life questionnaires, which combined the views of parents and teachers.Method: Seven classic experimental tasks were used to evaluate EFs in 33 NF1 children aged 3 to 5 years old, and BRIEF-P questionnaires were completed by their parents and teachers. These children's performance was compared with a control group of 52 healthy children matched in age, gender and socio-cultural status.Results: NF1 children have significantly lower scores for 5 out of 7 executive tasks than control children and significantly higher levels of EF concerns in the parent and teacher BRIEF-P ratings. The correlations between performance-based tests and questionnaires are weak.Conclusions: Our results support an early executive dysfunction in NF1 children and call for early and systematic assessment of EFs. Both performance-based tests and questionnaires are complementary tools to investigate early EFs dysfunction in children with NF1.

Reading Comprehension Impairment in Children With Neurofibromatosis Type 1 (NF1): The Need of Multimodal Assessment of Attention.

Attention span, which has been shown to have an impact on reading quality in many other conditions, is one of the main cognitive disorders of neurofibromatosis type 1 (NF1). The aim of this work is to observe the impact of attention on reading comprehension, in NF1 and non-NF1 children. A multicenter, cross-sectional study was conducted on 150 children (8-12 years old) with or without NF1 (75 NF1 vs 75 non-NF1; 72 female, 78 male), matched for age, sex, handedness, and reading level, thus forming a continuum from good to poor readers in both NF1 and non-NF1 groups. Children with intellectual deficiency or neurologic or psychiatric disorder were excluded. Attentional skills were assessed by combining a parent questionnaire (Child Behavior CheckList) and a performance-based assessment (Conner's Continuous Performance Test-Second Edition). Reading comprehension was assessed through a standardized reading comprehension test (ORLEC Lobrot). The performance-based attention scores were associated with text and sentence comprehension ability (P = .0235 and P = .0164, respectively), while indirect questionnaire attention scores were only associated with sentence comprehension (P = .0263). For both groups, the correlations between questionnaire and performance-based measures were low. We have shown that reading comprehension is greatly influenced by attention in NF1 and non-NF1, even if predictors of good reading comprehension also include IQ score and reading accuracy. Indirect observer-rated questionnaires and direct performance-based measures of attention do not assess the same variables, are linked to different components of reading skills, and are not interchangeable assessments of attention difficulties. Both assessments are complementary and must be used simultaneously, leading to recommendations that support multimodal assessment of attention.

Uncommon preputial localization of Langerhans cell histiocytosis.

We report a rare case of a 14-year-old boy with Langerhans cell histiocytosis localized to the prepuce. The patient was treated with a topical corticosteroid followed by imiquimod cream resulting in significant clinical improvement of the lesion. Although spontaneous remission is possible, the use of imiquimod may be an effective alternative therapy in cases of cutaneous Langerhans cell histiocytosis refractory to topical corticosteroids.

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.