Consensus recommendations on management of selumetinib-associated adverse events in pediatric patients with neurofibromatosis type 1 and plexiform neurofibromas.

Background: Selumetinib is the first approved treatment for pediatric patients with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN) in the EU and US, as well as in multiple other countries. Evidence for the management of selumetinib-associated adverse events (AEs) is mostly limited to clinical trials and expanded-access programs. We gathered a panel of European healthcare practitioners with clinical experience prescribing selumetinib and/or managing pediatric patients with NF1-PN to provide recommendations on the prevention and management of AEs. Methods: A modified Delphi approach was used to develop the recommendations among the group of experts. Initial statements were developed from a literature review of current management recommendations and regulatory reports. The panel refined the statements and rated the extent to which they agreed with them in 2 sessions and a follow-up survey. The panel comprised 2 pediatric neuro-oncologists, 1 pediatric oncologist, 1 pediatrician, 1 neuropediatrician, 1 oncologist, 1 neurologist, 2 psychologists, and 1 dermatologist. Results: The experts agreed on the relative frequency and impact of AEs potentially associated with selumetinib. Consensus-level agreement was reached for 36 statements regarding the prevention and management of AEs potentially associated with selumetinib. Experts recommended treatments for AEs based on their experience. Conclusions: The development of a variety of consensus statements indicates expert agreement on best practices for the prevention and management of AEs potentially associated with selumetinib in pediatric patients with NF1-PN. These events are generally manageable and should be considered alongside treatment benefit. Information sharing is warranted as further experience is gained.

Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules.

PURPOSE: Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function (LoF) LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs). METHODS: 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions. RESULTS: Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated, but occasionally associated with features recurring in RASopathies. In two families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating LoF. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate MAPK signaling. CONCLUSION: Our findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.

Quality of Life in Children with Neurofibromatosis Type 1: Agreement between Parents and Patients, and the Role of Disease Severity and Visibility.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic disorder that affects multiple systems in the body, often leading to physical disfigurements and a wide range of clinical symptoms. This study aims to investigate the relationship between NF1 severity and visibility and the quality of life (QoL) in children. METHODS: The Pediatric Quality of Life Inventory (PedsQL) and a modified version of the Ablon scale were used to assess QoL and NF1 severity and visibility, respectively. Self-reported and parent-reported QoL scores were compared, and the associations between NF1 severity/visibility and QoL were explored. RESULTS: Thirty-eight pediatric NF1 patients and their parents were enrolled. QoL scores did not differ significantly between patient self-reports and parent reports. However, correlational analyses revealed that higher NF1 severity was associated with lower physical QoL in patients, and greater NF1 visibility was linked to lower physical and social QoL. For parents, higher NF1 severity correlated with lower school functioning, whereas NF1 visibility did not show a significant correlation with QoL. CONCLUSION: The severity and visibility of NF1 have distinct impacts on various aspects of QoL in children, highlighting the need for tailored interventions that address both physical and psychological challenges. These findings underscore the importance of comprehensive care approaches in managing NF1 in pediatric populations.

Umbrella Review: Association Between Antipsychotic Drugs and Metabolic Syndrome Hallmarks in Children and Adolescents.

OBJECTIVE: To summarize the available evidence on metabolic parameters indicating metabolic adverse effects and risk of metabolic syndrome in children and adolescents treated with antipsychotics, following a pre-specified protocol (PROSPERO ID 252336). METHOD: We searched PubMed, Embase and PsycINFO until May 14, 2021, to identify systematic reviews (SR), meta-analyses (MA) and network meta-analyses (NMA) examining symptoms associated to metabolic syndrome in patients <18 years of age who required treatment with oral antipsychotic drugs. Evidence from quantitative analyses for all outcomes related to anthropometric, glyco-metabolic, and blood pressure parameters (measured from baseline to intervention-end and/or follow-up, in subjects exposed to antipsychotics and placebo) was reported on the basis of their metrics (median difference [medianD], mean difference [MD], standardized mean difference [SMD], odds ratio [OR], risk ratio ([RR]). A qualitative synthesis was also made. A formal quality assessment of the included studies was carried out by using the AMSTAR 2. We also provided a hierarchical stratification of the evidence from meta-analyses based on the class of evidence. RESULTS: A total of 23 articles (13 MA, 4 NMA and 6 SR) were included for review. As compared with placebo, an increase in triglyceride levels was associated with olanzapine (medianD [95% CI]: 37 [12.27, 61.74] mg/dL; MD [95% CI]: 38.57 [21.44, 55.77] mg/dL) and quetiapine (medianD [95% CI]: 21.58 [95% CI]: 4.27, 38.31 mg/dL; MD [95% CI]: 34.87 [20.08, 49.67] mg/dL; SMD [95% CI]: 0.37 [0.06, 0.068]), whereas decreased triglyceride levels were found for lurasidone. Increased total cholesterol level was associated with asenapine (medianD [95% CI]: 9.1 [1.73, 16.44] mg/dL), quetiapine (medianD [95% CI]: 15.60 [7.30, 24.05] mg/dL; olanzapine (MD [95% CI] from 3.67 [1.43, 5.92] mg/dL to 20.47 [13.97, 26.94] mg/dL]; and lurasidone (medianD [95% CI]: 8.94 [1.27, 16.90] mg/dL). Change in glucose levels did not differ among antipsychotics or placebo. Lurasidone, molindone, and ziprasidone were the best tolerated in terms of weight gain. According to the AMSTAR 2 scoring system, 13 (56.5%) reviews were rated as very low quality. According to classes of evidence, most MA were level 4, especially because of their limited total sample size. CONCLUSION: By collating meta-analyses assessing biochemical markers of metabolic syndrome in antipsychotic-treated children, we conclude that olanzapine should not be the antipsychotic of choice in patients at risk for hypertriglyceridemia or hypercholesterolemia. Aripiprazole and lurasidone appear to be better tolerated in terms of metabolic adverse events. Insufficient meta-analytic data are available to provide a precise risk estimate of metabolic syndrome, and, overall, the quality of evidence is low. STUDY REGISTRATION INFORMATION: Association between the use of antipsychotic drugs and alterations of the parameters defining the Metabolic Syndrome (MetS) in children and adolescents: an umbrella review; https://www.crd.york.ac.uk/prospero/; CRD42021252336.

Polysomnographic study in pediatric neurofibromatosis type 1.

Background: Neurofibromatosis type 1 (NF1) is a genetic disease that alters neurodevelopment. We aimed to analyze the sleep macrostructure of a sample of children affected by NF1 without neurocognitive co-morbidities and MRI reports of unidentified bright objects (UBOs). Methods: A 100 pre-pubertal children participated in the cross-sectional study: 50 subjects were children diagnosed with NF1 and 50 subjects were typically developing healthy children (TDC). All participants underwent polysomnographic evaluation through which conventional sleep parameters were collected: Total sleep time (TST), Sleep latency (SOL), first REM latency (FRL), number of stage shifts/h (SS/h), number of awakenings/h (AWN/h), wake after sleep onset (WASO%), sleep efficiency percentage (SE%), percentage of sleep time spent in sleep stages 1 (N1%) and 2 (N2%), slow-wave sleep (N3%), and REM sleep (REM%). Additionally, nocturnal respiratory events such as apnea/hypopnea index (AHI), oxygen desaturation index (ODI), and periodic limb movement index (PLMI) were recorded. Results: Neurofibromatosis type 1 children showed a reduction in sleep duration parameters (TST; p < 0.001), sleep efficiency (SE%; p < 0.001), and stage N2% (p < 0.001). Moreover, the number of awakenings per hour (AWN/h), wake after sleep onset (WASO%), and respiratory events such as AHI, ODI, and PLMI resulted higher in NF1 vs. TDC children. Conclusion: The data showed that the sleep macrostructure differs between NF1 and TDC children. These findings suggest that the evaluation of sleep may provide useful support in corroborating the diagnosis and offers additional therapeutic management perspectives in NF1 and genetic neurodevelopmental disorders in general.

Neurofibromatosis Type 1: Pediatric Aspects and Review of Genotype-Phenotype Correlations.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, with a birth incidence of approximately 1:2000-3000, caused by germline pathogenic variants in NF1, a tumor suppressor gene encoding neurofibromin, a negative regulator of the RAS/MAPK pathway. This explains why NF1 is included in the group of RASopathies and shares several clinical features with Noonan syndrome. Here, we describe the main clinical characteristics and complications associated with NF1, particularly those occurring in pediatric age. NF1 has complete penetrance and shows wide inter- and intrafamilial phenotypic variability and age-dependent appearance of manifestations. Clinical presentation and history of NF1 are multisystemic and highly unpredictable, especially in the first years of life when penetrance is still incomplete. In this scenario of extreme phenotypic variability, some genotype-phenotype associations need to be taken into consideration, as they strongly impact on genetic counseling and prognostication of the disease. We provide a synthetic review, based on the most recent literature data, of all known genotype-phenotype correlations from a genetic and clinical perspective. Molecular diagnosis is fundamental for the confirmation of doubtful clinical diagnoses, especially in the light of recently revised diagnostic criteria, and for the early identification of genotypes, albeit few, that correlate with specific phenotypes.

Neuropsychiatric Manifestations, Reduced Self-Esteem and Poor Quality of Life in Children and Adolescents with Neurofibromatosis Type 1 (NF1): The Impact of Symptom Visibility and Bullying Behavior.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, associated with neurocutaneous manifestations and neuropsychiatric manifestations. The present study explored the prevalence of bullying/cyberbullying behaviors and victimization behaviors in a cohort of children and adolescents with NF1. Possible gender differences and predictors of psychological symptoms, quality of life (QoL), and self-esteem were also examined. Thirty-eight school-aged participants with NF1 completed a psychological evaluation designed to assess anxiety and depression symptomatology, QoL, self-esteem, and the prevalence and extent of bullying/cyberbullying and victimization behaviors. We found that our participants frequently reported victimization behaviors rather than bullying/cyberbullying ones. Moreover, participants complained of depressive and anxiety symptomatology together with reduced self-esteem, and low psychosocial quality of life, with females reporting more severe performances than males. Furthermore, we found that reduced self-esteem was associated with more visibility of the NF1 symptoms, and victimization behaviors were found to mediate the relationship between anxiety and psychosocial QoL. Our findings indicated the presence of a maladaptive loop in children and adolescents with NF1 patients characterized by psychological symptoms, unfavorable self-perception, low self-esteem, and psychosocial difficulties that might be worsened by experiencing victimization behaviors. These results suggest the need to use a multidisciplinary approach in the diagnosis and treatment of NF1.

Mystery(n) Phenotypic Presentation in Europeans: Report of Three Further Novel Missense RNF213 Variants Leading to Severe Syndromic Forms of Moyamoya Angiopathy and Literature Review.

Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred de novo (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband's carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in RNF213 cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118-4122 and 4867 of RNF213 could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations.

Genotype-Phenotype Correlations in Neurofibromatosis Type 1: Identification of Novel and Recurrent NF1 Gene Variants and Correlations with Neurocognitive Phenotype.

Neurofibromatosis type 1 (NF1) is one of the most common genetic tumor predisposition syndrome, caused by mutations in the NF1. To date, few genotype-phenotype correlations have been discerned in NF1, due to a highly variable clinical presentation. We aimed to study the molecular spectrum of NF1 and genotype-phenotype correlations in a monocentric study cohort of 85 NF1 patients (20 relatives, 65 sporadic cases). Clinical data were collected at the time of the mutation analysis and reviewed for accuracy in this investigation. An internal phenotypic categorization was applied. The 94% of the patients enrolled showed a severe phenotype with at least one systemic complication and a wide range of associated malignancies. Spine deformities were the most common complications in this cohort. We also reported 66 different NF1 mutations, of which 7 are novel mutations. Correlation analysis identified a slight significant inverse correlation between age at diagnosis and delayed acquisition of psychomotor skills with residual multi-domain cognitive impairment. Odds ratio with 95% confidence interval showed a higher prevalence of learning disabilities in patients carrying frameshift mutations. Overall, our results aim to offer an interesting contribution to studies on the genotype-phenotype of NF1 and in genetic management and counselling.

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study.

Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (OPGs). Since they are slow-growing tumors, their diagnosis might be delayed, with consequences on long-term outcomes. We present a multicenter case series of nine children with DS associated with OPG, with the aim of providing relevant details about mortality and long-term sequelae. We retrospectively identified nine children (6 M) with DS (median age 14 months, range 3-26 months). Four patients had NF1-related OPGs. Children with NF1 were significantly older than sporadic cases (median (range) age in months: 21.2 (14-26) versus 10 (3-17); p = 0.015). Seven tumors were histologically confirmed as low-grade astrocytomas. All patients received upfront chemotherapy and nutritional support. Although no patient died, all of them experienced tumor progression within 5.67 years since diagnosis and were treated with several lines of chemotherapy and/or surgery. Long-term sequelae included visual, pituitary and neurological dysfunction. Despite an excellent overall survival, PFS rates are poor in OPGs with DS. These patients invariably present visual, neurological or endocrine sequelae. Therefore, functional outcomes and quality-of-life measures should be considered in prospective trials involving patients with OPGs, aiming to identify "high-risk" patients and to better individualize treatment.

A Translational Approach to Spinal Neurofibromatosis: Clinical and Molecular Insights from a Wide Italian Cohort.

Spinal neurofibromatosis (SNF), a phenotypic subclass of neurofibromatosis 1 (NF1), is characterized by bilateral neurofibromas involving all spinal roots. In order to deepen the understanding of SNF's clinical and genetic features, we identified 81 patients with SNF, 55 from unrelated families, and 26 belonging to 19 families with at least 1 member affected by SNF, and 106 NF1 patients aged >30 years without spinal tumors. A comprehensive NF1 mutation screening was performed using NGS panels, including NF1 and several RAS pathway genes. The main features of the SNF subjects were a higher number of internal neurofibromas (p < 0.001), nerve root swelling (p < 0.001), and subcutaneous neurofibromas (p = 0.03), while hyperpigmentation signs were significantly less frequent compared with the classical NF1-affected cohorts (p = 0.012). Fifteen patients underwent neurosurgical intervention. The histological findings revealed neurofibromas in 13 patients and ganglioneuromas in 2 patients. Phenotypic variability within SNF families was observed. The proportion of missense mutations was higher in the SNF cases than in the classical NF1 group (21.40% vs. 7.5%, p = 0.007), conferring an odds ratio (OR) of 3.34 (CI = 1.33−10.78). Two unrelated familial SNF cases harbored in trans double NF1 mutations that seemed to have a subclinical worsening effect on the clinical phenotype. Our study, with the largest series of SNF patients reported to date, better defines the clinical and genetic features of SNF, which could improve the management and genetic counseling of NF1.

Intermittent macrothrombocytopenia in a novel patient with Takenouchi-Kosaki syndrome and review of literature.

Takenouchi-Kosaki syndrome (TKS) is a recently delineated syndromic form of thrombocytopenia strictly related to an hot-spot missense variant, p.Tyr64Cys, in CDC42 (Cell Division Control protein 42). Herein we report an additional patient with the p.Tyr64Cys aminoacidic substitution who showed the well-defined phenotypical TKS features and an intermittent, very mild, macrothrombocytopenia at 10.7 years of age (93,000/mL), that was only retrospectively valorized. Outside of this value the PLT count had always been higher than 100,000/mL. We also review literature data from patients carrying this recurrent variant. Our female patient presented with prenatal onset of short stature and microcephaly, camptodactyly, heart defects, typical facial gestalt, developmental delay, and not specific brain abnormalities. After several genetic investigations (karyotype, CGH-Array, targeted NGS analysis for short stature genes), by whole exome sequencing we identified the p.Tyr64Cys in CDC42, occurring de novo. The case presented here provides further evidence that macrothrombocytopenia can be intermittent and thus it might escape attention of clinicians. Without this key feature, TKS clinical presentation can overlap other syndromic forms of short stature. Immunodeficiency, autoimmunity, and malignancies were recently reported in patients with the p.Tyr64Cys substitution, making imperative an early diagnosis of Takenouchi-Kosaki syndrome to organize the most proper follow-up of these pediatric patients. The whole exome sequencing can be a solving tool in the challenge to the rare diseases.

Natural History of Scoliosis in Children with NF1: An Observation Study.

(1) Background. Scoliosis is the most common musculoskeletal manifestation of Neurofibromatosis type 1 (NF1), and it might be dystrophic (D) or non-dystrophic (ND) depending on the presence of dysplastic changes of the spine. The aim of our study was to describe the characteristics and natural history of patients with NF1 and scoliosis. (2) Methods. We retrospectively reviewed records from patients with NF1 and scoliosis. Scoliosis was classified as D if at least two dystrophic changes were documented at imaging. (3) Results. Of the 438 patients reviewed, 43 fulfilled inclusion criteria; 17 were classified in D group and 26 in ND. The groups did not differ in age and localization of scoliosis curvature. Surgery was needed more often in D group, but the between-group difference was not significant. Male-to-female ratios of 3:1 and 4:1 were reported in surgically treated NF1 patients with ND and D scoliosis, respectively. (4) Conclusions. Our data suggests independently by the presence of dysplastic changes affecting the spine that males with NF1 are more often affected by scoliosis that requires surgery.

Auditory cortex hypoperfusion: a metabolic hallmark in Beta Thalassemia.

BACKGROUND: Sensorineural hearing loss in beta-thalassemia is common and it is generally associated with iron chelation therapy. However, data are scarce, especially on adult populations, and a possible involvement of the central auditory areas has not been investigated yet. We performed a multicenter cross-sectional audiological and single-center 3Tesla brain perfusion MRI study enrolling 77 transfusion-dependent/non transfusion-dependent adult patients and 56 healthy controls. Pure tone audiometry, demographics, clinical/laboratory and cognitive functioning data were recorded. RESULTS: Half of patients (52%) presented with high-frequency hearing deficit, with overt hypoacusia (Pure Tone Average (PTA) > 25 dB) in 35%, irrespective of iron chelation or clinical phenotype. Bilateral voxel clusters of significant relative hypoperfusion were found in the auditory cortex of beta-thalassemia patients, regardless of clinical phenotype. In controls and transfusion-dependent (but not in non-transfusion-dependent) patients, the relative auditory cortex perfusion values increased linearly with age (p < 0.04). Relative auditory cortex perfusion values showed a significant U-shaped correlation with PTA values among hearing loss patients, and a linear correlation with the full scale intelligence quotient (right side p = 0.01, left side p = 0.02) with its domain related to communication skills (right side p = 0.04, left side p = 0.07) in controls but not in beta-thalassemia patients. Audiometric test results did not correlate to cognitive test scores in any subgroup. CONCLUSIONS: In conclusion, primary auditory cortex perfusion changes are a metabolic hallmark of adult beta-thalassemia, thus suggesting complex remodeling of the hearing function, that occurs regardless of chelation therapy and before clinically manifest hearing loss. The cognitive impact of perfusion changes is intriguing but requires further investigations.

Clinical variability of neurofibromatosis 1: A modifying role of cooccurring PTPN11 variants and atypical brain MRI findings.

Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss-of-function variants in NF1, encoding neurofibromin, a protein negatively controlling RAS signaling. We evaluated whether concurrent variation in proteins functionally linked to neurofibromin contribute to the variable expressivity of NF1. Parallel sequencing of a RASopathy gene panel in 138 individuals with molecularly confirmed clinical diagnosis of NF1 identified missense variants in PTPN11, encoding SHP2, a positive regulator of RAS signaling, in four subjects from three unrelated families. Three subjects were heterozygous for a gain-of-function variant and showed a severe expression of NF1 (developmental delay, multiple cerebral neoplasms and peculiar cortical MRI findings), and features resembling Noonan syndrome (a RASopathy caused by activating variants in PTPN11). Conversely, the fourth subject, who showed an attenuated presentation, carried a previously unreported PTPN11 variant that had a hypomorphic behavior in vitro. Our findings document that functionally relevant PTPN11 variants occur in a small but significant proportion of subjects with NF1 modulating disease presentation, suggesting a model in which the clinical expression of pathogenic NF1 variants is modified by concomitant dysregulation of protein(s) functionally linked to neurofibromin. We also suggest targeting of SHP2 function as an approach to treat evolutive complications of NF1.

Poikiloderma With Neutropenia and Mastocytosis: A Case Report and a Review of Dermatological Signs.

Poikiloderma with neutropenia (PN) is a very rare genetic disorder mainly characterized by poikiloderma and congenital neutropenia, which explains the recurrence of respiratory infections and risk of developing bronchiectasis. Patients are also prone to develop hematological and skin cancers. Here, we present the case of a patient, the only child of apparently unrelated Serbian parents, affected by PN resulting from the homozygous mutation NM_024598.3:c.243G>A (p.Trp81Ter) of USB1; early onset of poikiloderma (1 year of age) was associated with cutaneous mastocytosis. We also provide a review of the literature on this uncommon condition with a focus on dermatological findings.