: Plexiform neurofibromas (pNFs) are benign neoplasms, primarily originating from Schwann cells, posing challenges in patients with type 1 neurofibromatosis (NF1) due to pain, disfigurement, ...compression of vital structures and potential for malignancy. Selumetinib, a MEK1/2 inhibitor, has shown promising results in treating inoperable pNFs, with clinical trials demonstrating tumor volume reduction and improved patient-reported outcomes. Despite its efficacy, dermatologic toxicities may impact the quality of life and treatment adherence. Evaluating the frequency and spectrum of such effects is crucial for effective management.
: In a four-year retrospective and prospective study, pediatric NF1 patients with symptomatic, inoperable plexiform neurofibromas (pNFs) were treated with selumetinib. Eligibility criteria included significant morbidity, pNF size exceeding 3 cm or surgical inoperability, and performance status >70%. Hematological, liver, lung and cardiac assessments established baseline health. Selumetinib, orally administered at 25 mg/m
twice, was administered for two years unless a response warranting extension occurred. Cutaneous AEs were documented and graded by severity according to CTCAE v5.0, with evaluations every three to six months. The impact on symptoms and pNF size was systematically recorded, and biopsies characterized histopathological features in those patients requiring surgery.
: Twenty patients were enrolled, with an average age at therapy initiation of 11.6 years. Cutaneous side effects were common, with all patients experiencing at least one and a median of two per patient. Xerosis, paronychia and acneiform rash were prevalent. Notably, pre-pubertal individuals were more susceptible to xerosis. Acneiform rash had a higher incidence in older patients and those with skin phototypes II and III. Successful management involved tailored approaches, such as clindamycin for acneiform rash and topical agents for paronychia. Hair abnormalities, including color changes and thinning, occurred, with female patients at higher risk for the latter. Paronychia presented challenges, necessitating various interventions, including surgical approaches. AEs led to treatment suspension in 20% of patients, with tumor rebound observed in 75%.
: According to our experience, successful management of selumetinib-induced cutaneous AEs requires tailored strategies including surgery. AEs might indirectly determine pNF regrowth due to therapy suspension. We thus emphasize the pivotal role of addressing cutaneous reactions for effective selumetinib management in pediatric patients.
Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in
and characterized by a heterogeneous phenotypic presentation. Relevant genotype-phenotype ...correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype-phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (
= 0.005). Skeletal abnormalities were associated with whole gene deletions (
= 0.05) and frameshift variants (
= 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (
= 0.031), whereas Lisch nodules (
= 0.05) and endocrinological disorders (
= 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype-phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.
Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by mutations in
gene, coding for neurofibromin 1. NF1 can be associated with Moyamoya disease (MMD), and this association, typical ...of paediatric patients, is referred to as Moyamoya syndrome (MMS). MMD is a cerebral arteriopathy characterized by the occlusion of intracranial arteries and collateral vessel formation, which increase the risk of ischemic and hemorrhagic events.
gene mutations have been associated with MMD, so we investigated whether rare variants of
could act as genetic modifiers of MMS phenotype in a pediatric cohort of 20 MMS children, 25 children affected by isolated MMD and 47 affected only by isolated NF1. By next-generation re-sequencing (NGS) of patients' DNA and gene burden tests, we found that
seems to play a role only for MMD occurrence, while it does not appear to be involved in the increased risk of Moyamoya for MMS patients. We postulated that the loss of neurofibromin 1 can be enough for the excessive proliferation of vascular smooth muscle cells, causing Moyamoya arteriopathy associated with NF1. Further studies will be crucial to support these findings and to elucidate the possible role of other genes, enhancing our knowledge about pathogenesis and treatment of MMS.
Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome caused by pathogenic variants in the
gene, encoding a multidomain inhibitor of Ras activity. Thus, NF1 is considered a RASopathy and drugs ...targeting the RAS/mitogen-activated protein kinase (MAPK) pathway, such as the MAP kinase (MEK) 1/2 inhibitor Selumetinib, are promising therapeutic options to treat NF1-associated tumors, especially plexiform neurofibromas and optic way gliomas. However, surgical treatment is often required for NF1-related cerebrovascular manifestations, such as moyamoya syndrome (MMS). We report a case of an 8-year-old patient receiving Selumetinib at the dose of 25 mg/m2 orally 2 times a day as a treatment for many plexiform neurofibromas. He suffered from two close strokes and brain MRI revealed a severe cerebral vasculopathy consistent with MMS, with marked stenosis of both the internal carotid arteries. A two-step surgical revascularization procedure was performed, consisting of a direct by-pass with an encephalo-mio-synangiosis (EMS) followed by encephalo-duro-arterio-synangiosis (EDAS). Surprisingly, despite the surgical technical success, follow-up MRI revealed lack of the expected revascularization. Selumetinib is a powerful therapeutic option in the treatment of severe NF1-related tumors. However, our findings suggest that this drug may interfere with cerebral neovascularization in patients with MMS requiring surgical revascularization. This is supported by the crucial role of the Vascular-Endothelial Growth Factor (VEGF), whose signaling pathway involve MAPK, as promoter of the neovascularization. Our observations suggest to adopt an imaging surveillance strategy to prevent unfavorable surgical outcome in patients with NF1-associated MMS receiving Selumetinib, and that priority should be given to surgical revascularization.
The wild‐type alleles of a control individual (CT) are also showed. (c) Partial sequence of RT‐PCR products generated by the RNF213 c.1471+1dupG of the patient (PT) and by the wild‐type allele (CT) ...showing the breakpoint of junction between the first 82 bps of exon 8 and the first bases of exon 9 causing by the intronic variant. (d) Schematic representation of the alternative splicing of RNF213 c.1471+1dupG variant. Of note, our patient was first diagnosed with NF1 based on her clinical features, but genetic testing revealed the correct diagnosis of Legius syndrome. Since NF1 and Legius syndrome share common cutaneous manifestations, namely café‐au‐lait spots and skinfold freckling, the differential diagnosis between these two conditions can be difficult. According to the current NIH criteria (Neurofibromatosis., 1988), skin features are particularly relevant for a diagnosis of NF1. SPRED1 protein plays instead a relevant role in inhibiting endothelial cell migration and proliferation through an impairment in cell motility and Rho‐mediated actin reorganization (Jansen et al., 2013).
Plaque-type glomuvenous malformations in a child Cavalli, Riccardo, MD; Milani, Gregorio P, Dr; Chelleri, Cristina, MD ...
The Lancet (British edition),
12/2015, Letnik:
386, Številka:
10012
Journal Article
Recenzirano
Musculoskeletal examination was normal, as were blood count, liver enzymes, renal function, and coagulation. The diagnosis of glomuvenous malformation was confirmed by examination of a biopsy sample, ...which showed dilated and irregular vascular channels lined by layers of glomus cells that stained positively for smooth muscle α-actin (figure).
Abstract Legius syndrome, commonly referred to as SPRED1‐related neurofibromatosis type 1‐like syndrome, is a rare autosomal dominant disorder characterized by café‐au‐lait macules, freckling, ...lipomas, macrocephaly, and heterogeneous neurodevelopmental manifestations, including a different degree of learning difficulties. Although a partial clinical overlap exists with neurofibromatosis type 1 (NF1), Legius syndrome is distinguished by its genetic etiology and the absence of neurofibromas, indicating an inherent lack of tumor risk. The SPRED1 gene encodes the Sprouty‐related protein with an EVH1 domain 1 (SPRED1), a negative regulator of the RAS‐MAPK signaling pathway with a crucial role in cellular growth and development. Despite various genetic variants and genomic deletions associated with Legius syndrome, the full genetic spectrum of this condition remains elusive. In this study, we investigated the underlying genetic etiology in a cohort of patients presenting with typical manifestations of Legius syndrome using a custom Next Generation Sequencing (NGS) panel and Multiplex Ligation‐Dependent Probe Amplification (MLPA) for NF1 and SPRED1. We identified 12 novel SPRED1 damaging variants segregating with the phenotype in all families. These rare variants affect conserved residues of the protein and are predicted damaging according to in silico tools. No clear genotype–phenotype correlations could be observed in the current cohort and previously reported patients, underscoring the heterogeneous genotype spectrum of this condition. Our findings expand the understanding of SPRED1 variants causing Legius syndrome and underscore the importance of comprehensively characterizing the genetic landscape of this disorder. Despite the absence of clear genotype–phenotype correlations, elucidating the genetic etiology of Legius syndrome is pertinent for facilitating accurate diagnosis, genetic counseling, and therapeutic interventions.
Acute hemorrhagic edema: Uncommon features Rinoldi, Pietro Olmo; Bronz, Gabriel; Ferrarini, Alessandra ...
Journal of the American Academy of Dermatology,
December 2021, 2021-12-00, 20211201, Letnik:
85, Številka:
6
Journal Article
PDF
