Intraparotid gland neurofibroma is a rare benign tumor that arises from Schwann cells of the facial nerve within the parotid gland. This case report discusses a 41-year-old woman who experienced a painless preauricular swelling on her right side for over 5 years. Clinical examination and ultrasound revealed a well-defined mass in the parotid gland. The patient underwent total mass excision, resulting in transient facial nerve dysfunction but complete recovery. These tumors often manifest as solitary masses in the parotid region and may compress nearby structures, causing facial paralysis or numbness. Their diagnosis can be challenging due to similarities with other parotid gland tumors and possible associations with neurofibromatosis. Managing intraparotid tumors, including neurofibromas, involves a multidisciplinary approach with input from cytopathologists, radiologists, and surgeons.

Tumors develop in an oxidative environment characterized by peroxynitrite production and downstream protein tyrosine (Y) nitration. We showed that tyrosine nitration supports schwannoma cell proliferation and regulates cell metabolism in the inheritable tumor disorder NF2-related Schwannomatosis (NF2-SWN). Here, we identified the chaperone Heat shock protein 90 (Hsp90) as the first nitrated protein that acts as a metabolic switch to promote schwannoma cell proliferation. Doubling the endogenous levels of nitrated Hsp90 in schwannoma cells or supplementing nitrated Hsp90 into normal Schwann cells increased their proliferation. Metabolically, nitration on either Y33 or Y56 conferred Hsp90 distinct functions; nitration at Y33 (Hsp90NY33) down-regulated mitochondrial oxidative phosphorylation, while nitration at Y56 (Hsp90NY56) increased glycolysis by activating the purinergic receptor P2X7 in both schwannoma and normal Schwann cells. Hsp90NY33 and Hsp90NY56 showed differential subcellular and spatial distribution corresponding with their metabolic and proliferative functions in schwannoma three-dimensional cell culture models. Collectively, these results underscore the role of tyrosine nitration as a post-translational modification regulating critical cellular processes. Nitrated proteins, particularly nitrated Hsp90, emerge as a novel category of tumor-directed therapeutic targets.

Congenital pseudarthrosis of the forearm bones (CPFBs) is rare, with only 106 reported cases, and is frequently associated with neurofibromatosis (NF). Approximately 5% of patients with NF develop pseudarthrosis, and 50% of patients with pseudarthrosis have NF. Achieving bone union is difficult in congenital pseudarthrosis. Many methods have been attempted, including casting, internal fixation with or without grafting, and electrical stimulation, but failure is frequent. Free vascularized fibular flaps (FVFs) have been used to bridge long bone defects since 1975 and in tibial pseudarthrosis since 1979. In CPFB, FVF is more successful than other methods in achieving union and is the current treatment of choice. Here, we presented three cases of forearm pseudarthrosis treated with FVF, reviewed the literature on CPFB, and discussed some technical aspects of FVF treatment. Three cases of congenital pseudoarthrosis were treated with free fibula flaps, diagnosed at ages of 7 years (ulna), 15 months (radius), and 9 years (radius and ulna). Two flaps were stabilized with intramedullary wires and latterly, one with compression plates. One persistent nonunion received revision nonvascularized bone grafting and plating. All patients achieved union by 11 months after index surgery. Reconstruction with vascularized fibula is the treatment of choice because it offers the highest published union rates and good functional results. Complete resection of the affected bone and stable fixation, latterly with compression plates are critical to success. Surgery is technically demanding, and complications are common. Secondary surgery may be required, but outcomes are favorable. LEVEL OF EVIDENCE: IV.

The skin manifestations of neurofibromatosis 1 significantly reduce health-related quality-of-life. However, data on the utility of existing surveys in capturing neurofibromatosis 1 skin treatment outcomes are lacking. This quantitative study examined the relationship between clinician-rated severity and visibility and patient-rated itch and quality-of-life (QoL) to (1) establish baseline levels of skin- and condition-specific-related QoL, itch, depression and anxiety; (2) identify patient concerns to inform the development and evaluation of skin interventions; and (3) compare the sensitivity of different QoL measures. Validated scales included Skindex-29, Dermatology Life Quality Index (DLQI), Neurofibromatosis 1-adult quality-of-life (NF1-AdQOL) questionnaire, and the Hospital Anxiety and Depression Scale (HADS). We recruited 100 participants (response rate: 95%). Of these, 42% reported itch and 23% had probable clinical anxiety. Our cohort had higher levels of anxiety and total HADS scores compared to a control population. Using multivariate regression analysis, increasing visibility significantly predicted poorer QoL using the Skindex-29, NF1-AdQOL, and DLQI (p < 0.05); and itch significantly predicted worse QoL in Skindex-29 and NF1-AdQOL (p < 0.05). The highest mean scoring questions in Skindex-29 and NF1-AdQOL concerned worry about worsening skin disease and embarrassment. The highest mean scoring questions in DLQI were regarding itch, pain, and embarrassment. Items asking specifically about cutaneous neurofibromas (cNF) scored higher than comparable skin-specific questions (t-test p value <0.05). In summary, this study provides insights into the factors contributing to impaired QoL, anxiety, and mood in NF1 patients with cutaneous neurofibromas. Key factors identified for use in cNF measures include visibility, itch, anxiety, embarrassment, fears of worsening skin disease, and cNF-specific questions.

OBJECTIVE: Elevated rates of social difficulties are evident for children and adolescents with neurofibromatosis type 1 (NF1) but the effects of social skills interventions have not been investigated for this population. The Program for the Education and Enrichment of Relational Skills (PEERS®), a widely established social skills intervention in autism spectrum disorders with expansion to other conditions, was recently modified to be offered virtually. This study examined the feasibility and acceptability of this telehealth intervention.
METHODS: 27 adolescents with NF1 with social skills difficulties and at least 1 caregiver enrolled in the study. 19 of those participants (Mage = 14.21 years, SD = 1.63; 7 females; 79% White) completed PEERS® via telehealth in a single-arm pilot study. Dropout rates, attendance records, helpfulness of the curriculum topics and caregiver-reported acceptability, including ratings on the Treatment Acceptability Questionnaire, were examined.
RESULTS: Low study drop out (30% of enrolled participants; 14% of participants who began the intervention) and high attendance rates were observed. Caregivers found sessions related to common, everyday interactions most helpful. Adolescents indicated sessions related to having get-togethers and social nuances (e.g., humor) as most helpful. Caregiver ratings indicated acceptability of the intervention.
CONCLUSIONS: This investigation supported the feasibility and acceptability of telehealth PEERS®, a social skills intervention program, among adolescents with NF1 and their caregivers based on attendance patterns as well as appraisal of the curriculum and telehealth modality.

Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.

Neurofibromas are benign peripheral nerve sheath tumors that typically develop within cutaneous nerve branches but can involve major nerves as well. They can be sporadic or associated with neurofibromatosis type 1. In this report, we describe the surgical treatment of a pediatric patient with neurofibromatosis type 1 presenting with a neurofibroma of a bifid median nerve. Involvement of the median nerve was not evident on preoperative examination or imaging, therefore altering the risk-benefit ratio of the procedure. After bifid nerve involvement was identified intraoperatively, the patient\'s parents were counseled on the risks and benefits of surgical excision before resuming the case. Ultimately, the neurofibroma was resected, and the patient experienced no neurological deficits after surgery.

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.

BACKGROUND: Subperiosteal hematoma (SPH) is a rare complication of neurofibromatosis type 1 (NF-1) which can be presented spontaneously or after a minor trauma a painful or painless growing lesion.
METHODS: Here, we presented a 10-year-old boy, a known case of NF-1, who presented with a painless growing leg lesion. The bony wall cystic lesion was suggested based on radiologic and pathologic investigation. During the operation, an SPH was detected and excised completely.
CONCLUSIONS: Consistent with previous reports, our case of subperiosteal hematoma in an NF-1 patient predominantly presented with well-established subperiosteal bone proliferation on plain radiographs, with the hematoma most commonly affecting the tibia.
CONCLUSIONS: The SPH in NF-1 and differentiating it from a malignant transformation should be considered for the rapidly enlarging bony mass.

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