BRIDGING THE GAP: A CONCEPTUAL MODEL FOR TRANSITIONING NF1 PATIENTS FROM PEDIATRIC TO ADULT CARE IN RESOURCE-LIMITED SETTINGS

Radiographic Findings in the Jaws of Patients With Neurofibromatosis 1

Understanding the biological pathways critical for common neurofibromatosis type 1 (NF1) peripheral nerve tumours is essential, as there is a lack of tumour biomarkers, prognostic factors and therapeutics. We used gene expression profiling to define transcriptional changes between primary normal Schwann cells (n = 10), NF1-derived primary benign neurofibroma Schwann cells (NFSCs) (n = 22), malignant peripheral nerve sheath tumour (MPNST) cell lines (n = 13), benign neurofibromas (NF) (n = 26) and MPNST (n = 6). Dermal and plexiform NFs were indistinguishable. A prominent theme in the analysis was aberrant differentiation. NFs repressed gene programs normally active in Schwann cell precursors and immature Schwann cells. MPNST signatures strongly differed; genes up-regulated in sarcomas were significantly enriched for genes activated in neural crest cells. We validated the differential expression of 82 genes including the neural crest transcription factor SOX9 and SOX9 predicted targets. SOX9 immunoreactivity was robust in NF and MPSNT tissue sections and targeting SOX9 – strongly expressed in NF1-related tumours – caused MPNST cell death. SOX9 is a biomarker of NF and MPNST, and possibly a therapeutic target in NF1.

Experimental therapy for neurofibromatosis I shows promise

INTRODUCTION Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder characterized by variable clinical expression and a predisposition to tumor development. Plexiform neurofibromas (PNs), a hallmark and often debilitating feature, contribute significantly to morbidity. This study presents a retrospective, single-center analysis of NF1 patients at King Faisal Specialist Hospital & Research Centre (KFSHRC) in Riyadh, Saudi Arabia, focusing on the distribution of PNs and associated comorbidities. METHODS We retrospectively reviewed the records of all patients diagnosed with NF1 at KFSHRC between 2020 and 2025. Data were extracted from electronic medical records, including demographics, family history, NF1 diagnostic criteria, PN presence and distribution, associated comorbidities, and additional tumor types. RESULTS Fifty-one NF1 patients were identified (28 females, 54.9%; 23 males, 45.1%). The most common clinical features included café-au-lait macules (n = 46, 90.2%) and cutaneous neurofibromas (n = 31, 60.8%), with PNs present in 25 patients (49.0%). Other features included skinfold freckling (33.3%), Lisch nodules (21.6%), skeletal abnormalities (13.7%), and optic pathway gliomas (11.8%). Parental consanguinity was noted in 21.6%, and a family history of NF1 in 60.8%. The mean age at NF1 diagnosis was 4.8 years, with PNs typically emerging by 8.2 years. Among PN patients, 44% had multiple tumors. PN distribution involved the extremities (56%), trunk (48%), head (24%), orbit (24%), neck (20%), face (8%), and other regions (12%). Common comorbidities included headache (13.7%), scoliosis (11.8%), epilepsy (9.8%), visual impairment (9.8%), cognitive delay (3.9%), and malignant peripheral nerve sheath tumors (3.9%). Additional tumors included gliomas (n = 5), schwannomas (n = 3), and rhabdomyosarcoma (n = 1). CONCLUSION This cohort of NF1 patients exhibited a high prevalence of plexiform and cutaneous neurofibromas, along with diverse comorbidities and tumor manifestations. These findings underscore the need for early diagnosis, multidisciplinary management, and sustained surveillance to optimize outcomes in this complex patient population.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a human autosomal dominant disorders that affects approximately 1 in 3,500 individuals worldwide. The most common features of NF1 are pigmentary abnormalities, such as cafe-au-lait macules, skinfold freckling, Lisch nodules and cutaneous and plexiform neurofibromas (PNs). These signs are age-dependent and present high variability in penetrance and expressivity even between affected members of a family. NF1 is the most common cancer predisposing syndrome affecting the nervous system. Glioma is the most common central nervous system neoplasia in NF1 patients: 15-20% NF1 children develop low grade optic gliomas. PNs occur in 30% of NF1 patients in peripheral nervous system. Patients with PNs have a 20-fold higher risk of developing malignant peripheral nerve sheath tumours (MPNSTs) than other NF1 patients. NF1 is caused by mutations in the neurofibromin gene encoding a negative regulator of Ras guanosine triphosphate (GTP)ase proteins: for this reason is considered a tumor suppressor gene. Mutation detection in the NF1 gene is complex, due to the large size of the gene (>350 kb), the presence of pseudogenes, the lack of hot spots, and the great variety of possible mutations. Hence, the clinical and molecular diagnosis of NF1 may be challenging and its fine-tuning is desirable. METHODS: During 2003-2013 NF1 mutation analysis of genomic DNA was performed in 458 patients using the multiplex ligation-dependent probe amplification (MLPA) to look for deletions or insertions located inside the NF1 gene. Subjects who tested negative for MLPA were investigated using denaturing high pressure liquid chromatography (DHPLC) and sequencing DNA. RNA-based cDNA-PCR sequencing was used in a limited group of patients. RESULTS: 299 of 458 patients were diagnosed according to NIH criteria. 54% were children and about 53% of all NF1 patients were found to have sporadic mutations. We identified 197 single mutations and more than 57% were novel. This genetic protocol permitted us to find mutations in 210 of 299 of clinically diagnosed patients (detection rate: 70%). To improve such detection rate we have recently developed a sensitive, integrated genetic protocol using MLPA and RNA-based cDNA-PCR sequencing. This protocol was validated in a cohort of 33 blood samples from NF1 patients with complete NF1 features, identifying the mutations in 30 cases (91% detection rate). CONCLUSIONS: These data suggest that integrated DNA/RNA-based protocols can improve detection rate in patients suspected to have NF1.

Neurofibromatosis type 1 (NF1), a common autosomal dominant neurogenetic disorder affecting 1 in 4000 individuals worldwide, results from functional inactivation of the 17q11.2-located NF1 gene. Plexiform neurofibroma (PNF) is a congenital benign tumour present in 30-50% of NF1 patients, which in about 10-15% of cases, can develop into a malignant peripheral nerve sheath tumour (MPNST). This study aimed to characterise the NF1 germline and somatic mutations associated with such tumours by DNA analysis in 51 PNFs resected from 44 unrelated NF1 patients. Germline mutations were identified in 35 patients, of which 21 were novel. Somatic NF1 mutations were found in 29 PNF DNAs, which included 9 point mutations, 5 being novel, and 20 tumour DNA samples exhibiting, either loss of heterozygosity (LOH) of the NF1 gene region (16 tumours), or complete or partial NF1 gene deletions analyzed by multiplex ligation-dependent probe amplification (MPLA) analysis. The type of NF1 germline mutations detected in patients with PNF were similar to those detected in most NF1 patients. LOH of the NF1 gene region, as identified by marker analysis and/or MLPA, was detected in only 20/29 (69%) PNFs, compared to the >90% LOH previously found in MPNST. This systematic analysis of the NF1 germline and somatic mutations associated with PNF development suggest that in most such tumours neither the NF1 somatic mutation type, nor its gene location, is influenced by the underlying NF1 germline mutation. Evidence for LOH involving the TP53 gene identified in the PNFs is also reported for the first time.

To the editor, Neurofibromas are relatively common benign tumors that are composed of neuromesenchymal cells, including Schwann cells, perineurial cells, fibroblast and mast cells. Multiple neurofibromas are found as part of neurofibromatosis type I (von Recklinghausen's disease) and neurofibromas are evenly distributed over the body surface. However, as a solitary lesion, a neurofibroma is not associated with neurofibromatosis type I and is common in young adults without a gender preference. Neurofibromas have been known to exhibit a predilection for the trunk and head compared to other body surfaces1. However, in 1949 Herzog2 first reported a plantar neurofibroma in a case of von Recklinghausen's disease. It has been thought that neurofibroma rarely occurs on the palm or sole of the hands or feet. Yamamoto et al.3 reported a plantar neurofibroma as a rare case that was not associated with neurofibromatosis type I. There has been a report of a solitary palmar neurofibroma as a rare case4. Other solitary neurofibromas in uncommon sites have been reported on the male breast5 and the subungual area6-10. In order to investigate the commonly affected sites of solitary neurofibromas, we reviewed the medical records of patients diagnosed with solitary neurofibroma between January 2005 and June 2010. There were 8 patients with solitary neurofibroma and these patients were otherwise healthy. The mean age of the patients was 54-years and the disease duration of solitary neurofibromas ranged from several months to several decades (Table 1). None of the patients had a personal or familial history of neurofibromatosis type I or cafe-au-lait patches. The histopathologic examinations, including S100 stains, were done in all cases for making the differential diagnosis. The histopathologic examination showed unencapsulated tumors in the dermis and the tumors were composed of a fine fibrillary lattice of haphazardly arranged slender spindle cells that showed S100 positivity. As was previously known, there was no gender difference. Interestingly, tumors on the palm and sole, which are considered to be uncommon sites of solitary neurofibroma, were observed in each case (Fig. 1A, B). There was also a case of solitary neurofibroma on the lower lip (Fig. 1C). We believe that these results necessitate the investigation of predilection sites of neurofibromas. Fig. 1 (A) A solitary, dome-shaped papule on the right sole in case No. 4. (B) A 0.5×0.5 cm sized, soft, dome-shaped papule on the left palm in case No. 7. (C) An obliquely arranged, 1×3 cm sized, rubbery nodule on the lower lip in case No. 8. ... Table 1 Gender, age, disease duration and locations of solitary neurofibromas (2005~2010) A previous report evaluated the electron microscopic findings of a solitary subungual neurofibroma, and the electron microscopic findings of a solitary neurofibroma on an exceptional location were in no way inconsistent with those of a neurofibroma on the commonly involved sites6. The histologic findings of our patients were also typical for neurofibroma regardless of the body locations of the tumors. Although several cases of solitary neurofibromas on uncommon sites have been reported, we concluded that neither a predilection site of neurofibroma nor an uncommon site exists for solitary neurofibromas. In our study, the mean age of patients with a solitary neurofibroma (54-years-old) was older than the previously reported age of young adults1. The pathogenesis of isolated solitary neurofibromas is still unclear and further studies on solitary neurofibroma with a larger number of cases are needed.

IntroductionPatients with Neurofibromatosis type 1 (NF1) develop plexiform neurofibromas (PNF) and cutaneous neurofibromas. These tumors are a major cause of the patient’s morbidity and mortality. An influence of estrogen and progesterone on tumor growth has been suggested but reports on growth or malignant transformation of tumors during pregnancy remain anecdotal. The purpose of this study was to quantify growth of cutaneous and plexiform neurofibromas in NF1 patients during pregnancy, and to assess the onset of NF1 related symptoms.Material and methodsRetrospectively, 13 mothers with NF1 were included and compared to nullipara, nulligravida, age-matched women with NF1. All women received whole-body magnetic resonance imaging (MRI) before and after pregnancy or after a matched time period. Presence of plexiform and cutaneous neurofibromas was evaluated. PNF were subjected to semi-automated volumetry (MedX). The sum of the longest diameters (SLD) of representative cutaneous neurofibromas was determined for both groups. Clinical symptoms and subjective tumor growth were assessed.ResultsPNF were identified in 12/26 women (46.2%). Follow up showed neither new PNF nor a significant difference in growth rate (median tumor-growth/year: pregnant group—0.38% (IQR -1.1–5.4%) vs control group 3.59% (IQR -2.1–5.5%; P = 0.69). Malignant transformation of PNF was not observed. There was a significant growth of cutaneous neurofibromas in both groups (median SLD increase: pregnant group 17mm; P = 0.0026 / control group 12mm; P = 0.0004) The difference in increase of SLD was not significant (P = 0.48). Singular cutaneous neurofibromas in the pregnant group displayed high levels of tumor growth (>20%/year). NF1-associated symptoms and subjective tumor growth were not significantly increased in pregnant patients.ConclusionsGrowth of plexiform and cutaneous neurofibromas in pregnant patients is not significantly different compared to non-pregnant patients. Cutaneous neurofibromas show a significant increase in growth over time in both, pregnant and non-pregnant patients and NF1 related clinical symptoms do not significantly aggravate during the course of pregnancy.

Background . Neurofibromatosis type 1 (NF1) is a monogenic disease with a wide range of clinical manifestations. NF1 is associated with increased risk of malignant peripheral nerve sheath tumors (MPNST), leukemia, gastrointestinal and breast cancer, rhabdomyosarcoma, carcinoid tumors, and pheochromocytoma. NF1 gene mutations serve as drivers of various sporadic malignancies. the purpose of the study was to evaluate the mechanisms by which epigenetic factors influence the development of NF1 and the potential for their use in diagnosis and treatment. Material and Methods . The search for relevant sources was carried out in Scopus, Web of Science, PubMed, Elibrary, including publications from February 1995 to February 2025. Of the 1432 scientific articles found, 56 were used to write the review. Results . An analysis of scientific literature showed that NF1 mRNA is a target of 13 microRNAs that are also involved in carcinogenesis of sporadic nervous system tumors (miR-9, miR-10b, miR-16, miR-21, miR-27a, miR-27b-3p, miR-34a, miR125a-3p, miR-128-3p, miR-137-3p, miR-147a, miR-193b, miR-204-5p). There is evidence of an evolutionary and functional relationship between NF1 gene and retroelements: the formation of 12 NF1 pseudogenes on 7 different chromosomes with the help of retroelement enzymes, NF1 introns contain Alu and LINE, which are sources of alternative splicing and recombination, and the presence of insertional mutagenesis hot spots in NF1. Conclusion . Genetic studies have not confirmed the role of modifier genes as triggers for the development and progression of tumor syndrome in NF1. However, changes in the expression of specific microRNAs have been identified in the development of cutaneous, subcutaneous, and plexiform neurofibromas, MPNST. This suggests the potential of studying of epigenetic factors in NF1 pathogenesis for targeted therapy. Further studies of the relationship between the NF1 gene and retroelements will identify new treatment options for NF1 and sporadic tumors by addressing the “vicious cycle” described in the relationship between other tumor suppressor genes and retroelements.

Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene NF1. A virtually pathognomonic finding of NF1 is the plexiform neurofibroma (PN), a benign, likely congenital tumor that arises from bi-allelic inactivation of NF1. PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-NF1 genetic contributions to PN pathogenesis, we performed whole-exome sequencing, RNASeq profiling and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time; for example, there was no pain or rapid growth. Deep (~500X) NF1 exon sequencing was also conducted on tumor DNA. Non-NF1 somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline NF1 mutations and found somatic NF1 inactivation in 74% of the PN. One individual with three PNs had different NF1 somatic mutations in each tumor. The median number of somatic mutations per sample, including NF1, was one (range 0-8). NF1 was the only gene that was recurrently somatically inactivated in multiple tumors. Gene Set Enrichment Analysis of transcriptome-wide tumor RNA sequencing identified five significant (FDR<0.01) and seven trending (0.01⩽FDR<0.02) gene sets related to DNA replication, telomere maintenance and elongation, cell cycle progression, signal transduction and cell proliferation. We found no recurrent non-NF1 locus copy-number variation in PN. This is the first multi-sample whole-exome and whole-transcriptome sequencing study of NF1-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of NF1 loss as the driver of PN tumorigenesis.

PRO85 IMPACT OF NEUROFIBROMATOSIS TYPE 1 AND PLEXIFORM NEUROFIBROMAS ON PATIENT-REPORTED HEALTH-RELATED QUALITY OF LIFE

BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic tumor predisposition disorder caused by germline mutations in tumor suppressor NF1. Plexiform neurofibromas (PN) are benign tumors that arise prenatally or early in childhood and affect 30-50% of NF1 population. Somatic inactivation of second copy of NF1 is believed to be primary genetic event leading to PN initiation. NF1 patients have 8-12% lifetime risk of developing malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft tissue sarcoma, often arising from pre-existing PN and atypical NF (ANF). ANF are pre-malignant tumors that often arise within PN and can transform into MPNST. They are distinct from both PN and MPNST clinically and histologically, thus representing an intermediate step in malignant transformation. Several studies identified deletion of the CDKN2A/2B locus as the most frequent genetic event in ANF, however it is not clear whether other genes or pathways play role in PN transformation into ANF and further into MPNST. In this study, we performed genomic analysis of 16 ANF and 4 MPNST matched with normal DNA obtained from 14 and 4 patients, respectively. METHODS: We performed whole exome sequencing and whole transcriptome RNASeq analyses on Illumina Hi-Seq 2500 platform and copy-number variant (CNV) analysis on Illumina HumanOmniExpressExome-8 SNP-arrays. In addition, we performed deep sequencing of NF1 and validation of select mutations on IonTorrent platform. For select tumors we estimated growth rate and metabolic activity by using volumetric MRI and FDG-PET. RESULTS: We identified inactivation of NF1 in the majority of ANF and all MPNST. We also detected CDKN2A/B locus deletion in the majority of ANF and MPNST (heterozygous in ANF and mostly homozygous in MPNST). We determined that PRC2 genes (EED and SUZ12) were mutated in multiple MPNST but never in ANF. We identified a low number of point mutations and small indels in the genomes of ANF (median 1, range 0-4) and somewhat elevated mutation burden in MPNST (median 23, range 18-31), however none of these mutations were recurrent and none of the mutant genes (other than NF1 and CDKN2A) were present in multiple samples. We found 93 CNV per tumor (median) in ANF that constituted ~2% of their genomes. In comparison, we observed 2,249 CNV (median) in MPNST that comprised ~75% of their genomes. We didn’t detect significant correlation between growth rate or metabolic activity and the degree of genomic instability or mutation burden in the tumors, however the size of the sample set was modest. RNAseq data analysis is pending. CONCLUSIONS: It appears that PN-ANF transition is predominantly if not exclusively driven by heterozygous deletion of the CDKN2A/2B locus. Further progression to MPNST likely involves homozygous loss of CDKN2A/B and complete inactivation of the PRC2 complex. Widespread LOH in MPNST may accelerate inactivation of key gatekeepers. Citation Format: Alexander Pemov, Nancy F. Hansen, Rajesh Patidar, Christine Higham, Eva Dombi, Joseph F. Boland, Settara C. Chandrasekharappa, NIH Intramural Sequencing Center, James C. Mullikin, Margaret Wallace, Javed Khan, Eric Legius, Brigitte Widemann, Douglas R. Stewart. Identifying early genetic steps in malignant transformation of neurofibromatosis type 1- associated plexiform neurofibromas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1456. doi:10.1158/1538-7445.AM2017-1456

Neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are autosomal dominant inherited neurocutaneous disorders or phakomatoses secondary to mutations in the NF1 and NF2 tumor suppressor genes, respectively. Although they share a common name, NF1 and NF2 are distinct disorders with a wide range of multisystem manifestations that include benign and malignant tumors. Imaging plays an essential role in diagnosis, surveillance, and management of individuals with NF1 and NF2. Therefore, it is crucial for radiologists to be familiar with the imaging features of NF1 and NF2 to allow prompt diagnosis and appropriate management. Key manifestations of NF1 include café-au-lait macules, axillary or inguinal freckling, neurofibromas or plexiform neurofibromas, optic pathway gliomas, Lisch nodules, and osseous lesions such as sphenoid dysplasia, all of which are considered diagnostic features of NF1. Other manifestations include focal areas of signal intensity in the brain, low-grade gliomas, interstitial lung disease, various abdominopelvic neoplasms, scoliosis, and vascular dysplasia. The various NF1-associated abdominopelvic neoplasms can be categorized by their cellular origin: neurogenic neoplasms, interstitial cells of Cajal neoplasms, neuroendocrine neoplasms, and embryonal neoplasms. Malignant peripheral nerve sheath tumors and intracranial tumors are the leading contributors to mortality in NF1. Classic manifestations of NF2 include schwannomas, meningiomas, and ependymomas. However, NF2 may have shared cutaneous manifestations with NF1. Lifelong multidisciplinary management is critical for patients with either disease. The authors highlight the genetics and molecular pathogenesis, clinical and pathologic features, imaging manifestations, and multidisciplinary management and surveillance of NF1 and NF2. Online supplemental material is available for this article. ©RSNA, 2022.

10042 Background: PNs occur in 30-50% of pediatric patients with NF1, often resulting in debilitating pain and dysfunction. Children with NF1 PN report significantly worse HRQoL than the general population, though real-world evidence is limited. Research is needed to better characterize HRQoL among this patient population in the US. Methods: Patients ages 8-18 years with NF1 PN in the US who were treatment naïve or new users of selumetinib (≤1 month of use) were recruited through the Children’s Tumor Foundation to participate with their caregivers in an online cross-sectional survey in December 2020 and January 2021. Caregivers of similar patients ages 2-7 years also participated. Measures included the Pediatric Quality of Life Inventory (PedsQL; Acute version), EQ-5D-Y, Pain Interference Index (PII), Numeric Rating Scale (NRS-11), and the Patient-Reported Outcomes Measurement Information System (PROMIS) mobility and upper extremity functioning subscales. Patients provided self-reported responses; caregivers provided proxy responses and patient demographic and clinical characteristics. Results: 61 patients and 82 caregivers responded to the survey. Median (range) age of patients was 12.0 (8-14) years, and 53.7% were female. Most were treatment naïve (97.6%), white/Caucasian (85.4%), and had an NF1 and PN diagnosis for &gt; 5 years (80.5% and 68.3%, respectively). On the PedsQL (range: 0-100; higher = better; mean scores typically &gt; 80 among healthy patients), mean patient scores were 50.3 (school functioning), 56.1 (emotional functioning), 60.7 (social functioning), and 63.7 (physical functioning); the mean total score was 58.5.Caregiver-proxy mean scores were similar, ranging from 54.0 for school functioning to 65.0 for physical functioning, with a mean total score of 59.1. On the EQ-5D-Y, more than half of patients reported experiencing “some” or “a lot” of problems with pain or discomfort (65.6%) and with feeling worried, sad or unhappy (62.3%). Among patients with pain in the last 7 days, mean scores on the PII (range: 0-6; higher = more interference) were 3.0 for patients and 2.7 for caregiver proxies. Almost 75% of them reported moderate or severe pain on the NRS-11. Among patients with movement difficulty in the past 7 days, mean t-scores from the PROMIS scales (distribution mean = 50; higher = better) were 40.2 for mobility and 39.5 for upper extremity functioning among patients and 36.0 and 29.1, respectively, among caregivers. Within dyads, patients generally reported better functioning, on average, than their caregiver proxies. Conclusions: The humanistic burden of NF1 PN among this pediatric patient population is substantial, especially regarding pain, emotional functioning, and physical functioning. Results highlight an unmet need to be addressed for improving HRQoL in pediatric patients with NF1 and PN.

Objectives: The objectives of this study were to retrospectively investigate the patient characteristics, treatment patterns, healthcare resource utilization (HCRU), and healthcare costs related to management of neurofibromatosis type 1 (NF1) in Japan. Methods: Cohorts of NF1 patients with or without plexiform neurofibromas (PN) were identified from the Medical Data Vision database in 2008-2019. Baseline characteristics, NF1 medications, HCRU, and associated costs were assessed using descriptive statistics. All-cause HCRU and costs following the first confirmed NF1 diagnosis date were analyzed per patient per year (PPPY) in Japanese Yen (JPY) and United States Dollar (USD). Results: A total of 4,394 NF1 patients without PN and 370 NF1 patients with PN were identified. The mean age was 35.0 and 36.9 years, respectively. The proportion of patients with PN treated with medications was higher than that in patients without PN (except for antirheumatic/immunologic agents). Analgesics/non-steroidal anti-inflammatory drugs were the most frequently prescribed NF1 medications (44.3% and 56.0% in patients without and with PN, respectively), followed by inpatient prescriptions of opioids/opioid-like agents (17.8% and 27.6%, respectively). Inpatient admissions accounted for the highest costs in both cohorts with the average cost PPPY being JPY 2,133,277 (USD 19,861) for patients without PN and JPY 1,052,868 (USD 9,802) for patients with PN. Conclusions: NF1 is treated primarily with supportive care with analgesics/non-steroidal anti-inflammatory drugs being the most frequently prescribed NF1 medications in Japan. Findings underscored the unmet need and substantial economic burden among patients with NF1 and highlighted the need for new treatment options for patients with this disease.