Manifestations Of Neurofibromatosis Type 1 Research Articles

Expert consensus for full course management of plexiform neurofibroma (2025 edition)

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene, affecting approximately 1 in 3 000 newborns worldwide. Plexiform neurofibroma (PNF) is one of the common clinical manifestations of NF1. PNF can lead to a range of clinical symptoms, with a high rate of disability and teratogenesis; furthermore, there is a risk for malignant transformation that poses significant threats to the life and health of patients. Currently, there is no unified standard regarding the definition, diagnosis, evaluation, monitoring, or treatment strategies for PNF. In order to further standardize the clinical diagnosis and treatment of PNF, initiated by the Group of Neurofibromatosis, Plastic and Reconstructive Surgery Society of Chinese Medical Association, the experts and scholars from various disciplines within the NF1 field across China were organized. Finally, based on existing evidence-based medicine evidence, a total of 18 recommendations have been proposed for the diagnosis, screening, surgical treatment, pharmacological treatment, disease monitoring, as well as patient education and psychological support related to PNF, aiming to serve as a reference for the standardized clinical diagnosis and treatment of PNF.

Investigating therapeutic nonsense suppression in a neurofibromatosis mouse model

Neurofibromatosis type 1 (NF1) is a human genetic disorder caused by variants in the NF1 gene. Plexiform neurofibromas, one of many NF1 manifestations, are benign peripheral nerve sheath tumors occurring in up to 50% of NF1 patients. A substantial fraction of NF1 pathogenetic variants are nonsense mutations, which result in the synthesis of truncated non-functional NF1 protein (neurofibromin). To date, no therapeutics have restored neurofibromin expression or addressed the consequences of this protein's absence in NF1 nonsense mutation patients, but nonsense suppression is a potential approach to the problem. Ataluren is a small molecule drug that has been shown to stimulate functional nonsense codon readthrough in several models of nonsense mutation diseases, as well as in Duchenne muscular dystrophy patients. To test ataluren's potential applicability in nonsense mutation NF1 patients, we evaluated its therapeutic effects using three treatment regimens in a previously established NF1 patient-derived (c.2041C > T; p.Arg681X) nonsense mutation mouse model. Collectively, our experiments indicate that: i) ataluren appeared to slow the growth of neurofibromas and alleviate some paralysis phenotypes, ii) female Nf1-nonsense mutation mice manifested more severe paralysis and neurofibroma phenotypes than male mice, iii) ataluren doses with apparent effectiveness were lower in female mice than in male mice, and iv) age factors also influenced ataluren's effectiveness.

Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.

The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1 manifestations (eg, neurocognitive function, growth reduction, and café-au-lait spots) are unknown. This open-label, phase II trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hours for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22 ± 5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P < .05). Prepubertal patients showed increases in height score and growth velocity (P < .05). Café-au-lait spot intensity decreased significantly (P < .05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. Selumetinib decreases PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in nonmalignant diverse NF1 manifestations. Cris.nih.go.kr Identifier (KCT0003700).

Ophthalmologic Findings in Children with Neurofibromatosis Type 1

ABSTRACT The purpose of this study was to evaluate the ophthalmologic findings in children with neurofibromatosis type 1 (NF1) and compare these findings in eyes with and without optic pathway gliomas (OPGs). We carried out a retrospective chart review of children with NF1. We recorded demographic characteristics, clinical manifestations of disease, and ophthalmologic findings including visual acuity, intraocular pressure, cup-to-disc ratio, visual field testing, and optical coherence tomography findings. Ophthalmologic findings were examined for the cohort for initial and final appointments. These findings were also compared between eyes with and without OPGs. The study included 119 participants with 238 total eyes. The most common clinical manifestations of NF1 in this cohort were café au lait macules (98%), axillary or inguinal freckling (91%), Lisch nodules (66%), and cutaneous neurofibromas (57%). Thirty-seven participants had imaging that allowed evaluation for choroidal abnormalities, and 28 (76%) had choroidal lesions. Twenty-seven participants (23%) had OPGs, and 44 eyes were affected. On initial assessment, eyes with OPGs had worse visual acuity. On final examination, eyes with OPGs were more likely to have a worse visual acuity and a thinner generalised retinal nerve fibre layer (RNFL) thickness, inferior RNFL thickness, and temporal RNFL thickness. This study provides longitudinal follow-up of children affected by NF1 with and without OPGs. Eyes with OPGs were found to be associated with worse visual acuity and thinner RNFLs overall on final testing.

Unilateral gingival enlargement in a patient with neurofibromatosis type 1 - Case report

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal disease caused by mutations in the NF1 tumor suppressor gene. NF1 affects bones, nerves, soft tissues and skin. Oral manifestations of NF1 consist of soft tissue tumors, bone defects, periodontal and dental changes, and altered salivary flow. We report one such case, a 26-year-old man with Gingival enlargement, Café au lait spots, axillary freckling, and multiple nodules on his body.

Prospects for diagnostics and treatment of neurofibromatosis type 1 in Russia

Purpose of the study. Analysis of available data on modern methods of diagnosis and treatment of neurofibromatosis type 1 (NF1) and their application in the Russian Federation. Material and Methods. The search for relevant sources was carried out in the Scopus, Web of Science, PubMed, Elibrary systems, including publications from February 1992 to December 2022. Of the 1873 scientific articles found, 48 were used to write a systematic review. Results. Neurofibromatosis type 1 (NF1) is caused by germline heterozygous mutations in the NF1 gene, which encodes the neurofibromin protein, which suppresses mitogen-activated signaling pathways necessary for cell proliferation. Clinical manifestations of NF1 are similar to Peutz–Jeghers, Laugier–Hunziker, Rusalkab–Muret–Smith, Bannayan–Zonnana, LEOPARD syndromes, neurofibromatosis type 2 and lipomatosis; therefore, to confirm the diagnosis, the most important criterion is the detection of a gene mutation by sequencing, since there are no mutagenesis hotspots in the NF1 gene. To detect 17q11.2 locus microdeletions, MLPA method is used. In Russia, such methods of molecular genetic identification of NF1 were carried out in Moscow and in the Republic of Bashkortostan. Surgical interventions using a neodymium laser and therapy with mitogen-activated protein kinase inhibitors are the most effective for the treatment of tumor syndrome. Scientific results of the use of a surgical laser in the treatment of plexiform neurofibromas and extramedullary tumors of the spinal cord have been published in Russia. Treatment of NF1 with selumetinib in Russia was announced by the interregional public organization for assistance to patients with neurofibromatosis “22/17”, which provides the drug to children with inoperable neurofibromas free of charge. Conclusion. In modern medicine, it is necessary to widely use methods for identifying mutations in the NF1 gene by creating universal panels of targeted sequencing. This will allow not only the differential diagnosis of NF1, but also the identification of the cause of chemoresistance of sporadic malignant neoplasms for the introduction of mitogen-activated protein kinase inhibitors in their treatment. Combination of this method with surgical excision of neurofibromas using a neodymium laser is optimal.

A basket-platform trial for neurofibromatosis type 1: A potential model for rare cancer predisposition syndromes.

e22550 Background: Neurofibromatosis Type 1 (NF1) is a rare hereditary condition that predisposes to the development of a variety of tumors. Variability in disease manifestation, prevalence and severity, in combination with a low prevalence complicates the efficient conduct of clinical trials in NF1. NF1-associated tumors mainly but not exclusively affect the nervous system as well as the skin, and a percentage of those tumors exhibit a significantly increased risk of malignant transformation. There is an urgent need to identify effective treatments for NF1-associated tumors. The development of innovative trial designs that accelerate the ability to assess new investigational agents is essential. The European Patient-Centric Clinical Trial Platforms (EU-PEARL) is an Innovative Medicines Initiative (IMI) project, aiming to create platform trials for diseases with high unmet medical need. As part of EU-PEARL, we designed a basket-platform trial in NF1 that could serve as a prototype for accelerating drug studies in rare cancer predisposition syndromes. Methods: The trial was designed by NF1 experts, a dedicated statistician and a trial designer. Subprotocols were written for previously prioritized manifestations including plexiform neurofibroma, cutaneous neurofibroma, low-grade glioma, and optic pathway glioma. Collaboration with NF1 experts from the USA was sought to ensure alignment with trials for NF1 in the USA. Results: To optimally learn from a small number of potential participants, patients should be able to participate in both an observational and a treatment phase. The observational phase will serve as longitudinal natural history study, providing data that can be used as a comparator for the treatment arms. To enter the treatment phase, patients must meet additional eligibility criteria. Patients will be randomized to a sequence of available drugs, rather than one single drug. This may allow for the addition of newly identified drugs during the course of the trial. If a drug concept fails or unacceptable toxicity arises, patients may re-enter the observational phase or be re-randomized to a different treatment arm if eligible. Drug-specific eligibility criteria and endpoints are listed separately in Intervention-Specific-Appendices (ISAs), allowing flexibility and adaptability that is needed for a highly variable and progressive rare disorder like NF1. This trial design allows optimal learning from a limited number of patients. Conclusions: We designed a basket-platform trial for four manifestations of NF1. This trial design addresses challenges that may be encountered when designing a clinical trial for NF1. This trial will be the future of clinical trials for NF1 in Europe. Its design could serve as a prototype for other rare diseases: it enhances the chances of finding beneficial treatments by optimizing patient inclusion and invigorating international collaborations.

Comprehensive neurological evaluation of a cohort of patients with neurofibromatosis type 1 from a single institution

Neurofibromatosis type 1 (NF1) is a phenotypically heterogenous multisystem cancer predisposition syndrome manifesting in childhood and adolescents. Central nervous system (CNS) manifestations include structural, neurodevelopmental, and neoplastic disease. We aimed to (1) characterize the spectrum of CNS manifestations of NF1 in a paediatric population, (2) explore radiological features in the CNS by image analyses, and (3) correlate genotype with phenotypic expression for those with a genetic diagnosis. We performed a database search in the hospital information system covering the period between January 2017 and December 2020. We evaluated the phenotype by retrospective chart review and imaging analysis. 59 patients were diagnosed with NF1 [median age 10.6 years (range, 1.1-22.6); 31 female] at last follow-up, pathogenic NF1 variants were identified in 26/29. 49/59 patients presented with neurological manifestations including 28 with structural and neurodevelopmental findings, 16 with neurodevelopmental, and 5 with structural findings only. Focal areas of signal intensity (FASI) were identified in 29/39, cerebrovascular anomalies in 4/39. Neurodevelopmental delay was reported in 27/59 patients, learning difficulties in 19/59. Optic pathway gliomas (OPG) were diagnosed in 18/59 patients, 13/59 had low-grade gliomas outside the visual pathways. 12 patients received chemotherapy. Beside the established NF1 microdeletion, neither genotype nor FASI were associated with the neurological phenotype. NF1 was associated with a spectrum of CNS manifestations in at least 83.0% of patients. Regular neuropsychological assessment complementing frequent clinical and ophthalmologic testing for OPG is necessary in the care of each child with NF1.

Neurofibromatosis type 1 system-based manifestations and treatments: a review.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by a mutation in the NF1 gene. This disease presents with various system-based manifestations, including cardiac, musculoskeletal, and neuronal issues, which have been well-studied in previous research and have prompted the development of current and emerging treatments. These treatments, mainly medications targeting specific manifestations of NF1, aim to mitigate the negative impacts of the disease on patients' lives. NF1 is associated with an increased risk of malignancy and a significant decrease in life expectancy. In this paper, we review the current and emerging treatments for NF1 in relation to its system-based manifestations. We conducted an extensive literature search using specific keywords through databases such as PubMed, Scopus, and Cochrane. The articles we found were compiled and subjected to strict inclusion and exclusion criteria. Pharmacological advances have led to the development of products that hold promise as future treatments for NF1. Given the diverse manifestations that can affect multiple organ systems in patients with NF1, it is important to consider a variety of treatment options to achieve optimal results. However, one of the major challenges in diagnosing and treating NF1 is that patients present asymptomatically, making it necessary to rely on clinical features for diagnosis. In conclusion, NF1 is a complex disease with varying manifestations and a growing field of pharmacologic treatments. The information presented in this article synthesizes current knowledge and available therapies for NF1.

Selumetinib in Japanese pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas: An open-label, phase I study.

Plexiform neurofibromas (PN) are a manifestation of neurofibromatosis type 1 (NF1) that may cause morbidity and impact health-related quality of life (HRQoL). Selumetinib (ARRY-142886, AZD6244) is an orally available, selective, mitogen-activated protein kinase kinase 1/2 inhibitor approved for children with NF1 and symptomatic, inoperable PN in regions including the USA (aged ≥2 years), EU (≥3 years), and Japan (≥3 years). This open-label, single-arm, phase I study evaluated selumetinib in Japanese children with NF1 and symptomatic, inoperable PN. Eligible patients (aged 3-18 years) received oral selumetinib (25 mg/m2 twice daily) continuously in 28-day cycles in a fasted state. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, efficacy, PN-related morbidities, and HRQoL. Twelve patients (median age 13.3 years) were enrolled, received ≥1 selumetinib dose (data cutoff: cycle 13 day 1) with median follow-up of 11.5 months. All patients had baseline PN-related morbidities, most commonly disfigurement (91.7%) and pain (58.3%). Most frequently reported any-grade adverse events were dermatologic and gastrointestinal. Objective response rate was 33.3%; median duration of response was not reached. Most patients (83.3%) had target PN volume reduction versus baseline. No patients reported worsening of PN-related morbidities. Selumetinib was rapidly absorbed with moderate-to-high inter-patient variability in maximum plasma concentration and area under the concentration-time curve from time 0-6 hours. Consistent with results of the phase II SPRINT trial, 25 mg/m2 selumetinib twice daily was well tolerated with a manageable safety profile in Japanese children with NF1 and symptomatic, inoperable PN.

Ocular gamut of neurofibromatosis type 1

Background: Neurofibromatosis type 1 (NF1) is a multi-system autosomal dominant disorder affecting 1 in 3000 individuals. The diagnostic criteria of NF1 includes ocular manifestations. Objective: To study the ophthalmic manifestations of neurofibromatosis type 1 and evaluate complications, if any. Methodology: A total of 30 eyes of 15 neurofibromatosis cases presenting to the ophthalmology outpatient department (OPD) underwent a detailed ocular examination, and clinical manifestations in each case were analyzed. Results: Lisch nodules were the most common presentation. Twenty-eight eyes of 14 patients had bilateral and one had unilateral presentation. Six eyes of three patients had ectropion uveae, one eye had plexiform neurofibroma, and one eye had pulsatile proptosis with absence of lesser wing of sphenoid. Other manifestations seen were optic nerve glioma, secondary optic atrophy, closed angles with raised intraocular pressure (IOP), medullated nerve fiber and retinal pigment epithelium (RPE) atrophic changes. Conclusion: This case series represents a spectrum of ocular manifestations of NF1 and highlights the importance of ocular examination and regular follow-up in these patients.

A Review of Spinal Lesions in Neurofibromatosis Type 1 in a Large Neurofibromatosis Type 1 Center

Spinal lesions are a known manifestation of neurofibromatosis type 1 (NF1). The aim of this retrospective review was to analyze and report the prevalence of spinal lesions on imaging in a large NF1 center. The data were collected from a period of 62 months from a cohort of 514 patients. Data were collected from multidisciplinary team meeting reports that included radiologic reports of each patient investigating 20 distinct variables. The prevalence of each of these lesions was calculated, and any statistically significant associations were investigated using the χ2 test. Four-hundred forty-seven patients had classic NF1, and 67 patients had spinal NF1. Many of the patients had spinal abnormalities; 25.7% of these patients were found to have dural ectasia, whereas 44.9% of patients had a spinal deformity. A statistically significant association between dural ectasia and spinal neurofibromatosis was established (P < 0.05). An additional statically significant association was established between dural ectasia and spinal deformity (P < 0.00001). The patients with spinal nerve root tumors were identified, and it was found that 49.8% of patients possessed these tumors, whereas 56.3% of these tumors were intraspinal tumors. The most common region affected was the cervical spine, and the most common spinal level was C2. This high prevalence of spinal tumours in mobile areas of the spine is possibly the result of a combination of genetic predisposition and repeated microtraumas resulting in tumor formation. This is the largest reported study of spinal lesions in NF1 based on imaging and offers insights into the etiology and relationships between lesions.

Spontaneous Pneumothorax: A Rare Complication of Neurofibromatosis Type 1 Associated Diffuse Lung Disease

The visually striking neurocutaneous findings of neurofibromatosis type 1 (NF1) are well recognized and have been well documented throughout scientific literature. While not uncommon, the pulmonary manifestations of NF1 are unknown to many physicians. Complications of NF1 associated diffuse lung disease (NF-DLD) include pulmonary hypertension, pulmonary artery stenosis, subpleural cysts, and spontaneous pneumothorax. We present a case of a 34-year-old male with NF-DLD found incidentally in adolescence with previous apical bleb repair, presenting nearly twenty years later with spontaneous pneumothorax. In NF1 patients with pulmonary complaints, NF-DLD should be assessed with computed tomography (CT) and physicians should be familiar with associated complications.

Hallazgos cutáneos no considerados criterios diagnósticos de la NF1. Estudio de casos y controles

BackgroundThe diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. Patients and methodsCase–control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. ResultsThe prevalence of nevus anemicus (NA) (P<.001) and juvenile xanthogranulomas (JXG) (P<.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% (confidence interval): 95.4–99.96%] and a positive predictive value (PPV) of 98.80% [92.54–99.94%] were estimated for NA and a specificity of 99.27% [95.4–99.96%] and a PPV of 92.86% [64.17–99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (P=.025) and in relation to generalized itching with no other cause (P<.001). ConclusionsNA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated.

Questions on surgical treatment of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome caused by a mutation in tumor suppressor gene NF1. The disease occurs with a frequency of 1:3000 of the population. Typical manifestations of NF1 are multiple cutaneous, subcutaneous and plexiform neurofibromas, which cause serious cosmetic defects in the appearance of patients. Since an effective method for the treatment of NF1 has not yet been introduced into clinical practice, which makes it possible to completely get rid of multiple neoplasms, surgical removal or the use of photodestruction methods remains the method of choice for the treatment of cutaneous and subcutaneous neurofibromas. However, plexiform neurofibromas infiltratively grow into the surrounding tissues, so their complete excision is often impossible. Therefore, surgical excision is indicated for localized forms of plexiform neurofibromas and in emergency situations when they are located near vital structures or in the presence of a mass effect. Moreover, excision of cutaneous and subcutaneous neurofibromas may initiate formation and growth of new tumors. This is due to the degranulation of mast cells in response to tumor damage, since the pathology of the immune system plays an important role in the development of neurofibromas. In order to avoid dissemination of tumors, it is also important to adhere to the principles of antiblastic surgery. Therefore, the most promising is the complex treatment of NF1 with the combined use of a classical approach, surgical laser, ketotifen, and an inhibitor of mitogen-activated kinase. This method can be recommended for the treatment of malignant peripheral nerve sheath tumors, as well as sporadic neoplasms, the resistance of which is caused by a somatic mutation in the NF1 gene. The goal of NF1 treatment is to improve the quality of life of the patient as a whole and reduce pain using an integrated multidisciplinary approach.

Neurofibromatosis from Head to Toe: What the Radiologist Needs to Know.

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.

Neurofibromatosis type 1: A comparison of the 1997 NIH and the 2021 revised diagnostic criteria in 75 children and adolescents

PurposeExamining a cohort of patients suspicious of neurofibromatosis type 1 (NF1) we compared the revised diagnostic criteria with the previous National Institutes of Health (NIH) diagnostic criteria. We asked whether the refinement improved distinguishing between NF1, Legius syndrome, and constitutional mismatch repair deficiency (CMMRD). MethodsA database search in the hospital information system of the University Children’s Hospital Augsburg between 2017 and 2020 ascertained patients with International Classification of Diseases-10 code Q85.0; their clinical phenotype was evaluated by retrospective chart review. ResultsA total of 75 patients were identified (median age 11.0 years [range 1.1-22.6 years]; 35 female). At first suspicion of NF1, 44 patients met the NIH criteria and 56 met the revised diagnostic criteria. In total, 12 patients were diagnosed with NF1 after performing molecular genetic testing. In 31 patients, only pigmentary findings were present, whereas nonpigmentary NF1 manifestations presented with time in 9 patients. In 1 patient a heterozygous variant of uncertain significance was identified in SPRED1. Requirements for CMMRD testing were fulfilled in another patient. A total of 3 patients presented with segmental clinical findings. Three additional patients did not meet the NIH criteria, 1 of them presented with 1 additional feature of CMMRD without fulfilling requirements for testing. ConclusionIn our pediatric cohort, the revised diagnostic criteria discovered more patients with proven NF1 than the NIH criteria.

Progress in diagnosis and treatment of neurofibromatosis in children

Neurofibromatosis type 1（NF1） is an autosomal dominant genetic disease in which a mutation in the NF1 gene on chromosome 17q11.2 results in inactivation or down-regulation of neurofibromin. This results in a series of neurocutaneous lesions characterized by neurofibromatosis. Patients with plexiform neurofibromas（PN）, as one of the main manifestations of NF1, often experience pain, dysfunction, skeletal deformities, changes in appearance and other symptoms. In severe cases, compression of the airways and vital organs occurs, and the PN is at risk of malignancy progression. At present, its treatment is still challenging. Surgery is the primary treatment for PN, but complete resection is often difficult. In recent years, chemotherapy for PN has become a hot topic. This article reviews the research progress in the pathogenesis, diagnosis and treatment of PN in recent years.

Cutaneous Manifestations not Considered Diagnostic Criteria for Neurofibromatosis Type 1. A Case–Control Study

BackgroundThe diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. Patients and methodsCase–control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. ResultsThe prevalence of nevus anemicus (NA) (p<0.001) and juvenile xanthogranulomas (JXG) (p<0.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% [confidence interval (CI): 95.4–99.96%] and a positive predictive value (PPV) of 98.80% [92.54–99.94%] were estimated for NA and a specificity of 99.27% [95.4–99.96%] and a PPV of 92.86% [64.17–99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (p 0.025) and in relation to generalized itching with no other cause (p<0.001). ConclusionsNA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated.

Visual processing difficulties in children with NF1. A common but not widely recognized underlying cause of reading difficulties

Neurofibromatosis type 1 (NF1) is one of the most frequent multi-systemic autosomal dominant rare genetic disorder with an incidence as high as 1/2000 and prevalence of 1/3000 births. NF1 is caused by pathogenic variants of the NF1 gene located on chromosome 17q11.2 [ [1] Ottenhoff M.J. Rietman A.B. Mous S.E. Plasschaert E. Gawehns D. Brems H. Oostenbrink R. Van Minkelen R. Nellist M. Schorry E. Legius E. Moll H.A. Elgersma Y. Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1. Genet. Med. 2020; 22: 889-897https://doi.org/10.1038/s41436-020-0752-2 Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar ]. Of the affected individuals, 50% have a sporadic disease which causes challenges for early diagnosis. Up to 80% of children aged 6–18 years with NF1 present with moderate to severe impairment in one or more areas of cognitive functioning, and they are among the most important NF1 manifestations during school age [ [2] Johansson E. Kallionpää Böckerman P. Peltonen J. Peltonen S. A rare disease and education: neurofibriomatosis type 1 decreases educational attainment. Clin. Genet. 2021; 99: 529-539 Crossref PubMed Scopus (6) Google Scholar , [3] Van der Vaart T. Plasschaert E. Rietman A.B. Renard M. Oostenbrink R. Vogels A. de Wit M.C.Y. Descheemaeker M. Vergouwe Y. Catsman-Berrevoets C.E. Legius E. Elgersma Y. Moll H.A. Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial. Lancet Neurol. 2013; 12: 1076-1083 Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar ]. The average intelligence quotient (IQ) is 10–15 points lower in these children than in population or sibling control groups. Learning disabilities in reading, writing and mathematics have been reported in about 50% of children [ [2] Johansson E. Kallionpää Böckerman P. Peltonen J. Peltonen S. A rare disease and education: neurofibriomatosis type 1 decreases educational attainment. Clin. Genet. 2021; 99: 529-539 Crossref PubMed Scopus (6) Google Scholar ]. Furthermore, achievements may be undermined by attention-deficit–hyperactivity disorder (ADHD), difficulties in social functioning associated with autism spectrum disorder (ASD) and motor difficulties [ 2 Johansson E. Kallionpää Böckerman P. Peltonen J. Peltonen S. A rare disease and education: neurofibriomatosis type 1 decreases educational attainment. Clin. Genet. 2021; 99: 529-539 Crossref PubMed Scopus (6) Google Scholar , 3 Van der Vaart T. Plasschaert E. Rietman A.B. Renard M. Oostenbrink R. Vogels A. de Wit M.C.Y. Descheemaeker M. Vergouwe Y. Catsman-Berrevoets C.E. Legius E. Elgersma Y. Moll H.A. Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial. Lancet Neurol. 2013; 12: 1076-1083 Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar , 4 Krab L.C. Aarsen F.K. de Goede-Bolder A. Catsman-Berrevoets C.E. Arts W.F.A. Moll H.A. Elgersma Y. Impact of neurofibromatosis type 1 on school performance. J. Child Neurol. 2008; 23: 1002-1010 Crossref PubMed Scopus (93) Google Scholar ]. Cognitive and behavioural deficits lead to lower academic achievement and loss of quality of life, persisting into adulthood [ [2] Johansson E. Kallionpää Böckerman P. Peltonen J. Peltonen S. A rare disease and education: neurofibriomatosis type 1 decreases educational attainment. Clin. Genet. 2021; 99: 529-539 Crossref PubMed Scopus (6) Google Scholar ]. 40% of children with NF1 need special education and only approximately 10% of children with NF1 do not have any problems with school performance and also do not need remedial teaching [ [4] Krab L.C. Aarsen F.K. de Goede-Bolder A. Catsman-Berrevoets C.E. Arts W.F.A. Moll H.A. Elgersma Y. Impact of neurofibromatosis type 1 on school performance. J. Child Neurol. 2008; 23: 1002-1010 Crossref PubMed Scopus (93) Google Scholar ].