Neurofibromatosis Type 1 Patients Research Articles

A Posterior-Anterior Cephalometric Study of Skull Symmetry in Patients With Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome. Bone findings make a significant contribution to the clinical diagnosis of NF1. It has been suggested that there are characteristic skeletal features of the NF1 patients' skull that cause a specific 'NF1 facies'. To test this thesis, skull examinations were carried out on NF1 patients. The posteroanterior (PA) cephalograms of 76 patients with NF1 were analyzed using defined measuring points. Patients with confirmed facial plexiform neurofibromas (PNF) were excluded from the study. A special interest of the investigation was the symmetry of the measuring points defined as the distance to the median sagittal plane. NF1 patients have a slightly larger distance to the Z-plane than controls at the zygomatic arch and mastoid measurement points (p=0.027 and 0.028, respectively). In contrast, the distances of the juga and antegonion measurement points from the horizontal reference plane are larger in the control group (p=0.002 and 0.480, respectively). The transverse development of the midface at the level of the zygomatic arch showed no differences from the control group (p=0.841). The transverse diameter of the skull at the mastoid and juga measurement points is smaller in the NF1 group compared to the control group (p=0.010 and 0.002, respectively). There is a statistically significant left-right (LR) asymmetry of the distances to the median sagittal plane in favor of the left side in the patient group (p=0.002 to 0.037). However, the numerical deviations from the control group are small overall. Considering the natural, biological deviations of cephalometric measurements of the individual from idealized geometric norms, the facial skeleton of NF1 patients is symmetrically developed. It is unlikely that the calculated LR asymmetry of the patients has a visible effect. In comparison to cephalometric values of a normal population, no characteristic facial skeleton of the NF1 patient in the PA projection of the skull can be derived from these findings. Clear asymmetries of the facial skeleton should give rise to further diagnosis to clarify the suspicion of facial PNF.

Blockade of Serotonin 5-HT6 Receptor Constitutive Activity Alleviates Cognitive Deficits in a Preclinical Model of Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT6 receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT6 receptors contribute to increased mTOR activity in the brain of Nf1+/− mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT6 receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1+/− mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT6 receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT6 receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients.

An obstructive tongue neurofibroma

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by multiple manifestations, including the presence of neurofibromas. These benign lesions can potentially affect every site of the body; its location in the head and neck region is not uncommon, but the oral cavity, and specially the tongue, are rarely affected. We aim to present a case of a giant recurrent neurofibroma of the tongue in a NF1 patient, conditiong obstructive symptoms, as well as to ouline its successful treatment with topical mitomycin-C as an adjuvant therapy to surgical ressection. Keywords: neurofibromatosis; neurofibroma; recurrence; airway obstruction.

Impacts of NF1 Gene Mutations and Genetic Modifiers in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disorder that directly affects more than 1 in 3,000 individuals worldwide. It results from mutations of the NF1 gene and shows almost complete penetrance. NF1 patients show high phenotypic variabilities, including cafe-au-lait macules, freckling, or other neoplastic or non-neoplastic features. Understanding the underlying mechanisms of the diversities of clinical symptoms might contribute to the development of personalized healthcare for NF1 patients. Currently, studies have shown that the different types of mutations in the NF1 gene might correlate with this phenomenon. In addition, genetic modifiers are responsible for the different clinical features. In this review, we summarize different genetic mutations of the NF1 gene and related genetic modifiers. More importantly, we focus on the genotype–phenotype correlation. This review suggests a novel aspect to explain the underlying mechanisms of phenotypic heterogeneity of NF1 and provides suggestions for possible novel therapeutic targets to prevent or delay the onset and development of different manifestations of NF1.

Circulating tumor DNA for malignant peripheral nerve sheath tumors in neurofibromatosis type 1.

The leading cause of early death in patients with neurofibromatosis type 1 (NF1) is malignant peripheral nerve sheath tumor (MPNST). The principles of management include early diagnosis, surgical clearance and close monitoring for tumor recurrence. Current methods for diagnosis, detection of residual disease and monitoring tumor burden are inadequate, as clinical and radiological features are non-specific for malignancy in patients with multiple tumors and lack the sensitivity to identify early evidence of malignant transformation or tumor recurrence. Circulating tumor DNA (ctDNA) is a promising tool in cancer management and has the potential to improve the care of patients with NF1. In the following article we summarise the current understanding of the genomic landscape of MPNST, report on the previous literature of ctDNA in MPNST and outline the potential clinical applications for ctDNA in NF1 associated MPNST. Finally, we describe our prospective cohort study protocol investigating the utility of using ctDNA as an early diagnostic tool for MPNSTs in NF1 patients.

The many faces of neurofibromatosis type 1 in the pediatric brain

Background Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome. It is diagnosed based on a group of clinical criteria that were established by the National Institute of Health in 1988, yet, NF1 remains a challenging disorder to diagnose, mainly in the pediatric-age group. Aim The purpose of this study was to highlight the different MRI findings encountered in the brain of NF1 pediatric patients in order to evaluate if some of these findings can be added to the diagnostic criteria of NF1 and to assess the role of MR spectroscopy in differentiating non-neoplastic from tumefactive neoplastic lesions. Patients and methods This study was a single-center retrospective review of available brain MRIs from 40 children with NF1 in the period from June 2018 to January 2020. MRI examinations were done on a 1.5-Tesla MRI scanner. Magnetic resonance spectroscopy (MRS) was done in selected cases to differentiate foci of abnormal signal intensity (FASI) from neoplastic tumefactive lesions and assess the grade of such neoplastic masses. Results The studied group included 23 females (57.5%) and 17 males (42.5%) with mean age of 7.4±4.4 years. The findings encountered in MRI included FASI in all 40 patients (100%), brain neoplastic lesions in 24 patients (52.5%),18 of which were optic pathway gliomas and six were nonoptic gliomas, while five patients (12.5%) showed thickened corpus callosum. MRS was significantly different in tumefactive neoplastic lesions from FASI with elevated choline and reduced N-acetyl aspartate (NAA) in the former. Choline/creatine, NAA/choline, and NAA/creatine ratios were 3.7±0.93, 0.20±0.17, and 0.37±0.06, respectively, in neoplastic lesions compared with 0.74±0.13, 1.5±0.18, and 1.5±0.13, respectively, in FASI. Conclusion Pediatric neuroradiologists should be familiar with the different pathologies encountered within the brain of NF1 patients, not just obvious optic pathway gliomas, but more importantly the underlooked FASI. We recommend that these FASI should be included in the diagnostic criteria for NF1. MRS is also recommended to differentiate questionable tumefactive neoplastic lesions from FASI.

Sudden bilateral lower limb paralysis with dural ectasia in Neurofibromatosis type 1

Abstract Introduction: Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder characterized by pigmented lesions (café-au-lait macules, skinfold freckling, and Lisch nodules), and dermal neurofibromas. In some subjects, NF-1 presents with complications such as brain tumors, skeletal abnormalities, peripheral nerve tumors, and behavioral abnormalities. Patient concerns: We report the case of a 30-year-old man who presented with sudden bilateral lower limb paralysis and acute-onset lower back pain following a fall while rising from a seated position. He denied a history of back pain or muscle weakness before the index event. On examination, the patella and Achilles tendon reflexes were absent bilaterally. The patient presented with a power grade of 0 in all lower limb muscle groups and normal muscle bulk. Diagnosis: Bilateral lower limb paralysis was associated with sensory loss in the T11 dermatome. X-ray, computed tomography, and magnetic resonance imaging (MRI) showed vertebral canal enlargement (dural ectasia) at multiple levels suggestive of a lateral meningocele associated with neurofibromatosis. After repeated MRI studies, herniation of nerve root sleeves was noted, with marked compression of the traversing nerve roots. Notably, there was no evidence of cord compression on either the computed tomography or MRI. The cerebrospinal fluid studies were unremarkable. Interventions: No particular intervention was performed to address specific NF symptoms. In the hospital, the patient received analgesics and antibiotics (gentamicin and cefuroxime) for a urinary tract infection, lactulose for constipation and enoxaparin as anticoagulant prophylaxis. Outcomes: The patient experienced a clinical decline unrelated to his initial symptoms and succumbed to sepsis 6 weeks after admission. The cause of death was not directly linked with NF-1. Conclusion: We report a case of NF-1 with dural ectasia presenting with sudden bilateral lower limb paralysis and lower back pain following mild trauma. Although 70% of dural ectasia cases are associated with NF-1, there are few reports of NF-1 patients with dural ectasia and associated orthopedic complications. Here, we note that dystrophic changes in NF-1 may lead to rapidly aggravating neurological symptoms even after trivial trauma.

Phenotyping spinal abnormalities in patients with Neurofibromatosis type 1 using whole-body MRI

Neurofibromatosis Type 1 (NF1) has been reported to be associated with a variety of spinal abnormalities. The purpose of this study was to quantify the prevalence of spinal abnormalities in a collective of NF1 patients that is representative for the general NF1 population, to associate the co-appearance of spinal abnormalities with both NF1 and clinical symptoms and to investigate if different mutations of the NF1 gene affect the prevalence of these abnormalities. Retrospectively, 275 patients with NF1 and an age- and sex-matched collective of 262 patients were analyzed. The prevalence of spinal abnormalities was recorded. Mutational analysis of the NF1 gene was obtained in 235 NF1 patients. Associations between spinal abnormalities, clinical symptoms and genotype were investigated by binary logistic regression analysis. Prevalence of all spinal abnormalities was higher in NF1 patients than in the control group. Six characteristics of spinal abnormalities were significantly associated with NF1 (all p < 0.05). An influence of scalloping on scoliosis (OR 3.01; p = 0.002); of meningoceles (OR 7.63) and neuroforaminal tumors (OR 2.96) on scalloping, and of dural ectasia on neuroforaminal tumors (OR 1.93) was identified. Backpain and loss of motor function were associated with neuroforaminal tumors, spinal tumors and scalloping of vertebral bodies (all p < 0.05). Specific mutations of the NF1 gene were not relevantly associated with the development of spinal abnormalities. These findings can aid clinicians to improve clinical care of NF1 patients by creating awareness for co-appearences of specific spinal abnormalities and associated symptoms.

Role of the parental NF1 carrier in effects of pharmacological inhibition of anaplastic lymphoma kinase in Neurofibromatosis 1 mutant mice

Neurofibromatosis type 1 (NF1), a genetically determined neurodevelopmental disorder and tumor syndrome, is associated with cognitive impairments, including in executive function and sleep-related problems. Consistent with the human data, NF1 heterozygous (Het) mice show impaired spatial learning and memory in the water maze and extinction of contextual fear memory. It is not clear whether neurological phenotypes might depend on the parental carrier. In this study, we compared the behavioral and cognitive performance of NF1 Het and wild-type litter mates with either the father (PC) or the mother (MC) as the NF1 carrier on a F1 C57BL/66/129SvJ background. The behavioral and cognitive phenotypes and responsiveness to Alk inhibition in heterozygous NF1 offspring depended on whether the parental carrier was maternal or paternal. Alk inhibition (20 mg/kg) increased activity levels during the dark period in NF1 Het PC, but not MC, mice. In the water maze, NF1 Het PC, but not MC, mice showed reduced cognitive flexibility and impaired ability to locate the third hidden platform location, which was improved by Alk inhibition (3.6 mg/kg). Consistent with reduced cognitive flexibility, WT, but not NF1, mice showed better performance in the third than second water maze probe trial. Finally, Alk inhibition (10 mg/kg) increased baseline activity of NF1 MC, but not PC, mice during the fear conditioning test. Thus, the effective dose depends on the behavioral test and genotype but indicates that in NF1 patients cognitive flexibility might be particularly sensitive to Alk inhibition.

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.

Multiple jejunal gastrointestinal stromal tumors and Neurofibromatosis type 1: A rare association.

Introduction and importanceThe association between gastrointestinal stromal tumor (GIST), mesenchymal tumor arising from the interstitial cells of cajal and Neurofibromatosis type 1 (NF1), an autosomal dominant disease has been reported in the literature. GIST in NF1 patients are multiple and located in the small intestine. Tumorigenesis in NF1 associated GIST is different to that of sporadic GIST and hence the treatment. Here we report a rare case of an NF1 patient with multiple jejunal GISTs.Case presentationWe here present a rare case of a 57-year-old male diagnosed with NF1 30 years back, presented in our emergency department with complaints of black, tarry stools later diagnosed to have multiple GIST in jejunum. Contrast enhanced computed tomography (CECT) of the abdomen showed a large 10.1 × 7.33 × 6.2 cm heterogeneous, exophytic, solid mass with cystic areas originating from the jejunum. The microscopic examination of the specimen showed spindle shaped tumor cells while immunohistochemistry showed CD117 (c-KIT) and DOG-1 positivity. The primary treatment was complete surgical excision of the tumor.Clinical discussionThe incidence of GISTs in NF1 patient is around 6–7%; however, concomitant presence of multiple GISTs is rare. CECT of abdomen along with histopathological and immunohistochemistry studies are diagnostic. The management of GIST includes surgical and adjuvant therapy methods based on the tumorigenesis and recurrent risk stratification.ConclusionEarly clinical suspicion and imaging aids in early detection of the tumor in patients with NF1 presenting with gastrointestinal symptoms. Postoperatively, screening for recurrence with radiology is of utmost importance.

Optical coherence tomography angiography of choroidal nodules in neurofibromatosis type-1: A case series.

To describe optical coherence tomography angiography (OCTA) findings in the retina and choroid of patients with neurofibromatosis type 1 (NF1). We describe a series of four patients diagnosed with NF1 and choroidal nodules who underwent a comprehensive ophthalmic evaluation including a retinal multimodal imaging study based on retinography, near-infrared reflectance imaging (NIR), enhanced depth imaging (EDI) optical coherence tomography (OCT) and OCTA. Patients were three women and one man aged 36-47 years. In all patients, the choroidal nodules were not visible in retinographies but easily detectable with NIR, appearing as multiple bright patches. On OCTA, we observed reduced vessel density in the choriocapillaris in zones where choroidal nodules appeared in OCT images. In one patient, a corkscrew vessel was visible in the superficial capillary plexus. Choriocapillaris vessel density was reduced in zones where choroidal nodules occur in NF1 patients. Further work is needed to clarify the clinical relevance of this finding.

Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis.

SUMMARYNeurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T>C, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1.

Severe Phenotype in Patients with Large Deletions of NF1.

Simple SummaryNeurofibromatosis type 1 (NF1) is a genetic disorder caused by pathogenic variants in the NF1 tumor suppressor gene. In 5–10% of NF1 patients, a large heterozygous deletion of the whole NF1 gene is identified, leading to the commonly called “NF1 microdeletion syndrome”. NF1-deleted patients were previously reported to develop a particularly severe form of the disease with frequent cognitive impairment and an increased risk of benign and malignant tumors. Here, we performed a comprehensive clinical assessment of the largest NF1-deleted cohort to date, including 126 NF1 patients with a deletion of the NF1 gene. This work provides new insights into the specific phenotype associated with NF1 deletions and may contribute to improve the follow-up care of NF1 patients. Complete deletion of the NF1 gene is identified in 5–10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the NF1 locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. NF1-deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed versus an NF1 reference population. A deletion of the NF1 gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of NF1-deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described “classic” NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the NF1-deleted group. We described the largest NF1-deleted cohort to date and clarified the more severe phenotype observed in these patients.

Establishment of in-hospital clinical network for patients with neurofibromatosis type 1 in Nagoya University Hospital

Neurofibromatosis type 1 (NF1) is a genetic multisystem disorder. Clinicians must be aware of the diverse clinical features of this disorder in order to provide optimal care for it. We have set up an NF1 in-hospital medical care network of specialists regardless of patient age, launching a multidisciplinary approach to the disease for the first time in Japan. From January 2014 to December 2020, 246 patients were enrolled in the NF1 patient list and medical records. Mean age was 26.0 years ranging from 3 months to 80 years. The number of patients was higher as age at first visit was lower. There were 107 males (41%) and 139 females. After 2011, the number of patients has increased since the year when the medical care network was started. Regarding orthopedic signs, scoliosis was present in 60 cases (26%), and bone abnormalities in the upper arm, forearm, and tibia in 8 cases (3.5%). Neurofibromas other than cutaneous neurofibromas were present in 90 cases (39%), and MPNST in 17 cases (7.4%). We launched a multidisciplinary NF1 clinic system for the first time in Japan. For patients with NF1, which is a hereditary and systemic disease associated with a high incidence of malignant tumors, it will be of great benefit when the number of such clinics in Japan and the rest of Asia is increased.

Renal manifestations in children with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal-dominant neurocutaneous syndrome affecting various parts of the body, including the renovascular and urinary systems. We evaluated the renovascular, urinary, glomerular, and tubular functions of children with NF1. We compared blood pressures, urinary findings, and renal glomerular and tubular functions in children with NF1 with those of a healthy age- and gender-matched control group. We evaluated 46 NF1 patients and 33 healthy controls. The mean ages of the NF1 group (female/male: 20/26) and the control group (female/male: 15/18) were 10.1 ± 4.6 and 10.6 ± 4.3 years respectively. Six NF1 patients were hypertensive. The mean blood pressures of the NF1 group were significantly higher than those of the control group. Renal artery stenosis was detected in one NF1 patient. Urinary tract anomalies were evident in 21.7% of NF1 but only 9% of control subjects. The mean estimated glomerular filtration rate (eGFR) of the NF1 group was significantly lower than that of the control group. Six NF1 patients evidenced eGFRs < 90 mL/min. In the NF1 group, tubular phosphorus reabsorption was significantly lower and uric acid excretion significantly higher than in the control group.Conclusion: Hypertension, urinary tract anomalies, and impaired renal function were more common in NF1 patients than healthy controls. Regular blood pressure measurements and evaluation of urinary tract and kidney function are essential for NF1 patients. What is Known: • NF1 is most commonly associated with systemic hypertension due to renal artery vasculopathy and the development of a pheochromocytoma. • Hydronephrosis and bladder involvement have been documented in NF1. What is New: • Renal glomerular and tubular functions may be affected in NF1.

RARE-03 CENTRAL NERVOUS SYSTEM TUMORS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1, A COHORT FROM A NATIONAL PEDIATRIC ONCOLOGY CENTER

Approximately 15% of the children with Neurofibromatosis type 1 (NF1) develop a central nervous system (CNS) tumor, predominantly optic pathway glioma. However, other brain tumor types are also frequent, resulting in a heterogenous population regarding tumor type, symptoms and treatment. Even though many tumors are indolent, clinical deterioration or radiological progression requires surveillance and treatment. Pediatric oncology care in the Netherlands has been centralized into the Princess Máxima Center since June 2018, providing care for the majority of Dutch NF1 CNS tumor patients. This retrospective cohort study describes the course of disease in NF1 patients with a CNS tumor diagnosed between 2005–2020, based on data from patient files. The population consisted of 95 patients (48 males), median age at diagnosis 4.3 (range 0.8–17.2) and 12.6 (range 2.9–19.9) years at follow up, 27% familiar NF1, mostly nonsense or frameshift mutations. Neurological and/or visual symptoms were present in 64 (67.4%) patients. 63.6% of the tumors was in the optic pathway, 9.1% in the cerebellum. Biopsy in 19/95 revealed 1 ependymoma and 18 low grade glioma, with rarely additional molecular changes besides NF1. Kaplan Meier median PFS was 24 months (range 3–174.5, n=65) in symptomatic presenting patients, 34 months (range 5–165, n=20) in asymptomatic patients with abnormal ophthalmological and/or neurological exam and 67.3 months (range 7–130, n=10) in asymptomatic patients without abnormalities at exam. Treatment was indicated in 53 (55.8%), predominantly chemotherapy (n=49), with substantial toxicity. Carboplatin allergy was seen in 29/44 (65.9%) patients, peripheral neuropathy in 21/46 (45.7%) patients receiving vincristine, and 5/10 patients receiving irinotecan and bevacizumab ended treatment early due to toxicity. In conclusion: analysis of our extensive cohort of NF1 patients with a CNS tumor indicates the relevance of regular screening of NF1 patients without complaints and critical surveillance and systematical documentation of treatment toxicity.

Characterization of Two Loss-of-Function NF1 Variants in Chinese Patients and Potential Molecular Interpretations of Phenotypes.

Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by cafe’-au-lait spots, skinfold freckles, the formation of neurofibromas, skeletal dysplasia, vascular dysplasia, and an increased risk of malignant tumors. In this study, two Chinese NF1 children troubled with bone lesions or hypertension were reported. A de novo NF1 mutation (c.4925T > A/p.V1642E) and a maternally inherited NF1 mutation (c.4883T > A/p.L1628∗) were identified by molecular sequence. According to the ACMG/AMP guidelines, the c.4925T > A was classified as variants of uncertain significance (VOUS) while the c.4883T > A mutation was identified as likely Pathogenic. Further study found that these two NF1 mutants had lost their function to inhibit the Ras/Erk signaling and the proliferation of cells, which could interpretate some phenotypes of these two NF1 patients. We also observed these two NF1 mutants displayed decreased protein stability with increased ubiquitination levels compared with that of wild-type NF1.

Ocular biometric parameters changes and choroidal vascular abnormalities in patients with neurofibromatosis type 1 evaluated by OCT-A.

To analyze ocular biometric parameters alterations of the posterior pole and choroidal abnormalities in patients with neurofibromatosis type 1 (NF1) by adopting multimodal imaging, especially focusing on the role of novel diagnostic devices like swept-source optical coherence tomography angiography (SS-OCTA). In this prospective, case-controlled study, patients with NF1 and age-matched control subjects were quantitatively analyzed by using multimodal imaging. All the subjects underwent confocal scanning laser ophthalmoscopy (SLO), SS-OCT and SS-OCTA examinations. SS-OCT analysis revealed a lower macular retinal nerve fiber layer (RNFL) thickness in patients with NF1 compared with those with suspected NF1 (95.0±15.9 vs 109.7±11.3 μm; P = 0.001) and control subjects (106.8±14.4 μm, P = 0.003). Retinal thickness was significantly lower in NF1 patients compared to those with suspected NF1 (280.7±23.0 vs 304.2±15.3 μm; P < 0.001) and control subjects (298.7±23.8 μm, P = 0.003). The mean vascular flow area of the SCP was significantly higher in patients with NF1 (42.6±2.2%) and suspected NF1 (43.1±2.5%) compared to control subjects (41.0±2.0%; respectively, P = 0.017 and P = 0.002). In the second choroidal layer, the flow area was significantly lower in patients with NF1 compared to control subjects (45.4±4.8 vs 49.0±4.0%,; P = 0.011). Retinal thicknesses alterations and choroidal nodules are described as ocular manifestations in patients with NF1. In addition, OCTA could represent an important novel advanced imaging technique, capable of detecting early altered retinal and choroidal vascular flow area in patients with NF1.

Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth.

Neurofibromatosis type-1 (NF1) patients suffer from cutaneous and subcutaneous neurofibromas (CNF) and large plexiform neurofibromas (PNF). Whole gene deletions of the NF1 gene can cause a more severe phenotype compared to smaller intragenic changes. Two distinct groups of NF1 whole gene deletions are type-1 deletions and atypical deletions. Our aim was to assess volumes and averaged annual growth-rates of CNF and PNF in patients with NF1 whole gene deletions and to compare these with NF1 patients without large deletions of the NF1 gene.We retrospectively evaluated 140 whole-body MR examinations of 38 patients with NF1 whole gene deletions (type-1 group: n = 27/atypical group n = 11) and an age- and sex matched collective of 38 NF1-patients. Age-dependent subgroups were created (0–18 vs >18 years). Sixty-four patients received follow-up MRI examinations (NF1whole gene deletion n = 32/control group n = 32). Whole-body tumor-volumes were semi-automatically assessed (MedX, V3.42). Tumor volumes and averaged annual growth-rates were compared.Median tumor-burden was significantly higher in the type-1 group (418ml; IQR 77 – 950ml, p = 0.012) but not in the atypical group (356ml;IQR 140–1190ml, p = 0.099) when compared to the controls (49ml; IQR 11–691ml). Averaged annual growth rates were significantly higher in both the type-1 group (14%/year; IQR 45–36%/year, p = 0.004) and atypical group (11%/year; IQR 5–23%/year, p = 0.014) compared to the controls (4%/year; IQR1–8%/year). Averaged annual growth rates were significantly higher in pediatric patients with type-1 deletions (21%/year) compared with adult patients (8%/year, p = 0.014) and also compared with pediatric patients without large deletions of the NF1 gene (3.3%/year, p = 0.0015).NF1 whole gene deletions cause a more severe phenotype of NF1 with higher tumor burden and higher growth-rates compared to NF1 patients without large deletions of the NF1 gene. In particular, pediatric patients with type-1 deletions display a pronounced tumor growth.