Diagnostic Criteria For Neurofibromatosis Type 1 Research Articles

DRI Triton SS-OCT applied to detect choroidal nodules in paediatric patients affected by NF1

PurposeTo examine whether image processing of non-mydriatic DRI Triton SS-OCT (Topcon Corporation, Tokyo, Japan) using the red free filter could assess the presence of choroidal nodules and thus include their detection as a diagnostic criterion in neurofibromatosis type 1 (NF1). Material and methodsWe included 417 eyes from 210 patients, 377 - from 190 patients diagnosed with NF1 according to the criteria established by the National Institutes of Health Consensus Development Conference (NIH) and 40 from 20 healthy patients as a control group. The mean age was 9.4 years (range 2 years–18 years). All patients had their visual acuity measured by a test according to age, were examined for the presence of lisch nodules and an Optical Coherence Tomography (OCT) of the macular area was performed. All the OCT images were analysed to check if visible nodules could be identified. ResultsAges 14 (95% CI=(9.7,18.3)) and 12 years (95% CI=(9.1,14)) are the cut-off points that best separate those with choroidal nodules with Triton OCT and lisch with slit lamp, respectively, from those without. lisch nodules were detected in 50% of cases of NF1 patients. The presence of choroidal nodules did not present a statistically significant correlation with the occurrence of optic pathway glioma (p = 0.96) nor with the patient's visual worsening (p = 0.072). A statistically significant correlation was observed between the presence of choroidal nodules and the presence of lisch nodules (p < 0.05). ConclusionThe Topcon Triton OCT red free tool would not be a good tool to detect choroidal nodules in patients with NF1 because of its low sensitivity. If the presence of choroidal nodules were to be included in the diagnostic criteria for NF1, it would be convenient to use a device with red and infrared radiations.

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.

The Association of Malignancies with The Clinical Profile of Children with Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF-1) is a significant autosomal dominant disorder with a wide spectrum of clinical findings. These signs (Café au lait spots, bone dysplasia, Lisch nodules) usually start to emerge after the first months of life and most are benign in nature. On the other hand, neoplasms (optic glioma, neurofibroma, malignant peripheral nerve sheath tumor, soft tissue sarcoma, leukemia, breast cancer) are a major cause of morbidity and mortality in NF-1 patients. Cancer risk during the lifetime of an NF-1 patient is almost 10 times more than a person without NF-1, but what drives these patients into cancer is still unknown.&#x0D; This study aims to analyze the possible association of clinical findings with malignancies in children with NF-1.&#x0D; Medical records of 55 children with NF-1 who were followed up in a tertiary care pediatric oncology clinic between January 2005 and December 2014 were analyzed. We assessed clinical and demographic characteristics of patients, as well as the NF-1 diagnostic criteria, NF-1 related complications, and malignancies. The NF-1 patients without malignancy were classified in Group 1 while patients with malignancy were in Group 2. Logistic regression analysis was used to determine the risk factors of malignancy in NF-1.&#x0D; The mean age was 7.68 ± 4.65 years. Female sex was dominant in both groups. Café au lait spots were present in all patients. Axillary-inguinal freckling was observed in 76.4% of patients, followed by neurofibromas in 30.9%, Lisch nodules in 29.1%, bone dysplasia in 14.5%, optic gliomas in 23.6%, and a history of first degree relative with NF-1 in 63.6%. Central nervous system (CNS) tumors were present in 40%. Tumors other than CNS tumors were acute myeloid leukemia and schwannoma. None of the diagnostic criteria was a risk factor for predisposing to malignancy by itself. Having &gt;3 criteria was found to be the risk factor for malignancy in NF-1 (OR:5.891, CI 95%: 1.676-20.705, p=0.006).&#x0D; There are no clearly defined risk factors predicting occurance of malignancies in NF-1 at present. However, we found a higher risk of malignancy association in patients who meet more than 3 diagnostic criteria of NF-1.

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.

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation (S27.002)

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation (S27.002)

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.

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

PurposeBy incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). MethodsWe used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. ResultsWe reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. ConclusionThe revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS. [Display omitted]

Saliva a mirror to oral health in neurofibromatosis type-1 patients

Background Neurofibromatosis (NF) consists of a complex group of syndromes, which occur as a result of inactivation of the various tumor suppressor genes precipitating multiple cutaneous neuromas and schwannomas in the body. Neurofibromatosis type 1 (NF1)/Von Recklinghausen disease/Watson disease affects 1 in 30,000 individuals and is caused by a mutation in the tumor suppressor gene NF1, locus 17 q11.2; this is one of the largest genes in the human genome and is inherited in an autosomal dominant pattern. Case Summary A cross-sectional study was conducted in a family suffering from NF over 3 generations, consisting of 20 members, and those meeting the diagnostic criteria for NF1 according to the National Institutes of Health (Stumpf et al., 1988) were selected. Pedigree analysis, clinical examination, Ramfjord periodontal index, and sialometry were performed for the following parameters: (1) salivary flow rate—whole unstimulated saliva was considered for salivary flow rate, which was measured by asking the patient to spit out saliva into a sterile container and the amount of saliva is quantitatively measured; (2) salivary pH—salivary pH of whole unstimulated saliva was measured by using the pH meter; (3) salivary alpha amylase activity—this was measured by using the starch–saliva–iodine test. Conclusions On clinical examination, all the members of the family showed distinctive osseous lesions at the base of the tongue. Salivary analysis revealed decreased salivary flow rate and increased pH, making the individuals prone to periodontitis caused by decreased clearance and enzymatic activity. Alterations in the salivary glands (acini and ducts) is caused by mutations in the NF1 gene. Neurofibromin is known to play important role in salivary glands cell division and differentiation via the Rho–rock–LIM kinase-2 pathway; hence the defect in neurofibromin results in defective salivary gland cell differentiation, causing nonfunctional cells and making the individual prone to hyposalivation.

TMOD-23. PRECLINICAL DRUG EVALUATION IN A GENETICALLY ENGINEERED MINIPIG MODEL OF NEUROFIBROMATOSIS TYPE 1

Abstract We have employed gene-editing technology to create a Neurofibromatosis Type 1 (NF1) minipig that replicates the broad spectrum of disease that develops in NF1 patients and meets the National Institute of Health’s diagnostic criteria for NF1. The NF1 boars are fertile and the NF1 mutant allele is transmitted at a Mendelian rate with no reduction in fitness of offspring that inherit this allele. To date, we have observed 100% penetrance of café au lait macules, a phenotype that occurs in nearly every NF1 patient, but has never been demonstrated in any other animal model. The NF1 minipig develops cutaneous neurofibromas and optic pathway glioma, that histologically resemble human tumors. Additionally, we have observed other NF1-associated phenotypes including Lisch nodules, tibial dysplasia, white matter decompaction, hypopigmentation, and freckling of the skin. The FDA has emphasized the need for development and testing of new therapies in large animal disease models prior to human studies. Therefore, we have conducted pharmacological studies in our NF1 swine to look at the pharmacokinetic and pharmacodynamic properties MEK inhibitors, currently in clinical trials for NF1. We have demonstrated that oral administration of the MEK inhibitors results in clinically relevant plasma levels of the drug and inhibition of Ras signaling, and that certain MEK inhibitors can cross the blood brain barrier and have a pharmacodynamic effect, suggesting that they may be effective in treating NF1-associated brain tumors. We envision this large animal model of NF1 will become a standard in the evaluation of the safety and efficacy of new drugs prior to Phase I clinical trials. Further, an NF1 minipig may enable researchers to better understand the biological and genetic mechanisms underlying this complex disease, detect NF1-related tumors earlier, identify biomarkers, discover novel drug targets, and test new drugs and combination therapies for safety and efficacy.

Abstract 5311: Establishment of neurofibroma cells and dedifferentiated fat (DFAT) cells from tumor tissues from patients diagnosed with NF1 (Neurofibromatosis type 1)

Abstract Background: The NF1 tumor suppressor gene encodes neurofibromin and is a functional Ras GTPase-activating protein (RasGAP) that negatively regulates the Ras signaling pathway by accelerating the conversion of activated Ras-GTP to inactive Ras-GDP. NF1 gene germline mutations cause various Neurofibromatosis type 1 (NF1) symptoms, including neurofibroma development. We are developing in vitro models that recapitulate the pathological and clinical properties of neurofibromas with the aim of developing therapeutic strategies to treat patients with NF1 gene-deficient tumors. Methods: Neurofibroma cells and dedifferentiated fat (DFAT) cells were established from NF1 patient tumors. Tissue samples were obtained during tumor resection at our hospital from patients who met NIH clinical diagnostic criteria for NF1. Whole-blood specimens were also obtained for gene analysis. All patients provided written informed consent. The institutional review board at our university approved this aspect of our study. Tumor tissues were dissociated in DMEM containing collagenase. The neurofibroma cells at the bottom of the tube and the floating stromal adipocytes were collected separately after centrifugation. To establish DFAT cells, the stromal adipocytes were placed in a culture flask filled with 20% FBS-DMEM, and then the flask was inverted and incubated at 37 °C in a humidified atmosphere of 5% CO2. The stromal adipocytes floated up through the medium and adhered to the ceiling of the flask. After 1 week, the cells were firmly attached to the ceiling and had dedifferentiated. The DFAT cells as well as the neurofibroma cells can be passaged. The DFAT cells exhibited multipotent differentiation abilities into a variety of cell types. Results: We established neurofibroma cells and DFAT cells from NF1-associated neurofibromas. We performed flow cytometry analysis and found that the cells derived from NF1 patients expressed SOX10, S100, and CD90, all of which are expressed in Schwann cells. We identified the NF1 mutations in patients by next-generation sequencing. Peripheral blood specimens from patients 1 and 2 were positive for c.1466A&amp;gt;G, p.Tyr489Cys and c.3213_3214delAA, p.Ser1072Hisfs*16 mutations of NF1, respectively. We also identified NF1 mutations in the cells that we had established from tumors. In the tumor specimen of patient 1, we identified an additional somatic mutation, c.6772C&amp;gt;T, p.Arg2258X of NF1 gene. Conclusions: We established NF1 gene-deficient neurofibroma cells and NF1 gene-deficient DFAT cells from the tumor tissues from NF1 patients with NF1 gene mutations. These cells may well be useful in studying the pathophysiology of NF1 gene-deficient tumors as well as cell-based drug screening to facilitate the development of new treatments. Note: This abstract was not presented at the meeting. Citation Format: Yoshimi Arima, Hiroyuki Nobusue, Shigeki Sakai, Kazuo Kishi, Toshiki Takenouchi, Kenjiro Kosaki, Hideyuki Saya. Establishment of neurofibroma cells and dedifferentiated fat (DFAT) cells from tumor tissues from patients diagnosed with NF1 (Neurofibromatosis type 1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5311.

PP-35 Clinical features and therapeutic options in children with neurofibromatosis 1: a single centre experience

Background Neurofibromatosis type 1 (NF1) is a genet-ic disorder that affects the growth and development of nerve cell tissue, with subsequent development of mul-tiple benign tumours of the nervous system and the skin, as well as the areas of abnormal skin colour and other clin-ical manifestations. Our study aimed to examine the in-cidence of clinical features and diagnostic parameters of NF1, as well as to identify the current therapeutic options. Methods We analysed retrospectively the medical doc-umentation of the patients of the Clinic of Neurology and Psychiatry for Children and Youth in Belgrade, in the peri-od from 2003–2016, fulfilling clinical diagnostic criteria for NF1. In addition to demographic data, the clinical mani-festations were obtained based on diagnostic criteria, ad-ditional clinical manifestations and supplementary diag-nostic tests. In statistical analysis, we used the methods of descriptive statistics, χ² and Mann-Whitney test. In order to identify the current treatment for the NF1, we analysed the recent pharmacological data, as well as the clinical tri-als registered in the ClinicalTrials.gov registry. Results The study group consisted of 65 patients (35 males/30 females) up to 18 years old at the first exam-ination. Multiple cafe au lait spots (patches of tan or light brown skin) were present in all patients (65, 100%). The frequency of axillary and inguinal freckles and Lisch nodules were 70.8% and 61.5%, respectively, while neu-rofibromas (cutaneous, subcutaneous and plexiform) were present in 66.2% of patients. Glioma optic pathway (GOP) was present in 13.2%, pathological findings of visu-al evoked potentials (VEP) were recorded in one third of patients, epilepsy with 10.8% and pathological electroen-cephalographic (EEG) patterns were described at 27.7% patients. Unidentified bright objects (UBO) on the MRI were described in 50.0% of patients, with no statistical dif-ferences regarding to the age of patients (p=0.635). Char-acteristic bone lesions were diagnosed in 27.7% patients, and positive family history was in 63.1%. Mental disorders and learning disabilities were diagnosed in 26.2% of patients. Furthermore, there was no correlation between the appearance of axillary/inguinal spots and Lisch nod-ules regarding to the age of patients (p=0.419; p=0.521, respectively); however, there was a statistically significant correlation between GOP and VEP (p=0.003). The current NF1 treatment includes the symptomatic therapy, includ-ing surgery and chemotherapy, while the specific treat-ment is not available yet. A total of 122 clinical trials were identified in the ClinicalTrials.gov registry; however, there are only few, phase 2, interventional studies in children: with mTOR inhibitors (sirolimus and everolimus) and RAS kinase inhibitor (tapifarnib). Conclusion NF1 is a multi-system disease that requires multidisciplinary approach and monitoring. The wide range of clinical features, inability to predict the severity of features/complications and limited therapeutic options make NF1 management a real clinical challenge. Future directions: to find therapeutic strategies or specific mol-ecule(s) to prevent/treat the harmful NF1 complications.

LATEST DIAGNOSIS OF NEUROPHYBROMATOSIS I TYPE IN 14-YEAR-OLD BOY

The article presents modern views on the problem of hereditary progressive pathology: phakomatosis, including neurofibromatosis as the most common in the population of the neurocutaneous syndrome. The main clinical manifestations, diagnostic criteria for neurofibromatosis type I, are considered. Presented clinical case shows the later diagnosis of neurofibromatosis a child 14 years of age with mental retardation. It shows that this issue is highly relevant, socially significant and requires further study. The above observation makes us pay attention to the necessity of continuity of medical support by doctors of various specialties of this contingent of patients.

Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis.

To determine the specificity of the current clinical diagnostic criteria for neurofibromatosis type 2 (NF2) relative to the requirement for unilateral vestibular schwannoma (VS) and at least 2 other NF2-related tumors. We interrogated our Manchester NF2 database, which contained 205 individuals meeting NF2 criteria who initially presented with a unilateral VS. Of these, 83 (40.7%) went on to develop a contralateral VS. We concentrated our genetic analysis on a group of 70 who initially fulfilled NF2 criteria with a unilateral vestibular schwannoma and at least 2 additional nonintradermal schwannomas. Overall, 5/70 (7%) individuals with unilateral VS and at least 2 other schwannomas had a pathogenic or likely pathogenic LZTR1 mutation. Twenty of the 70 subsequently developed bilateral disease. Of the remaining 50, 5 (10%) had a germline LZTR1 mutation, equivalent to the number (n = 5) with a germline NF2 mutation. The most common etiology for unilateral VS and 2 additional NF2-associated tumors in this cohort was mosaic NF2. Germline LZTR1 and germline NF2 mutations were equally common in our cohort. This indicates that LZTR1 must be considered when making a diagnosis of NF2 in the presence of unilateral VS in individuals without a germline NF2 mutation.

Plexiform Neurofibroma

Plexiform neurofibromas represent an uncommon variant (30%) of neurofibromatosis type 1 (NF-1) in which neurofibromas arise from multiple nerves as bulging and deforming masses involving also connective tissue and skin folds.We report a rare case of a 30-year-old man who presented with a progressive facial deformity that began in early childhood. Skin examination also revealed multiple neurofibromas and café-au-lait macules on the trunk and arms. Histopathological examination on biopsy samples showed overgrowth of peripheral nerve components and connective tissue. Two diagnostic criteria for NF-1 (plexiform variant) were met, the patient did not accept to undergo genetic testing. Craniofacial MRI confirmed the presence of a deforming mass arising from the left side of his face giving homolateral eye dislocation.Surgery is the mainstay of the treatment. However, the patient expressed the preference to avoid surgery and chose to undergo clinical follow-up every 6 months.Diagnosis of plexiform neurofibromas is usually made clinically, especially if classical hallmarks of NF-1 are present. Therapy is surgical, aiming at resecting deforming masses and cancerous tissue when malignant transformation occurs.

Type 1 neurofibromatosis with periodontal manifestations

Neurofibromatosis type 1 (NF1) also known as von Recklinghausen's disease is an autosomal dominant disease transmitted with a high degree of penetrance. The disease is expressed in different forms. NF1 accounts for almost 90% of the cases although nine types have been described to date. We report one such case of a 36-year-old female who presented with multiple nodules on the body. He was diagnosed to have NF1, having satisfied the diagnostic criteria for the same. Oral manifestations can be found in almost 72% of NF1 patients. This case report highlights the clinical features and diagnostic criteria of NF1, the prevalence and the significance of intraoral neurofibromas and the need for the dental practitioner to be aware of this condition.

Neurofibromatosis type 1 (NF1) with an unusually severe phenotype due to digeny for NF1 and ryanodine receptor 1 associated myopathy

We describe a 5-year-old girl with marked hypotonia, poor feeding and reduced facial expression since birth. Congenital myopathy was suspected; muscle biopsy showed unspecific type 1 fibre predominance. The possibility of a ryanodine receptor 1 gene (RYR1)-associated myopathy was considered, but not further investigated. At the age of 2 years, she presented with exophthalmos. Brain MRI revealed optic pathway glioma. On clinical examination, she had six café-au-lait spots, thus fulfilling the diagnostic criteria for neurofibromatosis type 1 (NF1). The hypotonia was then attributed to NF1. At the age of 3 years, she developed scoliosis and had an unusually severe motor delay for NF1, as she was not able to walk independently. Dual pathology was suspected, and muscle MRI showed the typical pattern for RYR1-related myopathy. This was genetically confirmed with the discovery of two heterozygous mutations. NF1 is one of the most frequent genetic diseases in children. RYR1-related myopathy is one of the most frequent causes of congenital myopathy. The combination of these two pathologies has not yet been described. In cases of unusual presentations or clinical course, the possibility of genetic "double trouble" should be considered.

Multiple café au lait spots in familial patients with MAP2K2 mutation

Recent advances in genetic diagnostic technologies have made the classic disease nosology highly complicated. This situation is exemplified by rasopathies, among which neurofibromatosis type 1 and Noonan syndrome represent prototypic entities. The former condition is characterized by multiple café au lait spots and neurofibromas, while the latter is characterized by distinct facial features, webbed neck, congenital heart disease, and a short stature. On rare occasions, the features of both neurofibromatosis and Noonan syndrome co-exist within an individual; such patients are diagnosed as having neurofibromatosis-Noonan syndrome. Here, we report familial patients with multiple café au lait spots and Noonan syndrome-like facial features. A mutation analysis unexpectedly revealed a mutation in MAP2K2 in both the propositus and his mother. The propositus fulfilled the diagnostic criteria for neurofibromatosis type 1, but his mother did not. Their phenotype was not consistent with that of cardio-facio-cutaneous syndrome, which is classically known to be associated with MAP2K2 mutations. The mother of the propositus had cervical cancer at the age of 23 years, consistent with the oncogenic tendency associated with rasopathies. The phenotypic combination of multiple café au lait spots and Noonan syndrome-like facial features suggested a diagnosis of neurofibromatosis-Noonan syndrome. Whether this condition represents a discrete disease entity or a variable expression of neurofibromatosis type 1 has long been debated. The present observation suggests that some perturbation in the RAS/MAPK signaling cascade results in multiple café au lait spots, a key diagnostic phenotype of rasopathies, although the exact mechanism remains to be elucidated.

Jaffe–Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder

"Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1. We performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe-Campanacci syndrome or Jaffe-Campanacci syndrome-related features. We also performed somatic NF1 mutation testing on nonossifying fibromas and giant cell lesions. Pathogenic germline NF1 mutations were identified in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions ("classical" Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe-Campanacci syndrome, nonossifying fibromas, or giant cell lesions. In this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline NF1 mutation, suggesting that many Jaffe-Campanacci syndrome cases may actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.

Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis

BackgroundConsensus clinical diagnostic criteria for neurofibromatosis type I (NF1) include café-au-lait macules and skinfold freckling. The former are frequently the earliest manifestation of NF1, and as such are of particular...

Concomitant Meningioma and Glioma Within the Same Optic Nerve in Neurofibromatosis Type 1

A patient with neurofibromatosis type 1 and the rare finding of concomitant meningioma and optic pathway glioma within the same optic nerve is presented. A 4-year-old boy was admitted to our hospital with right-sided proptosis. He also had numerous café-au-lait macules and axillary freckling on physical exam. According to National Institutes of Health (NIH) criteria, he met the diagnostic criteria for neurofibromatosis type 1. On magnetic resonance imaging (MRI), a mass originating from the right optic nerve sheath with normal appearance of the optic nerve was observed, which was consistent with optic nerve sheath meningioma. Another mass lesion was observed in the prechiasmatic region of the same optic nerve, which was consistent with optic nerve glioma. Two different types of optic pathway tumors in the same optic nerve is an extraordinary case. It is important to recognize imaging findings of these tumors and make correct diagnosis.