Manifestations Of Neurofibromatosis Research Articles

SAT613 A Novel NF1 Mutation As The Underlying Cause Of Dysmorphic Features And Acromegaly In An Atypical Case Of Neurofibromatosis Type 1

Abstract Disclosure: O. Alsagheir: None. L.A. Alobaid: None. M. Alswailem: None. H. Al-Hindi: None. A.S. Alzahrani: None. Introduction: Neurofibromatosis type 1 is an autosomal dominant disease with an estimated incidence of about 1:2000 cases. It is caused by genetic alterations in the gene NF1 encoding the tumor suppressor gene, neurofibromin. Patients with neurofibromatosis 1 are at an increased risk of a number of benign and malignant tumors including optic nerve gliomas, CNS tumors, malignant peripheral nerve sheath tumors, pheochromocytomas and many others. However, pituitary adenomas have been rarely described in neurofibromatosis type 1 and NF1 mutations have been found rarely in patients without manifestations of neurofibromatosis. In this report, we describe a patient with acromegaly who had some dysmorphic features but no clear skin or other manifestations of neurofibromatosis. He was found to have a deletion mutation in NF1 suggesting that his dysmorphic features and acromegaly are atypical manifestations of a previously undiagnosed neurofibromatosis type 1. Case Description: A 26-year-old-man presented at 18 years of age for evaluation of possible ventricular septal defect, which was ruled out by echocardiography, but he was found to have a subaortic membrane with moderate aortic regurgitation. He was also noticed to have coarse facial and body features which raised the possibility of acromegaly. He didn’t notice any facial changes, change in the size of hands and feet, headache or visual disturbances. In the family history, he reported that a number of his siblings are tall with large body habitus; none of them was evaluated or known to have medical illness. Physical examination: height 184 cm, weight 87 Kg, BMI 25, and BP 117/77 mmHg. He has frontal bossing, large supraorbital ridges, macrognathia, and hoarse deep voice but no skin tags, café au let spots, skin fibromas or freckling. Eye examination was unremarkable. Investigations: IGF-1 415 ng/ml (188-400), random GH 1.09 ng.ml (0.1-1.2). An oral glucose tolerance test showed baseline GH 0.99 increased to 8.05 ng/ml. An MRI of the pituitary gland showed a lobulated sellar and suprasellar heterogeneously enhancing pituitary adenoma. A Gallium 68 PET-CT scan showed an intense focus of uptake at the same location. Whole exome sequencing revealed a heterozygous NF1 mutation (NM_001128147.3: c.1782_*2del). This variant is likely pathogenic according to ACMG criteria. Conclusion: This case illustrates the value of whole exome sequencing for genetic testing in diagnosing atypical dysmorphia and other conditions when the diagnosis is not clear on clinical evaluation or conventional investigations. It also describes a rare association of acromegaly with neurofibromatosis. Presentation: Saturday, June 17, 2023

Relative size of fungiform papillae in patients with neurofibromatosis Type 1

ObjectiveTo explore possible manifestations of neurofibromatosis on the tongue, especially, enlarged papillae fungiformes. According to the literature, enlarged fungiform papillae of the tongue are a very common oral finding in patients with Neurofibromatosis Type 1 (NF1). Materials and MethodsFirstly, photos of 18 NF1 patients’ tongues, taken at different times were compared to rule of possible fluctuating papillae size. Secondly, 60 photos of 60 patients with NF1 were age/sex matched, blinded and compared to 60 photos of 60 healthy patients. Three independent medical doctors rated the photos in regard of the fungiform papillae as smaller/same/larger at two different times. The inter- and intraindividual results were compared.Thirdly, fungiform papillae of 11 NF1 patients were quantitatively measured using the Denver protocol. ResultsThe fungiform papillae showed a stable size. The comparison of the healthy individuals to the NF1 patients suggests that the larger papillae are significantly more frequent in NF1 patients than in age- and gender-matched non-NF1 individuals. The agreement between two ratings of each of the 3 raters at different time points was two moderate and one substantial, the agreement among raters was only fair, since the Fleiss’ Kappa value of all 6 ratings was 0.38. ConclusionAlthough this study confirms that the evaluation of the size of the fungiform papillae by visual inspection only is very subjective, the fungiform papillae in NF1 patients do seem to be enlarged at a statistically significant level. Nonetheless the statistical difference is not distinctive enough to establish this as a diagnostic tool in diagnosing NF1. Clinical RelevanceFacilitating the diagnosis of NF1 is an important factor in finding the correct treatment for these patients. A clinical inspection of the tongue is a simple and non-invasive procedure. This paper addresses the question if an inspection of the tongue, especially the fungiform papillae is a reliable indicator for the diagnosis of NF1.

Neurofibromatosis 1 (von Recklinghausen Disease).

Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. Because of medical progress, molecular testing for NF1 after genetic counseling is now available in Japan. In addition, revised diagnostic criteria for NF1 were proposed by NF1 experts of an international panel in 2021. Because the overall degree of severity and manifestations in each patient are not predictable, age-specific annual monitoring and patient education by a multidisciplinary team are important for the management of NF1. Although treatment of plexiform neurofibroma has been challenging, selumetinib (an oral selective MEK1/2 inhibitor), which targets a pathway downstream of RAS, was approved in 2022 for use in children with inoperable, symptomatic plexiform neurofibromas in Japan. This article summarizes recent progress in diagnosis, clinical characteristics, and treatment of various manifestations of NF1 and proposes the future direction required to resolve unmet needs in patients with NF1 in Japan.

Clinical aspects of Neurofibromatosis type 1 seen in the Department of Dermatology at University Hospital Antananarivo, Madagascar

RésuméIntroductionLa neurofibromatose type 1 (NF1) est une maladie autosomique dominante, à expression multisystémique. Sa prévalence varie selon les pays et peu de données sur la NF1 sont connues à Madagascar.MéthodologieUne étude transversale rétrospective a été réalisée au service de dermatologie du Centre hospitalier universitaire Joseph Raseta Befelatanana d'Antananarivo, Madagascar, sur une période de 6 ans (de janvier 2014 à décembre 2019). Ont été inclus dans cette étude les patients vus en consultation porteurs de NF1 dont le diagnostic a été confirmé et chez lesquels une enquête généalogique a pu être faite.RésultatsVingt-huit cas de neurofibromatose ont été inclus avec un sexe-ratio H/F de 0,87. L’âge moyen était de 24 ans avec des extrêmes de 11 et 54 ans. La tranche d’âge 16-35 ans était la plus touchée. Dix-sept patients présentaient la forme sporadique. Tous les patients présentaient des taches café au lait et des neurofibromes cutanés, 15 patients portaient des nodules iridiens de Lisch. Les difficultés d'apprentissage, l’épilepsie et la scoliose étaient les complications les plus représentées.ConclusionLes manifestations cliniques de la NF1 sont extrêmement variables. Même si les complications systémiques sont rares, le suivi des patients est indispensable.

Malignant spiradenoma in a patient with Recklinghausen syndrome: a potential association

Recklinghausen syndrome or neurofibromatosis type 1(NF1) is a hereditary condition transmitted with a dominant autosomal inheritance pattern. It’s a systemic disorder characterized by involvements of skin, nerves, bone, soft tissues, iris and nervous system. Specifically a mutation of one allele of the oncosoppressor gene NF1 is the cause of the syndrome. Manifestations of neurofibromatosis include: benign tumors like neurofibromas, pheocromocytoma, juvenile xanthogranulomas, Lisch nodules, cafe-au-lait macules and freckles. Neurofibromatosis also correlates with an increased risk for malignant tumors like malignant melanoma, leukemia, brain gliomas. In this manuscript we report the association of NF1 with a malignant spiradenoma. A literature review has been made to investigate a possible correlation between these two entities.

Dural Ectasia in Neurofibromatosis 1: Case Series, Management, and Review.

The natural history and management of dural ectasia in Neurofibromatosis 1 (NF1) is still largely unknown. Dural ectasias are one of the common clinical manifestations of NF1; however, the treatment options for dural ectasias remain unstudied. To investigate the natural history, diagnosis, management, and outcome of the largest case series of patients with NF1-associated dural ectasia to date. Records from our NF1 clinic were reviewed to identify NF1 patients with computed tomography or magnetic resonance imaging evidence of dural ectasia(s) to determine their clinical course. Demographics, symptoms, radiographic and histopathologic findings, treatment, and clinical course were assessed. Thirty-four of 37 patients were managed without surgery. Of the 18 initially asymptomatic patients, 5 (27.8%) progressed to symptoms attributable to a dural ectasia (onset of 2.7% per patient-year). Three patients required surgical intervention because of extraspinal mass effect. All 3 initially improved but had symptom recurrence within 2 yr. Reoperation involved shunt placement for cerebrospinal fluid (CSF) diversion. On imaging review, 26 (76.5%) of the nonsurgical patients harbored an associated nearby plexiform neurofibroma. Pathology of one surgical case revealed dural infiltration by diffuse neurofibroma. Using the largest NF1-associated dural ectasia group to date, we report the first symptom-onset rate for nonsurgical patients. In the few cases requiring surgery for decompression, primary resection, and patching of ectasias failed, subsequently requiring CSF shunting. We demonstrate imaging evidence of nearby plexiform neurofibroma in a majority of cases, which, when combined with histopathology, provides a novel explanation for the formation of dural ectasias.

Various Retinal Vascular Manifestations of Neurofibromatosis-1 in a Single Patient

Objectives: To report an Iranian woman with a variety of retinal vascular manifestations secondary to Neurofibromatosis -1.Case Report: A 49 years old woman known case of Neurofibromatosis-1 (NF-1) presented with decreased vision in her right eye. We found peculiar retinal and choroidal findings. Mild vascular tortuosity and few hard exudates were the prominent finding in right eye fundus examination; however, left eye showed inferior hemi retinal artery macro aneurysm. Fluorescein angiography, revealed multiple bright choroidal nodules in both eyes. Left eye findings were in favor of branch retinal artery occlusion and branch retinal vein occlusion. Discussion: As vascular and microvascular manifestations of NF-1 are being reported recently, further investigational studies for retinal vascular associations in NF-1 patients appears reasonable. Complete ophthalmic examinations in each NF-1 patient seems essential to prevent potential threatening complications of vascular events in these patients.

An update on the central nervous system manifestations of neurofibromatosis type 1.

Neurofibromatosis 1 (NF1) is an autosomal dominant genetic disorder that presents with variable phenotypes as a result of mutations in the neurofibromatosis type 1 (NF1) gene and subsequently, abnormal function of the protein product, neurofibromin. Patients with NF1 are at increased risk for central nervous system (CNS) manifestations including structural, functional, and neoplastic disease. The mechanisms underlying the varied manifestations of NF1 are incompletely understood, but the loss of functional neurofibromin, resulting in sustained activation of the oncoprotein RAS, is responsible for tumorigenesis throughout the body, including the CNS. Much of our understanding of NF1-related CNS manifestations is from a combination of data from animal models and natural history studies of people with NF1 and CNS disease. Data from animal models suggest the importance of both Nf1 mutations and somatic genetic alterations, such as Tp53 loss, for development of neoplasms, as well as the role of the timing of the acquisition of such alterations on the variability of CNS manifestations. A variety of non-neoplastic structural (macrocephaly, hydrocephalus, aqueductal stenosis, and vasculopathy) and functional (epilepsy, impaired cognition, attention deficits, and autism spectrum disorder) abnormalities occur with variable frequency in individuals with NF1. In addition, there is increasing evidence that similar appearing CNS neoplasms in people with and without the NF1 syndrome are due to distinct oncogenic pathways. Gliomas in people with NF1 show alterations in the RAS/MAPK pathway, generally in the absence of BRAF alterations (common to sporadic pilocytic astrocytomas) or IDH or histone H3 mutations (common to diffuse gliomas subsets). A subset of low-grade astrocytomas in these patients remain difficult to classify using standard criteria, and occasionally demonstrate morphologic features resembling subependymal giant cell astrocytomas that afflict patients with tuberous sclerosis complex ("SEGA-like astrocytomas"). There is also emerging evidence that NF1-associated high-grade astrocytomas have frequent co-existing alterations such as ATRX mutations and an alternative lengthening of telomeres (ALT) phenotype responsible for unique biologic properties. Ongoing efforts are seeking to improve diagnostic accuracy for CNS neoplasms in the setting of NF1 versus sporadic tumors. In addition, MEK inhibitors, which act on the RAS/MAPK pathway, continue to be studied as rational targets for the treatment of NF1-associated tumors, including CNS tumors.

Late Onset Segmental Neurofibromatosis (Mosaic Neurofibromatosis Type 1): A Case Report with Review of Literature

Segmental neurofibromatosis (SNF) is a rare manifestation of neurofibromatosis. Very few cases have been reported in older population. Here, we present a case of 73 year old male with four years history of multiple, skin coloured, dome shaped, soft nodules situated over left lumbar region. The histopathological evaluation of the excised nodule revealed neurofibroma. Recognition of this condition is important, as there may be associated systemic involvement, malignancies and possibility of transmission to the offspring.

Unilateral congenital glaucoma may be the earliest presenting sign of orbitofacial neurofibromatosis and intracranial lesions: a case series

Purpose The aim was to report a number of cases initially presenting with unilateral congenital glaucoma within the first year of life that subsequently were found to be associated with the orbitofacial variant of neurofibromatosis-1 (NF1) as well as with variable intracranial lesions. Patients and methods The records of 340 patients presenting with unilateral congenital glaucoma were retrospectively reviewed to identify patients who subsequently developed orbitofacial NF ipsilateral to the glaucoma or other manifestations of NF1. All clinical, radiological, or histopathological data for enucleated globes, if available, were reviewed. Results Seven patients were identified with a mean age at presentation of 4.3±5.4 months. They presented with unilateral buphthalmos and high intraocular pressure with subtle proptosis and/or lid swelling. The mean age at NF1 diagnosis was 23.14±18.5 months. Initial imaging reports were either read as ‘normal’ or described a lesion near the cavernous sinus (CS): CS thrombosis, clival meningioma, histiocytosis, carotid cavernous fistula, or CS hemangioma. Once the diagnosis of NF1 was made, subsequent imaging studies (computed tomography and/or MRI) showed a defect at the greater wing of sphenoid bone (all patients); neurofibroma involving the CS, orbit, and nearby intracranial and subcutaneous structures to varying degrees (all patients); and hamartomas at the level of the basal ganglia (six patients). Associated intracranial lesions were sphenoid wing meningioma, optic nerve glioma, and trigeminal schwannoma. Histopathology of two enucleated eyes showed glaucomatous changes with prominent ciliochoroidal hyperplasia in one case and a ciliary body schwannoma in another. Conclusion In newborns with unilateral congenital glaucoma, the differential diagnosis should include NF1. Targeted radiologic examinations may reveal diagnostic signs and decrease disease morbidity. The glaucoma surgeon may opt for earlier aggressive intervention in this potentially blinding disease.

Spinal Schwannomatosis

Schwannomatosis is a rare tumor syndrome characterized by more than one schwannoma without any evidence of other manifestations of neurofibromatosis (NF). A 32-year-old woman was admitted to our hospital because of weakness in her lower extremities. Neurological examination revealed paraparesis with hypoesthesia below T8 level. Magnetic ressonanceimaging (MRI) showed well-defined masses with strong contrast enhancement at the dorsal and lumbosacral spinal regions. After removal of six tumors compressing the spinal cord, the patient improved rapidly. The histological diagnosis was schwannomas. A detailed clinical examination and MRI scanning of the central nervous system excluded NF2. Not all patients with multiple schwannomas of cranial nerves, spinal nerve roots or peripheral nerves origin have NF-1 or NF-2. Surgery is indicated for symptomatic lesions, while asymptomatic tumors are followed conservatively.

Characterization and utilization of an international neurofibromatosis web-based, patient-entered registry: An observational study.

The neurofibromatoses (neurofibromatosis type 1, neurofibromatosis type 2 and schwannomatosis) are rare disorders having clinical manifestations that vary greatly from patient to patient. The rarity and variability of these disorders has made it challenging for investigators to identify sufficient numbers of patients with particular clinical characteristics or specific germline mutations for participation in interventional studies. Similarly, because the natural history of all types of neurofibromatosis (NF) is variable and unique for each individual, it is difficult to identify meaningful clinical outcome measures for potential therapeutic interventions. In 2012, the Children’s Tumor Foundation created a web-based patient-entered database, the NF Registry, to inform patients of research opportunities for which they fit general eligibility criteria and enable patients to contact investigators who are seeking to enroll patients in approved trials. Registrants were recruited through CTF-affiliated NF clinics and conferences, through its website, and by word-of-mouth and social media. Following online consent, demographic information and details regarding manifestations of NF were solicited on the Registry website. Statistical analyses were performed on data from a cohort of 4680 registrants (the number of registrants as of October 9, 2015) who met diagnostic criteria for one of the 3 NF conditions. The analyses support our hypothesis that patient-reported symptom incidences in the NF Registry are congruent with published clinician-sourced data. Between April 26, 2013 and July 8, 2016, the registry has been useful to investigators in recruitment, particularly for observational trials, especially those for development of patient-reported outcomes.

Clinical severity in Japanese patients with neurofibromatosis 1 based on DNB classification.

Neurofibromatosis 1 (NF1) is a genetic disease characterized by cutaneous, neurological and osseous complications. Although clinical manifestations of NF1 are variable, there has been no report on evaluation of severity in patients with NF1. To elucidate the grade of severity of NF1, a retrospective study was conducted in 124 NF1 patients at the Department of Dermatology of Tottori University Hospital in 2007-2016. The DNB classification (dermatological, neurological and bone manifestations) in Japan was used for assessment. Based on our current epidemiological data, there were 55 patients (44.3%) in stage 1, 23 (18.6%) in stage 2, three (2.4%) in stage 3, one (0.8%) in stage 4 and 42 (33.9%) in stage 5. The grade of severity in patients with NF1 tended to be higher with aging. Remarkably, 61.8% of the patients in stage 5 had diffuse plexiform neurofibromas with functional disability. We should pay attention to diffuse plexiform neurofibromas that greatly affect quality of life in patients with NF1.

Anesthetic management of a parturient with segmental neurofibromatosis

Abstract Segmental neurofibromatosis is a rare, but likely under reported form of neurofibromatosis. The traditional definition is that of dermatologic manifestations of neurofibromatosis, including neurofibromas and cafe-au-lait

Constitutional mismatch repair deficiency syndrome: Do we know it?

Constitutional mismatch repair deficiency syndrome is a rare autosomal recessive syndrome caused by homozygous mutations in mismatch repair genes. This is characterized by the childhood onset of brain tumors, colorectal cancers, cutaneous manifestations of neurofibromatosis-1 like café au lait spots, hematological malignancies, and occasionally other rare malignancies. Here, we would like to present a family in which the sibling had glioblastoma, and the present case had acute lymphoblastic lymphoma and colorectal cancer. We would like to present this case because of its rarity and would add to literature.

Giant Solitary Intramuscular Cystic Plexiform Neurofibroma of the Thigh: A Case Report and Literature Review

Objective: To report a rare occurrence of giant, solitary, cystic, intramuscular plexiform neurofibroma in the thigh. Case Report: A 45-year-old architect presented with a 5-year history of painless, progressively enlarging soft tissue mass in the right thigh, which was diagnosed on histology as cystic plexiform neurofibroma after excision biopsy. Conclusion: A plexiform neurofibroma should be considered in the differentials of a solitary cystic mass in the thigh even in the absence of usual manifestations of Neurofibromatosis.

Schwannoma of the cheek: clinical case and literature review.

Schwannoma is a relatively uncommon benign tumor that apparently originates from Schwann cells of peripheral nerves. The most common intraoral site is the tongue followed by the palate, floor of mouth, buccal mucosa, lips and the jaws. The preoperative diagnosis is often difficult, and in the majority of cases, the diagnosis can only be made during surgery and by histological study. The immunohistochemistry reveals that the schwannoma cells test positive for S-100 protein. The authors report here a case of an intraoral schwannoma situated in the cheek, treated by complete surgical excision. In the present case the schwannoma presented as a slow growing, circumscribed swelling without any particular features to distinguish it from other benign soft-tissue lesions. The final diagnosis was established based on the clinical, histopathologic and immunohistochemical findings. The presence of schwannoma calls for the careful search for nerve tumors in other parts of the body, although in most cases none may be found. The differentiation of schwannoma from neurofibroma is essential, because an apparently solitary neurofibroma may be a manifestation of neurofibromatosis.

PP-199 INTRACORONARY THROMBUS OBSERVED DURING CORONARY ANGIOPLASTY

This is the youngest reported case that underwent the coronary bypass surgery due to spontaneous coronary artery dissection in a patient with neurofibromatosis type 1. Recognition of a possible association between neurofibromatosis and coronary artery dissections will further facilitate successful and prompt management of this otherwise rare entity. The vascular manifestations of neurofibromatosis and the causes of coronary aneurysms are reviewed.

Myocardial infarction in a 17-year-old patient due to neurofibromatosis-associated coronary aneurysm

Neurofibromatosis is an autosomal dominant multi-system genetic disorder. Extra-cardiac vascular manifestations of neurofibromatosis have been previously described in many reports. However, coronary arterial involvements have been rarely described. A 17-year-old girl with neurofibromatosis presented to our institute with subacute myocardial infarction. Coronary angiogram revealed an aneurysm with thrombus in the left anterior descending artery.

Atypical Presentation of a Periocular Neurofibroma

Neurofibromas of the eyelid are a well-recognized manifestation of neurofibromatosis. Several different presentations have been described. The authors present a case of a 52-year-old man with an unusual eyelid neurofibroma that presented as sudden vision loss from obstruction secondary to prolapse of the palpebral conjunctiva.