Histologic correlates of "Choroidal abnormalities" in Neurofibromatosis type 1 (NF1).

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder characterized by proliferation of cells from neural crest origin. The most common manifestations are cutaneous, neurologic, skeletal and ocular. The distinction of NF1 from other syndromes with multiple café-au-lait macules may be difficult in the pediatric age group, and ocular findings, especially Lisch nodules (i.e., melanocytic hamartomas on the irides), are a useful, early diagnostic tool. In recent years, novel ocular manifestations descriptively referred to as "choroidal abnormalities", choroidal "hyperpigmented spots" and "retinal vascular abnormalities" have been recognized in NF1. Choroidal abnormalities (CA) appear as bright patchy nodules that can be best detected with near-infrared ocular coherence tomography imaging (NIR-OCT). Because of their high specificity and sensitivity for NF1, CA have been added as an ocular diagnostic criterion of NF1 as an alternative to Lisch nodules. Although CA are important ocular diagnostic criteria for NF1, the histologic correlates are controversial. We present the postmortem ocular pathology findings of an NF1 patient for whom clinical notes and ocular imaging were available. Findings in this patient included choroidal hyperpigmented spots on funduscopy and retinal vascular abnormalities, both of which have been reported to be closely associated with CA. Histologic examination of the eyes showed multiple clusters of melanocytes of varying sizes in the choroid. Pathologic review of 12 additional postmortem eyes from 6 NF1 patients showed multiple, bilateral choroidal melanocytic aggregates in all eyes. These findings suggest that the CA seen on NIR-OCT and the hyperpigmented spots seen clinically in NF1 patients are manifestations of multifocal choroidal melanocytic clusters, consistent with choroidal melanocytic hamartomas. Lisch nodules, often multiple, were present in all eyes with morphology that differed from the choroidal hamartomas. As such, although CA and Lisch nodules are melanocytic hamartomas, there are clear phenotypical differences in their morphologies.

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

Purpose: To 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 methods: We 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. Results: Ages 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). Conclusion: The 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.

Segmental neurofibromatosis with Lisch nodules.

Neurofibromatosis (NF) is an inherited neuroectodermal abnormality that primarily affects the growth of neural tissues, and Riccardi classified it into eight types. Segmental neurofibromatosis, which is a rare form of neurofibromatosis, is classified as type 5. We report a case for very unusual presentation of segmental NF with unilateral lisch nodules and uncommon sites involving the scalp. Moreover, we could find only one case report of segmental NF with lisch nodules in the literature and could not find any case report involving the scalp.

Novel Variants and Clinical Characteristics of 16 Patients from Southeast Asia with Genetic Variants in Neurofibromin-1.

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders. It is caused by mutations in the neurofibromin-1 gene ( NF1 ) and affects the formation and growth of nerve tissues. More than 3,600 pathogenic variants in the NF1 gene have been identified from patients with most of the germline variants are from the Western populations. We found 16 patients (15 Chinese and 1 Asian Indian) who had heterozygous variants in NF1 through targeted next-generation sequencing. There were 15 different variants: 4 frameshift, 4 nonsense, 5 missense, and 2 splice variants. One nonsense variant and three frameshift variants had never been reported in any population or patient database. Twelve of the 16 patients met the NF1 diagnostic criteria, and each was found to have a pathogenic or likely pathogenic variant. Three different missense variants of unknown significance were discovered in the other four patients who did not meet NF1 diagnostic criteria. Our findings add four novel variants to the list of genetic mutations linked to NF1's various clinical manifestations.

Choroidal Hyperreflective Nodules Detected by Infrared Reflectance Images Are a Diagnostic Criterion for Neurofibromatosis Type 1 Patients Excluding Those with High Myopia.

Neurofibromatosis type 1 (NF1) is one of the central nervous system's most common autosomal dominant conditions. The diagnosis is based on the clinical diagnostic criteria and/or a molecularly confirmed mutation in the NF1 gene. This study investigated the possibility of substantiating choroidal nodules as a diagnostic criterion for the disease, including patients affected with and without high myopia. A cross-sectional study was carried out in 60 eyes of 30 adult patients diagnosed with NF1. A total of 30 healthy individuals of equivalent age and sex served as control. The Spectralis HRA+OCT MultiColor (Heidelberg Engineering GmbH, Heidelberg, Germany) evaluated the presence of choroidal abnormalities with near-infrared reflectance imaging. Secondly, the presence of iridian Lisch nodules was evaluated by slit lamp examination. Near-infrared reflectance imaging showed the presence of choroidal hyperreflective nodules in 83% of the patients diagnosed with NF1, while these choroidal abnormalities were not observed in any control subject. The patients diagnosed with NF1 associated with high myopia were the only ones who did not present the characteristic choroidal disorders. Therefore, when excluding patients diagnosed with high myopia, choroidal nodules were more frequent than Lisch nodules in a statistically significant proportion. Hyperreflective nodules detected by near-infrared reflectance imaging are as regular as Lisch nodules or even significantly more frequent when excluding high myope patients. Our observation of the mutual exclusion of choroidal hyperreflective nodules and high myopia in the NF1 patients seems a novel and interesting remark.

[Lisch nodules: an ophthalmic marker of neurofibromatosis type 1]. / Nodules de Lisch: marqueur ophtalmologique de la neurofibromatose de type 1.

Von Recklinghausen disease or neurofibromatosis type I (NF1) is the most common phacomatosis. It is inherited in an autosomal dominant manner. Lisch nodules are the most common ophthalmic manifestation of NF1. They are reported in 73-95% of cases. We here report the case of a 49-year-old female patient referred for a consultation with an ophthalmologist for routine eye check-up after the onset of the following symptoms: coffee-with-milk colored spots and multiple neurofibromas (A). She reported similar family history. Visual acuity was 10/10 P2 in both eyes. Examination of the anterior segment showed several Lisch nodules in both irises. They were scattered over the entire iris surface and varied in size (B). Fundus examination was unremarkable. CT scan of the brain and the orbit as well as thoracoabdominal CT scan showed no associated lesion. The patient met NIH diagnostic criteria for NF1. Lisch nodules are small brown dome-shaped lesions developing on the surface of the iris, with well-defined edges, embedded in the stroma and lighter than iris pigmentation. Differential diagnosis includes iris mammillations, iris naevi, iris melanoma, iris granulomatous nodules. Unlike skin signs, the presence of multiple Lisch nodules are considered a specific indication of NF1. These nodules may occur in childhood and their prevalence and number increase with age. Thus, periodic eye examinations in subjects with suspected neurofibromatosis type I may help to improve early diagnosis.

Neurofibromatosis 1: A family case series.

Neurofibromatosis type 1 (NF1) or Von Recklinghausen disease comes under a group of multisystem hereditary syndromes called phakomatoses. It presents with skin, ophthalmic, bony, and systemic manifestations. We present a photographically well-documented case series of NF in a family (n = 3). Skin manifestations were present in all the patients. The ophthalmic manifestations were Lisch nodules (100% of eyes), subcutaneous neurofibroma of eyelids (33% of eyes), mechanical ptosis (33% of eyes), and mechanical ectropion (16.5% of eyes). We report the rare occurrence of multiple solitary neurofibromas causing mechanical ptosis and mechanical ectropion.

[Prognostic factors of neurofibromatosis type 1-associated optic pathway gliomas in children]. / Facteurs pronostiques des gliomes des voies optiques associés à la neurofibromatose de type 1 chez les enfants.

INTRODUCTION: Optic pathway glioma (OPG) is a classic complication of neurofibromatosis type 1 (NF1) and can impair visual function in children with this condition. The objective of this study is to describe clinical, paraclinical and prognostic characteristics of OPG associated with NF1. MATERIALS AND METHODS: In this retrospective observational study of children followed for OPG associated with NF1 in a University Hospital, we analyzed the ophthalmological examination, brain and orbital imaging, management and the presence of associated endocrinopathy. RESULTS: We examined 114 children with NF1, of which 26 (22.81%) presented with OPG. Mean ages at diagnosis of NF1 and OPG were 3.83 years and 6.23 years, respectively. Mean visual acuity was 20/24.4 for the worse eye and 20/23.1 for the better eye. The RNFL (retinal nerve fiber layer) was thinner in subjects than in age-matched controls (p <0.0001). Retrochiasmal location of the OPG (DodgeC) was associated with lower binocular visual acuity than other locations and <20/32 (p=0.028); 28.03% of OPG (5 girls and 1 boy) were treated with chemotherapy, and the others were monitored; 19.23% had an associated endocrinopathy. CONCLUSIONS: OPG complicates 22.81% of NF1 cases in our series. Our study shows that retrochiasmal location of the glioma and female sex are poor prognostic factors. It also highlights the important role of OCT, since a decrease in RNFL is statistically associated with the presence of an OPG.

Lisch nodules and iris mammillations in two siblings with familial legius syndrome.

Legius syndrome is characterized by numerous café-au-lait macules and intertriginous freckling, but typically lacks the distinctive tumor manifestations of neurofibromatosis type 1. We report two siblings with Legius syndrome and Lisch nodules illustrating the importance of eye surveillance in these patients.

Plexiform neurofibroma with neurofibromatosis type I/ von Recklinghausen's disease: A rare case report.

INTRODUCTION: Plexiform neurofibroma with neurofibromatosis type 1 (NF1) or Von Recklinghausen's disease is a rare entity and occurs in approximately 5-15% patients. These are slow growing, painless and locally infiltrating tumors. The pattern of inheritance is autosomal dominant and its penetrance is almost complete by 5 years of age. PRESENTATION OF CASE: We hereby report a case of 13 years old boy visited presenting with swelling of right eyelid and forehead. After surgical removal, the tissue was sent for histopathological evaluation. Microscopy revealed an unencapsulated tumor mass comprising of well organized mixture of multiple nerve bundles with interlacing neural tissue in background of spindle shaped cells along with myxoid areas and numerous blood vessels. DISCUSSION: The NF1 gene responsible for the disease is located on chromosome 17 at locus 17q11.2 that codes for the protein neurofibromin. The frequency of neomutations is particularly high and almost half of the cases are sporadic. NF1 is characterized by a wide variability of clinical expressions, even within a given family. Majority of patients can be diagnosed only after thorough physical examination. CONCLUSION: The wide variation of the clinical expression, the tumor risk and the totally unpredictable evolution of the disease impose regular monitoring of NF1 patients. This surveillance is mainly clinical and has to be adapted to the patient's age in order to assure early management of complications.

Neurofibromatosis tipo 1 (nf1): presentación de un caso clínico con variable expresividad fenotípica y revisión de la literatura / Review and presentation of neurofibromatosis type 1 (nf1): clinical case with variable phenotypic exressivity

RESUMEN La neurofibromatosis tipo 1 (NF1) o enfermedad de Von Recklinghausen, es un desorden genético hereditario, que se transmite bajo un patrón autosómico dominante con penetrancia casi del 100%, progresiva, multisistémica con afectación predominante de piel y sistema nervioso. Siendo el más frecuente de los síndromes neurocutáneos. Tiene una incidencia de 1 por cada 3.000 nacimientos a nivel mundial. Las manifestaciones clínico dermatológicas más comunes son: maculas café con leche, nódulos de Lisch y efélides en áreas no foto expuestas. Se reporta el caso de paciente masculino de 8 años de edad, con antecedentes contributorios y rasgos fenotípicos, diagnósticos para la enfermedad.

SUMMARY Neurofibromatosis type 1 (NF1) or Von Recklinghausen disease, is an hereditary genetic disorder with autosomal dominant inheritance and almost 100% of penetrance. Characteristically progressive and multisystemic, with predominant skin and nervous system involvement. It is the most frequent neurocutaneous syndrome with an incidence of 1 per 3,000 births worldwide. Usual skin findings include cafe-au-lait macules, neurofibromas and freckles in non-photo exposed areas. We report the case of an 8-year-old male with a contributory family history and diagnostic phenotypic features for this disease.

Near-infrared imaging: an in vivo, non-invasive diagnostic tool in neurofibromatosis type 1.

PURPOSE: Only a few reports in the literature have investigated the presence of ocular abnormalities in neurofibromatosis type 1 (NF-1) patients. The aim of this study was to evaluate the prevalence of ocular abnormalities in a large population of NF1 patients, focusing on the choroidal changes. METHODS: This study was conducted on 160 consecutive patients with NF1 and 106 sex- and age-matched healthy subjects (control). Each patient underwent a complete ophthalmological examination inclusive of best-corrected visual acuity, intraocular pressure measurement, slit-lamp biomicroscopy, indirect fundus biomicroscopy, and near-infrared reflectance (NIR) retinography by using the spectral domain OCT. Moreover, all patients underwent complete dermatological exam and 1.5-Tesla MRI scan of the brain to assess the presence of optic nerve gliomas. RESULTS: Choroidal abnormalities were detected in 97% of patients, with a positive predictive value of 100% and a negative predictive value of 96.4%. Interestingly, a small number of patients (4/160; 2.5%) showed Lisch nodules without choroidal abnormalities, whereas a larger number of patents (22/160; 13.75%) presented choroidal lesions in absence of Lisch nodules. None of the patients showed the absence of both choroidal lesions and Lisch nodules. The number of choroidal lesions increased with age (r = 0.364, p = 0.0001) and with the severity of pathology (r = 0.23, p = 0.003). Any statistically significant correlation between choroidal lesions, visual acuity, and intraocular pressure was observed. CONCLUSIONS: NIR imaging represents an in vivo, non-invasive, sensitive and reproducible exam to detect choroidal nodules in NF-1 patients, suggesting that choroidal changes may represent an additional diagnostic criteria for NF1.

Ophthalmic manifestations in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a relatively common multisystemic inherited disease and has been extensively studied by multiple disciplines. Although genetic testing and confirmation are available, NF1 remains a clinical diagnosis. Many manifestations of NF1 involve the eye and orbit, and the ophthalmologist, therefore, plays a significant role in the diagnosis and treatment of NF1 patients. Improvements in diagnostic and imaging instruments have provided new insight to study the ophthalmic manifestations of the disease. We provide a comprehensive and up-to-date overview of the ocular and orbital manifestations of NF1.

[Lisch nodule in neurofibromatosis type 1]. / Nodules de lisch dans la neurofibromatose type 1.

Neurofibromatosis type 1 (NF1) or Von Recklinghausen disease manifests as cutaneous café-au-lait spots and neurofibromas. It is one of the most common autosomal dominant genetic diseases. It is extremely variable in its individual manifestation. Cutaneous and neurologic symptoms are the most common manifestations but it can also affect other organs including eyes, bones and other areas. Lisch nodules are the most common ocular manifestations in NF-1. They are asymptomatic small pigmented iris tumors (iris hamartomas) which can help suggest the diagnosis of NF1 as they are characteristic of this disease and mostly occur in adult patients. We report the case of a 45-year old female patient followed for a neurofibromatosis type 1 retained on the presence of multiple cutaneous café-au-lait spots and neurofibromas. Ophthalmologic examination showed visual acuity of 10/10 P3 in both eyes. Biomicroscopic examination showed Lisch nodules of the iris in both eyes (A,B).

Neurofibromatosis: an update of ophthalmic characteristics and applications of optical coherence tomography.

Neurofibromatosis (NF) is a multisystem disorder and tumor predisposition syndrome caused by genetic mutation on chromosome 17-17q11.2 in NF type 1 (NF1), and on chromosome 22-22q12.2 in NF type 2. The disorder is characterized by considerable heterogeneity of clinical expression. NF1 is the form with the most characteristic ocular manifestations. Lisch nodules of the iris are among the well-known diagnostic criteria for the disease. Glaucoma and associated globe enlargement have been described in a significant proportion of patients with NF1 and orbital-facial involvement. Optic nerve glioma may cause strabismus and proptosis, and palpebral neurofibroma may reach considerable size and occasionally show malignant transformation. Near infrared reflectance has greatly contributed to enhancing our knowledge on choroidal alterations in NF1. Indeed, some authors have proposed to include these among the diagnostic criteria. Optical coherence tomography has given new insight on retinal alterations and is a noninvasive tool in the management of optic nerve gliomas in children. Ocular manifestations in NF type 2 can range from early-onset cataracts in up to 80% of cases to optic nerve hamartomas and combined pigment epithelial and retinal hamartomas.

Ocular Alterations in a Rare Case of Segmental Neurofibromatosis Type 1 with a Non-Classified Mutational Variant of the NF-1 Gene.

BACKGROUND: Neurofibromatosis type 1 (NF-1) is an autsomal dominant disorder which can occasionally result from somatic mosaicism and manifest as segmental forms of the disease. METHODS: A 37-year-old woman with ascertained NF-1, based on clinical diagnostic criteria and genetic analysis, was referred for ophthalmological evaluation. Genetic analysis, magnetic resonance imaging (MRI), complete ophthalmological examination, and near infrared reflectance (NIR) images at 815 nm of the retina were obtained. RESULTS: Genetic analysis revealed a non-classified mutational variant of the NF-1 gene identified as NM_000267.3:c2084T > C (p.Leu695Pro.T). MRI demonstrated non-symptomatic bilateral optic nerve gliomas. The only cutaneous sign was a subcutaneous neurofibroma of the posterior cervical region. Slit-lamp examination showed bilateral Lisch nodules. NIR images of the retina did not show any choroidal hamartomas. DISCUSSION: We report a rare case of segmental neurofibromatosis with a non-classified mutational variant of the NF-1 gene described in only one previous case in the literature. The patient presented with clinical features of NF-1 localized to the head and neck region, compatible with diagnosis of segmental NF-1. Interestingly, ocular manifestations included bilateral optic nerve gliomas and Lisch nodules, but no choroidal hamartomas.