Genetic changes in the FH gene cause vagal paraganglioma.

Vagal paraganglioma (VPGL) is a rare neuroendocrine tumor that originates from the paraganglion associated with the vagus nerve. VPGLs present challenges in terms of diagnostics and treatment. VPGL can occur as a hereditary tumor and, like other head and neck paragangliomas, is most frequently associated with mutations in the SDHx genes. However, data regarding the genetics of VPGL are limited. Herein, we report a rare case of a 41-year-old woman with VPGL carrying a germline variant in the FH gene. Using whole-exome sequencing, a variant, FH p.S249R, was identified; no variants were found in other PPGL susceptibility and candidate genes. Loss of heterozygosity analysis revealed the loss of the wild-type allele of the FH gene in the tumor. The pathogenic effect of the p.S249R variant on FH activity was confirmed by immunohistochemistry for S-(2-succino)cysteine (2SC). Potentially deleterious somatic variants were found in three genes, SLC7A7, ZNF225, and MED23. The latter two encode transcriptional regulators that can impact gene expression deregulation and are involved in tumor development and progression. Moreover, FH-mutated VPGL was characterized by a molecular phenotype different from SDHx-mutated PPGLs. In conclusion, the association of genetic changes in the FH gene with the development of VPGL was demonstrated. The germline variant FH: p.S249R and somatic deletion of the second allele can lead to biallelic gene damage that promotes tumor initiation. These results expand the clinical and mutation spectra of FH-related disorders and improve our understanding of the molecular genetic mechanisms underlying the pathogenesis of VPGL.

Multiple paragangliomas: a case report.

BACKGROUND: Carotid and vagal paragangliomas (CPGLs and VPGLs) are rare neoplasms that arise from the paraganglia located at the bifurcation of carotid arteries and vagal trunk, respectively. Both tumors can occur jointly as multiple paragangliomas accounting for approximately 10 to 20% of all head and neck paragangliomas. However, molecular and genetic mechanisms underlying the pathogenesis of multiple paragangliomas remain elusive. CASE PRESENTATION: We report a case of multiple paragangliomas in a patient, manifesting as bilateral CPGL and unilateral VPGL. Tumors were revealed via computed tomography and ultrasound study and were resected in two subsequent surgeries. Both CPGLs and VPGL were subjected to immunostaining for succinate dehydrogenase (SDH) subunits and exome analysis. A likely pathogenic germline variant in the SDHD gene was indicated, while likely pathogenic somatic variants differed among the tumors. CONCLUSIONS: The identified germline variant in the SDHD gene seems to be a driver in the development of multiple paragangliomas. However, different spectra of somatic variants identified in each tumor indicate individual molecular mechanisms underlying their pathogenesis.

Mutation profiling in eight cases of vagal paragangliomas.

BACKGROUND: Vagal paragangliomas (VPGLs) belong to a group of rare head and neck neuroendocrine tumors. VPGLs arise from the vagus nerve and are less common than carotid paragangliomas. Both diagnostics and therapy of the tumors raise significant challenges. Besides, the genetic and molecular mechanisms behind VPGL pathogenesis are poorly understood. METHODS: The collection of VPGLs obtained from 8 patients of Russian population was used in the study. Exome library preparation and high-throughput sequencing of VPGLs were performed using an Illumina technology. RESULTS: Based on exome analysis, we identified pathogenic/likely pathogenic variants of the SDHx genes, frequently mutated in paragangliomas/pheochromocytomas. SDHB variants were found in three patients, whereas SDHD was mutated in two cases. Moreover, likely pathogenic missense variants were also detected in SDHAF3 and SDHAF4 genes encoding for assembly factors for the succinate dehydrogenase (SDH) complex. In a patient, we found a novel variant of the IDH2 gene that was predicted as pathogenic by a series of algorithms used (such as SIFT, PolyPhen2, FATHMM, MutationTaster, and LRT). Additionally, pathogenic/likely pathogenic variants were determined for several genes, including novel genes and some genes previously reported as associated with different types of tumors. CONCLUSIONS: Results indicate a high heterogeneity among VPGLs, however, it seems that driver events in most cases are associated with mutations in the SDHx genes and SDH assembly factor-coding genes that lead to disruptions in the SDH complex.

Tumor multifocality with vagus nerve involvement as a phenotypic marker of SDHD mutation in patients with head and neck paragangliomas: A 18 F-FDOPA PET/CT study.

BACKGROUND: 18 F-FDOPA PET/CT was proved to be a highly sensitive imaging method for detecting head and neck paraganglioma (HNPGL). The primary aim of the study was to evaluate the relationship between tumor characteristics and the SDHx-mutational status in a large series of patients with HNPGL evaluated by 18 F-FDOPA PET/CT. METHODS: A total of 104 patients with HNPGL (65 sporadic/39 SDHx-mutated) were included. RESULTS: In comparison to SDHB/SDC/SDHx-negative cases, patients with SDHD were younger at diagnosis and had a higher rate of multifocal, vagal, and carotid paraganglioma. In patients with SDHD, vagal paraganglia represented the primary site of tumor origin. Multicentric involvement of the vagus nerve alone or in association with other locations was found to be a typical feature of SDHD cases compared to other cases (odds ratio = 59.4). CONCLUSION: The present study shows that tumor multifocality within the vagus nerve is a phenotypic marker of SDHD mutation. This information is essential in the choice of the therapeutic strategy.

YAP, TAZ and AREG expression in eighth cranial nerve schwannoma.

BACKGROUND: Although the diagnosis and treatment of eighth cranial nerve (VIII CN) schwannoma (acoustic neuroma) has improved over the years, no factors capable of predicting tumor growth have been identified as yet. This study is a preliminary investigation of the expression in sporadic VIII CN schwannomas of Yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), and amphiregulin (AREG), a direct target gene of YAP and TAZ. The expression of YAP, TAZ and AREG was correlated with the volumetric dimensions of tumors on contrast-enhanced magnetic resonance imaging (ceMRI). METHODS: YAP, TAZ and AREG expression was assessed immunohistochemically in surgical specimens of 36 consecutive sporadic VIII CN schwannomas. 3D reconstructions of the tumors and their corresponding volumes in cm3 were obtained from measurements on ceMRI images using the OsiriX® software. RESULTS: We found a significant direct correlation between TAZ expression and VIII CN schwannoma volumes on latest preoperative ceMRI (p<0.0003). Mean TAZ expression was also significantly higher in VIII CN schwannomas with a volume ≥2.1 cm3 than in those with a volume <2.1 cm3(p<0.0018). No significant correlations emerged for YAP or AREG expression and VIII CN schwannoma volume. CONCLUSIONS: The immunohistochemical expression of TAZ (but not YAP or AREG) correlated significantly with schwannoma volume measured on ceMRI. Further investigations are needed to identify the biological factors influencing tumor proliferation (ideally secreted proteins like AREG) that might be detected using non-invasive approaches (i.e., blood samples).

First insight into the somatic mutation burden of neurofibromatosis type 2-associated grade I and grade II meningiomas: a case report comprehensive genomic study of two cranial meningiomas with vastly different clinical presentation.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant nervous system tumor predisposition disorder caused by constitutive inactivation of one of the two copies of NF2. Meningiomas affect about one half of NF2 patients, and are associated with a higher disease burden. Currently, the somatic mutation landscape in NF2-associated meningiomas remains largely unexamined. CASE PRESENTATION: Here, we present an in-depth genomic study of benign and atypical meningiomas, both from a single NF2 patient. While the grade I tumor was asymptomatic, the grade II tumor exhibited an unusually high growth rate: expanding to 335 times its initial volume within one year. The genomes of both tumors were examined by whole-exome sequencing (WES) complemented with spectral karyotyping (SKY) and SNP-array copy-number analyses. To better understand the clonal composition of the atypical meningioma, the tumor was divided in four sections and each section was investigated independently. Both tumors had second copy inactivation of NF2, confirming the central role of the gene in meningioma formation. The genome of the benign tumor closely resembled that of a normal diploid cell and had only one other deleterious mutation (EPHB3). In contrast, the chromosomal architecture of the grade II tumor was highly re-arranged, yet uniform among all analyzed fragments, implying that this large and fast growing tumor was composed of relatively few clones. Besides multiple gains and losses, the grade II meningioma harbored numerous chromosomal translocations. WES analysis of the atypical tumor identified deleterious mutations in two genes: ADAMTSL3 and CAPN5 in all fragments, indicating that the mutations were present in the cell undergoing fast clonal expansion CONCLUSIONS: This is the first WES study of NF2-associated meningiomas. Besides second NF2 copy inactivation, we found low somatic burden in both tumors and high level of genomic instability in the atypical meningioma. Genomic instability resulting in altered gene dosage and compromised structural integrity of multiple genes may be the primary reason of the high growth rate for the grade II tumor. Further study of ADAMTSL3 and CAPN5 may lead to elucidation of their molecular implications in meningioma pathogenesis.

Bilateral ganglioglioma of the trigeminal nerve in an 83-year-old man.

Gangliogliomas are well-differentiated, mixed glio-neuronal tumors of the CNS that are most frequently localized within the temporal lobe. In a minority of cases, gangliogliomas have been described in the brain stem where they may critically impinge anatomical structures. Rarely, ganglioglioma develop in cranial nerves, almost exclusively in the optic pathway, where they usually present as singular space-occupying masses. Here, we report on an 83-year-old patient who presented with unusual symmetrical, bilateral gangliogliomas of the trigeminal nerves. These tumors showed an exophytic growth within the subarachnoid space toward the Gasserian ganglion and surprisingly appeared as isointense masses on T1- and T2-weighted MRI. Due to their bilateral appearance, we performed array-comparative genomic hybridization (aCGH) on the gangliogliomas to address the possibility of an underlying tumor syndrome in this patient. To our knowledge, this is the first case of bilateral ganglioglioma of the trigeminal nerve described so far.

DNA copy gains of tumor-related genes in vestibular schwannoma.

DNA copy gains are a common event in tumor growth. This study determines the gene dosage/amplification of seven tumor-related genes in patients undergoing vestibular schwannoma (VS) surgery and analyzes its clinical implications. Thirty-three patients undergoing surgery for VS were studied. Seven genes (EGFR, ERBB2, ERBB3, ERBB4, MDM2, MDM4, and NMYC) were analyzed by Quantitative real-time PCR. Copy gains were correlated with demographic, clinical and radiological data. Of the 33 samples, 48 % were positive for copy gains in at least one gene. There were no positive samples for gene amplification. A clinical correlation between tumor size and copy gains of ERBB2 was found. Patients with copy gains of this gene had larger tumors measured by diameter (p = 0.027) and volume (p = 0.005). Copy gains of EGFR, ERBB2, ERBB4, and MDM4 were associated with preoperative tinnitus. Contrary to other tumors of the central nervous system, development of VS does not appear to involve gene amplification. However, copy gains of certain tumor-related genes may play a role in the biological behavior of these neoplasms. Our findings support the role of ERBB2 in VS development and growth.

[Standardizing a central nervous system tumor DNA biobank]. / Estandarización de un biobanco de ADN de tumores del sistema nervioso central.

BACKGROUND: Brain tumors are one of the leading cancers worldwide; in the National Institute of Neurology and Neurosurgery (INNN) these tumors are the leading cause of morbitity and mortality. OBJECTIVE: Standardize biopsies, colletion, processing and storage biologic material of molecular studies. METHODS: with a previously signed surgical consent, a tumor and blood biopsy was done to 134 patients. Their DNA was extracted and a database was filled considering technical, ethical and legal aspects. In order to have optimal biologic material the procedure was standardized between the surgical and research laboratory teams. RESULTS: The biopsy, transportation, processing and storage were standardized. 134 patients were included (67 male and 67 female) with an average age of 46.28 years (range 15-81). The most frequently biopsied tumor was the meningioma (42%). The integrity of the obtained material was determined by agarose gel electrophoretic analysis. CONCLUSION: the INNN biobank has a standardized system that biopsies, processes and stores optimum quality biologic material that will be the basis of future molecular studies.

Coexisting cranial and multiple spinal meningioma in a child-report of a case.

Von Ricklinghausen's disease is commonly associated with simultaneous cranial and spinal meningioma but these are not true meningiomas. Craniospinal meningiomas without Von Ricklinghausen's disease are very rare. We report a 13-year-old girl who presented with two episodes of right focal seizure with secondary generalisation of three year's duration, weakness of both lower limbs for 6 months, and retention of urine of three month's duration. MRI brain showed enhancing lesion in the left fronto-parietal region. MRI spine revealed enhancing intradural extramedullary lesion at D(4-5), D(9-10), and L(1-2). The tumours were excised completely in a single stage, first by craniotomy then by multi level laminectomy. On histology the spinal meningioma had predominant meningothiliomatous. We followed up for 6 months and the patient recovered with power grade 4/5 both lower limb.

MicroRNA-21 overexpression contributes to vestibular schwannoma cell proliferation and survival.

HYPOTHESIS: Elevated levels of hsa-microRNA-21 (miR-21) in vestibular schwannomas (VSs) may contribute to tumor growth by downregulating the tumor suppressor phosphatase and tensin homolog (PTEN) and consequent hyperactivation of protein kinase B (AKT), a key signaling protein in the cellular pathways that lead to tumor growth. BACKGROUND: Vestibular schwannomas are benign tumors that arise from the vestibular nerve. Left untreated, VSs can result in hearing loss, tinnitus, vestibular dysfunction, trigeminal nerve dysfunction, and can even become life threatening. Despite efforts to characterize the VS transcriptome, the molecular pathways that lead to tumorigenesis are not completely understood. MicroRNAs are small RNA molecules that regulate gene expression posttranscriptionally by blocking the production of specific target proteins. METHODS: We examined miR-21 expression in VSs. To determine the functional significance of miR-21 expression in VS cells, we transfected primary human VS cultures with anti-miR-21 or control, scrambled oligonucleotides. RESULTS: We found consistent overexpression of miR-21 when compared with normal vestibular nerve tissue. Furthermore, elevated levels of miR-21 correlated with decreased levels of PTEN, a known molecular target of miR-21. Anti-miR-21 decreased VS cell proliferation in response to platelet-derived growth factor stimulation and increased apoptosis, suggesting that increased miR-21 levels contributes to VS growth. CONCLUSION: Because PTEN regulates signaling through the growth-promoting phosphoinositide 3-kinase/AKT pathway, our findings suggest that miR-21 may be a suitable molecular target for therapies aimed specifically at reducing VS growth.

Ablation of T cell immunity differentially influences tumor risk in inbred BD rat strains.

Inbred rat strains BDIX and BDIV are constitutionally susceptible and resistant, respectively, to the development of malignant peripheral nerve sheath tumors (MPNST) induced by neonatal exposure to N-ethyl-N-nitrosourea (EtNU). They represent a model system for analysis of molecular and cellular processes underlying differential cancer susceptibility. A point mutation in the Neu/ErbB-2 gene is an early marker of Schwann precursor cells at high risk of malignant conversion and is diagnostic of the resulting MPNST predominantly developing in the trigeminal nerves. Initially considerable amounts of Neu/ErbB-2-mutant cells arise in nerve tissue of both rat strains subsequently disappearing in resistant BDIV rats, but persisting and giving rise to MPNST in susceptible BDIX animals. An almost identical cellular immune response-sequentially involving macrophages, T helper- and cytotoxic T lymphocytes-is mounted in the trigeminal nerves of EtNU-treated rats of both strains. In this study, T cell maturation was prevented by neonatal thymectomy following EtNU-exposure. While resistance against MPNST development significantly decreased in BDIV rats MPNST incidence and survival time remained unaltered in thymectomized BDIX rats. Contrary to euthymic animals a number of both thymectomized BDIV and BDIX rats developed MPNST lacking the Neu/ErbB-2-mutation. This suggests that Schwann cells initiated by other genetic alterations can progress to full malignancy in immune-compromised rats only. T cell-dependent resistance against tumorigenesis originating from non-Neu/ErbB-2-mutant Schwann precursors might thus be shared by both strains while BDIV T lymphocytes additionally prevent the development of Neu/ErbB-2-mutant MPNST. Rat strain-specific differences in the interaction of T lymphocytes with (pre)malignant Neu-mutant cells may thus critically contribute to susceptibility and resistance towards EtNU-induced MPNST development.

Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas.

The INI1/SMARCB1 protein product (INI1), a component of a transcription complex, was recently implicated in the pathogenesis of schwannomas in two members of a single family with familial schwannomatosis. Tumors were found to have both constitutional and somatic mutations of the SMARCB1 gene and showed a mosaic pattern of loss of INI1 expression by immunohistochemistry, suggesting a tumor composition of mixed null and haploinsufficient cells. To determine if this finding could be extended to all tumors arising in familial schwannomatosis, and how it compares with other multiple schwannoma syndromes [sporadic schwannomatosis and neurofibromatosis 2 (NF2)] as well as to sporadic, solitary schwannomas, we performed an immunohistochemistry analysis on 45 schwannomas from patients with multiple schwannoma syndromes and on 38 solitary, sporadic schwannomas from non-syndromic patients. A mosaic pattern of INI1 expression was seen in 93% of tumors from familial schwannomatosis patients, 55% of tumors from sporadic schwannomatosis, 83% of NF2-associated tumors and only 5% of solitary, sporadic schwannomas. These results confirm a role for INI1/SMARCB1 in multiple schwannoma syndromes and suggest that a different pathway of tumorigenesis occurs in solitary, sporadic tumors.

Cyclin D1 expression and histopathologic features in vestibular schwannomas.

OBJECTIVE: To evaluate cyclin D1 expression in vestibular schwannoma and its relationship with histologic, clinical, and radiologic features. PATIENTS: Twenty-one patients with histologically confirmed vestibular schwannoma. INTERVENTION: Immunohistochemistry analysis was performed with anticyclin D1. Histopathologic features studied included Antoni pattern and nuclear and stromal degenerative changes. Clinical charts, audiometric data, and magnetic resonance imaging characteristics were reviewed. MAIN OUTCOME MEASURES: Cyclin D1 expression and its association with histologic, clinical, and radiologic findings. RESULTS: Cyclin D1 expression was found in 52% of cases. Cyclin D1 expression was more frequent in right-sided tumors (p = 0.02) and in tumors with nuclear degenerative changes (p < 0.0001). Patients with negative cyclin D1 expression had longer duration of deafness (p = 0.02) and higher 2,000-Hz hearing thresholds (p = 0.04) than cyclin D1+ patients. CONCLUSION: Cyclin D1 expression, present in nearly half of the cases, may play a role in the development of these tumors. Further studies are needed to fully understand the contributions of histopathologic and immunohistochemical factors to vestibular schwannoma biological activity.

Expression of VEGF and its receptor genes in intracranial schwannomas.

Vascular endothelial growth factor (VEGF) is considered to be a major regulator of angiogenesis in various brain tumors. In this study, we determined the expression levels of VEGF, and vascular endothelial growth factor receptor (VEGFR)-1 and -2 mRNA in 46 intracranial schwannomas by quantitative real-time PCR, and correlated these with various clinical factors or other molecular markers. We found that these tumors expressed significant amounts of VEGF mRNA in comparison with other brain tumors, including malignant gliomas and meningiomas. In addition, we performed immunohistochemical studies for VEGF and VEGFR-1, and confirmed that these tumors prominently express these proteins. The expression levels of VEGF and VEGFR-1 mRNA in recurrent tumors were higher than those in primary tumors. When we divided patients into two groups according to VEGF mRNA expression in the tumor, there was no significant difference in patient age, gender, or cranial nerves of origin between groups; however, the tumor volume tended to be larger in the high VEGF group than in the low VEGF group. The levels of VEGFR-1 mRNA and neurofibromatosis-2 mRNA in the high VEGF group were significantly greater than those in the low VEGF group. Levels of VEGFR-2 mRNA and DNA topoisomerase IIalpha mRNA, and the MIB-1 labeling index in the high VEGF group were slightly higher than those in the low VEGF group; however, the difference was not statistically significant. Based on these observations, the significance of VEGF and its receptor genes in intracranial schwannomas is discussed.

The interaction mode of premalignant Schwann and immune effector cells during chemically induced carcinogenesis in the rat peripheral nervous system is strongly influenced by genetic background.

Contrary to rats of the highly sensitive inbred strain BDIX, BDIV rats are resistant to the induction of malignant schwannomas by N-ethyl-N-nitrosourea, arising predominantly in the trigeminal nerves. A point mutation of the neu/erbB-2 gene diagnostic of N-ethyl-N-nitrosourea-induced rat schwannomas is an early marker of Schwann precursor cells at high risk of subsequent malignant transformation. Neu-mutant cells initially arise at a similar frequency in sensitive and resistant animals. However, these cells disappear from the trigeminal nerves of resistant rats while giving rise to highly malignant schwannomas in susceptible animals. The resistance of BDIV rats obviously includes mechanisms to recognize and eliminate premalignant cells. The involvement of a cellular immune response was investigated in trigeminal nerves of both strains at different times after neonatal carcinogen exposure. An inflammatory reaction involving sequentially CD4(+) macrophages and T helper cells, CD8(+) cytotoxic T cells, and ED1(+) and ED2(+) macrophages was detected as a consequence of N-ethyl-N-nitrosourea treatment as early as postnatal day 40, briefly after the emergence of premalignant neu-mutant Schwann cells. It persisted throughout the observation period (40-250 days). However, there were no gross differences in immune cell counts between tumor-susceptible and tumor-resistant rats, except for a moderate increase of ED2(+) macrophages in N-ethyl-N-nitrosourea-treated BDIX rats only. Differential interactions of immune effector cells with premalignant Schwann cells may thus be involved in genetically determined tumor susceptibility or resistance, which could include functional differences of immune effector cells and/or a differential capability of premalignant Schwann cells to escape or counteract the cellular immune response.

Melanotic nonpsammomatous trigeminal schwannoma as the first manifestation of Carney complex: case report.

OBJECTIVE: Melanotic schwannoma is a rare neoplasm, classifiable as a peripheral nerve sheath tumor, and differentiated from a typical schwannoma by heavy pigmentation. Psammoma bodies can be visualized in more than 50% of melanotic schwannomas. Half of patients with such "psammomatous melanotic schwannomas" have Carney complex, a dominantly transmitted autosomal disorder. Most recently, the tumor suppressor gene, PRKAR1A, coding for the Type 1alpha regulatory subunit of protein kinase A was found to be mutated in approximately half of the known Carney complex families. Although cranial schwannomas have been described in patients with Carney complex, their numbers are too small to be considered a definite part of the syndrome. Furthermore, only melanotic schwannomas with psammoma bodies are included as diagnostic criteria for Carney complex. The objective of this report is to communicate a case of trigeminal nonpsammomatous melanotic schwannoma as the first manifestation of Carney complex. CLINICAL PRESENTATION: A 34-year-old woman presented with odontalgia, right V3 hypoesthesia, V2 paresthesia, and diplopia. Magnetic resonance imaging scans of the brain revealed a small tumor with homogenous contrast in the right trigeminal pathway. INTERVENTION: We performed an extradural approach to the right cavernous sinus by a middle fossa approach. The lateral wall was opened between the cranial nerves, and a soft and black tumor was resected in a piecemeal fashion. Histology and immunohistochemical analysis of the tumor were compatible with melanotic schwannoma, but no psammomatous bodies were identified. Endocrine evaluation showed that this patient's symptoms fulfilled the diagnostic criteria of Carney complex, with lentiginosis, multiple breast ductal adenomas, multiple hypoechoic nodules on thyroid ultrasonography, and a 4 x 5-cm asymptomatic atrial cardiac myxoma, which was removed 15 days after the neurosurgery. Three months later, a recurrence of melanotic schwannoma was identified. Molecular analyses of genomic and somatic deoxyribonucleic acid from the patient found a 578 to 579delTG mutation of PRKAR1A. CONCLUSION: We present the unusual case of a nonpsammomatous trigeminal melanotic schwannoma associated with Carney complex, with confirmed PRKAR1A gene mutation. Our case highlights that neurosurgeons, in the presence of a melanotic schwannoma, should be aware of the features of the Carney complex because, in such cases, pre- and postoperative management is significantly affected. We also postulate that the absence of psammoma bodies or cranial localization do not exclude this diagnosis.

[Neurofibromatosis--an inborn genetic disorder with susceptibility to neoplasia]. / Nerwiakowlókniakowatosc--wrodzona, genetycznie uwarunkowana choroba predysponujaca do nowotworzenia.

Among different subtypes of neurofibromatosis (Nf), type 1 (Nf-1) predominates in frequency (approximately 97% of Nfs' patients) with an incidence of approximately 1 in 3500 live births. Nf-2, comprises 2% of the Nf population and is a very rare disease (1:40,000). Both are autosomal dominant disorders with 100% penetration, variable expression and 50% rate of new (de novo) mutations. The protein products of both, NF1 andNF2 genes are best known and the genes serve as tumour suppressors. Mutations result in a predisposition to develop a variety of tumours of the central and peripheral nervous systems, as well as other malignancies. Nf-2 is a multisystem genetic disorder associated with bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas, gliomas, and juvenile cataracts with a paucity of cutaneous features, which are seen more consistently in Nf-1. In contrast to Nf-1, Nf-2 is associated with significant morbidity and decreased life span and a higher incidence of CNS tumours. However, morbidity and mortality rates in Nf-1 are not negligible. The cardinal features of Nf-1 are cafe-au-lait spots, axillary and inguinal freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules). Optic gliomas and both malignant and benign peripheral nerve sheet tumours are the most common malignancies arising in Nf-1 patients. Among neurological symptoms epilepsy, intellectual disability and learning difficulty are also observed. Bone dysplasia results in scoliosis. There is no known medical treatment beneficial to both groups of patients. The mainstay of care for Nf patients is anticipatory guidance, and early detection and symptomatic treatment of disease complications.