Long-term clinical outcomes of stereotactic radiotherapy for bilateral vestibular schwannomas in neurofibromatosis type 2 patients.

PURPOSE: The evidence for treating patients with neurofibromatosis 2-related vestibular schwannoma (VS-NF2) using hypofractionated stereotactic radiation therapy (HSRT) is limited. This study aimed to investigate clinical outcomes in patients with VS-NF2 treated with Robotic HSRT. METHODS: We retrospectively analyzed 25 NF2 patients with 48 VSs who were treated using Robotic HSRT at Ramathibodi Hospital from January 2009 to January 2020. RESULTS: Median follow-up was 98 months (range, 24-155 months). Median tumor volume was 2.3 cm3 (range, 0.4-28.3 cm3). Median prescribed dose was 18 Gy (range, 18-25 Gy) in three fractions (range, 3-5). The 5- and 10-year local control rates were 87% and 80%, respectively. The 5- and 10-year hearing preservation rates were 59% and 35%, respectively. Three patients developed new symptoms associated with transient volume expansion after treatment: hydrocephalus in one, facial weakness in one, and ataxia in one. No patient developed worsening of trigeminal nerve function. No histologically confirmed of radiation induced malignancy was reported in the study. CONCLUSIONS: Robotic HSRT demonstrated excellent long-term tumor control with a low non-auditory complication rate in patients with VS-NF2. However, preservation of hearing remains a major concern.

Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis.

Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients.

Neurofibromatosis tipos 1 y 2 / Neurofibromatosis type 1 and 2

La neurofibromatosis (NF) comprende un grupo de enfermedades genéticas de herencia autosómica dominante, que se clasifican de la siguiente manera: neurofibromatosis tipo 1 (NF1), neurofibromatosis tipo 2 (NF2) y schwannomatosis (también conocida como neurofibromatosis tipo 3). Esta última es una enfermedad muy infrecuente, con una prevalencia aproximada de 1/126 000 personas, por lo que solo profundizaremos las dos primeras. La NF1, también conocida como la enfermedad de Von Recklinghausen, es la más frecuente de las tres y afecta principalmente la piel y el sistema nervioso periférico. Se caracteriza por la presencia de máculas "café con leche", pecas axilares o inguinales, nódulos de Lisch (hamartomas en el iris) y neurofibromas (tumores de la vaina de nervios periféricos). Otras manifestaciones menos frecuentes, aunque de mayor gravedad, incluyen gliomas del nervio óptico, meningiomas, neurofibromas malignos, escoliosis y displasia de la tibia. Su diagnóstico se suele realizar al nacimiento o durante los primeros años de vida, y se estima que un 50% de quienes la padecen presenta dificultades cognitivas. No hay datos concluyentes sobre la mortalidad en los pacientes con NF1, aunque se sabe que la expectativa de vida es menor que en la población general. La NF2 tiene una prevalencia considerablemente menor que la NF1 y su inicio es más tardío, afectando principalmente a adultos jóvenes. La presentación clínica típica se caracteriza por acúfenos, hipoacusia y ataxia en contexto de la presencia de schwannomas vestibulares bilaterales. Otros hallazgos menos frecuentes incluyen schwannomas de nervios periféricos, meningiomas, ependimomas o astrocitomas. La esperanza de vida es de unos 36 años, con una supervivencia media desde el momento del diagnóstico de 15 años. (AU)

Neurofibromatosis (NF) includes a group of genetic diseases with an autosomal-dominant inheritance pattern, and they are classified as follows: Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and Schwannomatosis (also known as neurofibromatosis type 3). This last one is a very rare disease, with an approximate prevalence of 1/126000, so we will only deepen in the first two. NF1, also known as von Recklinghausen disease, is the most frequent, and mainly affects the skin and peripheral nervous system. Its typical manifestations are the presence of café-au-lait macules, axillary or inguinal freckles, Lisch nodules (hamartomas in the iris) and neurofibromas (peripheral nerve sheath tumors). Less frequent manifestations, although more serious, include optic nerve gliomas, meningiomas, malignant neurofibromas, scoliosis and tibial dysplasia. The diagnosis is usually made at birth or during the first years of life, and approximately 50% of patients present cognitive difficulties. There is no conclusive data on mortality in patients with NF1, although it is known that life expectancy is lower than in general population. NF2 has a considerably lower prevalence than NF1, and its onset is later in life, mainly affecting young adults. Its typical clinical presentation is characterized by tinnitus, hearing loss and ataxia in the context in the presence of bilateral vestibular schwannomas. Less frequent findings include peripheral nerve schwannomas, meningiomas, ependymomas or astrocytomas. Life expectancy is about 36 years old, with a median survival from the moment of diagnosis of 15 years. (AU)

First report of quality of life in adults with neurofibromatosis 2 who are deafened or have significant hearing loss: results of a live-video randomized control trial.

PURPOSE: To test the feasibility, acceptability, and preliminary efficacy of a mind-body program for patients with neurofibromatosis 2 (NF2) who are deaf or have significant hearing loss (d3RP-NF2) against an attention placebo control (dHEP-NF2) in a single-blind randomized control trial. Both were delivered using Communication Access Real-Time Translation and live group videoconferencing. METHODS: Forty-five adults with NF2 were randomized. Co-primary outcomes were physical quality of life (QoL) and psychological QoL and secondary outcomes were social QoL and environmental QoL, all measured with the World Health Organization Quality of Life Abbreviated Instrument (WHOQOL-BREF). Assessments were conducted at baseline, post-treatment, and six-month follow-up. RESULTS: Forty-one participants (91%) completed the intervention, and 29 (64%) completed the six-month follow up. Participants in the d3RP-NF2 showed significantly greater improvements from baseline to post-treatment on physical QoL (14.79, 95% CI 5.41-24.18; p ≤ 0.001), psychological QoL (18.77, 95% CI 7.09-30.44, p ≤ 0.001), and environmental QoL (13.25, 95% CI 1.10-25.39, p = 0.03) compared to the dHEP-NF2. Social QoL also significantly increased in the d3RP-NF2 (16.32, 95% CI 6.66-25.97, p = 0.001), but improvement was not beyond the dHEP-NF2. Gains in QoL were clinically meaningful and maintained at the 6-month follow-up for d3RP-NF2 participants across all QoL domains. There were more treatment responders in the d3RP-NF2 compared to the dHEP-NF2. CONCLUSIONS: The d3RP-NF2 was well accepted, highly feasible, and resulted in sustained improvements in QoL in patients with NF2 who are deaf or have significant hearing loss.

From process to progress-2017 International Conference on Neurofibromatosis 1, Neurofibromatosis 2 and Schwannomatosis.

The neurofibromatoses are inherited, tumor suppressor disorders that are characterized by multiple, benign peripheral nerve sheath tumors and other nervous system tumors. Each disease is associated with a distinct genetic mutation and with a different pathogenesis and clinical course. Neurofibromatosis 1 (NF1) is common and epitomized by multiple neurofibromas with widespread complications. NF2 and schwannomatosis are rare diseases that are typified by multiple schwannomas that are particularly painful in people with schwannomatosis. Since 1985, the Children's Tumor Foundation (formerly the National Neurofibromatosis Foundation) has hosted an international Neurofibromatosis Conference, bringing together international participants who are focused on NF research and clinical care. The 2017 Conference, held in Washington, DC, was among the largest gatherings of NF researchers to date and included presentations from clinicians and basic scientists, highlighting new data regarding the molecular and cellular mechanisms underlying each of these diseases as well as results from clinical studies and clinical trials. This article summarizes the findings presented at the meeting and represents the current state-of-the art for NF research.

2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis.

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

Cranial irradiation in childhood mimicking neurofibromatosis type II.

Neurofibromatosis type II (NF2) is a genetic disease characterized by bilateral vestibular schwannomas (VS) and other nerve system tumors. However, such tumors may be associated with environmental, rather than a genetic, etiology. Individuals fulfilling the clinical criteria of NF2 who had been treated by head ionized irradiation at a young age were compared for disease characteristics and molecular analysis with non-irradiated sporadic NF2 cases. In the study cohort, three of 33 sporadic adult cases fulfilling NF2 diagnostic criteria had a history of early age cranial irradiation exposure. None of the irradiated patients had bilateral VS compared with 73.3% of the non-irradiated individuals. One of the irradiated patients had no VS, while none of the non-irradiated NF2 cases had absence of VS. All of the irradiated individuals had brain meningiomas and thyroid tumors compared with 47% and 0%, respectively, of the non-irradiated individuals. Molecular analyses for NF2 mutations in blood of the irradiated individuals failed to detect disease-causing mutations. This study suggest that environmental factors may mimic NF2. Identifying such non-genetic cases fulfilling clinical criteria of the genetic disease may be crucial for the purposes of genetic counseling and patient management.

YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2-EGFR Signaling Axis.

The Hippo-YAP pathway has emerged as a major driver of tumorigenesis in many human cancers. YAP is a transcriptional coactivator and while details of YAP regulation are quickly emerging, it remains unknown what downstream targets are critical for the oncogenic functions of YAP. To determine the mechanisms involved and to identify disease-relevant targets, we examined the role of YAP in neurofibromatosis type 2 (NF2) using cell and animal models. We found that YAP function is required for NF2-null Schwann cell survival, proliferation, and tumor growth in vivo Moreover, YAP promotes transcription of several targets including PTGS2, which codes for COX-2, a key enzyme in prostaglandin biosynthesis, and AREG, which codes for the EGFR ligand, amphiregulin. Both AREG and prostaglandin E2 converge to activate signaling through EGFR. Importantly, treatment with the COX-2 inhibitor celecoxib significantly inhibited the growth of NF2-null Schwann cells and tumor growth in a mouse model of NF2. Cancer Res; 76(12); 3507-19. ©2016 AACR.

CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies.

The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a "state-of-the-field" for NF research in 2012.

Multisession stereotactic radiosurgery for vestibular schwannomas: single-institution experience with 383 cases.

BACKGROUND: Single-session stereotactic radiosurgery (SRS) treatment of vestibular schwannomas results in excellent tumor control. It is not known whether functional outcomes can be improved by fractionating the treatment over multiple sessions. OBJECTIVE: To examine tumor control and complication rates after multisession SRS. METHODS: Three hundred eighty-three patients treated with SRS from 1999 to 2007 at Stanford University Medical Center were retrospectively reviewed. Ninety percent were treated with 18 Gy in 3 sessions, targeting a median tumor volume of 1.1 cm3 (range, 0.02-19.8 cm3). RESULTS: During a median follow-up duration of 3.6 years (range, 1-10 years), 10 tumors required additional treatment, resulting in 3- and 5-year Kaplan-Meier tumor control rates of 99% and 96%, respectively. Five-year tumor control rate was 98% for tumors < 3.4 cm3. Neurofibromatosis type 2-associated tumors were associated with worse tumor control (P = .02). Of the 200 evaluable patients with pre-SRS serviceable hearing (Gardner-Robertson grade 1 and 2), the crude rate of serviceable hearing preservation was 76%. Smaller tumor volume was associated with hearing preservation (P = .001). There was no case of post-SRS facial weakness. Eight patients (2%) developed trigeminal dysfunction, half of which was transient. CONCLUSION: Multisession SRS treatment of vestibular schwannomas results in an excellent rate of tumor control. The hearing, trigeminal nerve, and facial nerve function preservation rates reported here are promising.

Foramen magnum meningiomas: experiences in 114 patients at a single institute over 15 years.

BACKGROUND: Although there has been great development in the anatomical understanding and operative techniques for skull base tumors, controversy still exists regarding the optimal surgical strategies for the FMMs. We report clinical and radiologic features as well as the surgical findings and outcome for patients with FMM treated at our institution over the last 15 years. METHODS: We reviewed 114 consecutive cases of FMM operated between May 1993 and June 2008 in the neurosurgery department at Beijing Tiantan Hospital. RESULTS: There were 68 female and 46 male patients (mean age, 52.3 years; range, 28-76 years). Foramen magnum meningiomas were classified as anterior (80 cases), anterolateral (24 cases), and posterolateral (10 cases). Mean duration of symptoms was 11.7 months (ranging from 1.5 to 240 months). Cervico-occipital pain (80.7%) and headache and dizziness (42.1%) were the most common presenting symptoms. The preoperative KPS was 72.5 +/- 8.3. Mean maximum diameter of the tumors on MRI was 3.35 cm (range, 1.5-4.7 cm). Posterior midline approach was performed in 10 cases, far-lateral retrocondylar approach in 97 cases, and extended far-lateral approach in 7 cases. Gross total resection was achieved in 86.0% of patients and subtotal resection in 14.0%. Surgical mortality was 1.8%. Follow-up data were available for 93 patients, with a mean follow-up of 90.3 months (range, 1-180 months), of which 59 (63.4%) lived a normal life (KPS, 80-100). CONCLUSION: Our experience suggests that most anterior and anterolateral FMMs can be completely resected by a far-lateral retrocondylar approach without resection of the occipital condyle. Complete resection of the tumor should be attempted at the first operation. Postoperative management of FMM is important for the prognosis.

Modern management of vestibular schwannomas.

Within the last 3 decades, microsurgery and stereotactic radiosurgery (SRS) have become well-established management options for vestibular schwannomas (VSs). Advancement in the management of VSs can be separated into three periods: the microsurgical pioneer period, the demonstration of SRS as a first-line therapy for small and medium-sized VSs, and currently, a period of SRS maturity based on a large worldwide patient accrual. The Marseille SRS experience includes 1,500 patients, with 1,000 patients having follow-up longer than 3 years. A long-term tumor control rate of 97%, transient facial palsy lower than 1%, and a probability of functional hearing preservation between 50 and 95% was achieved in this large series of patients treated with state-of-the-art SRS.

Neurological complications after acoustic neurinoma radiosurgery: revised risk factors based on long-term follow-up.

CONCLUSIONS: The precise risk factors for neurological complications after acoustic neurinoma radiosurgery were identified on long-term follow-up. Type 2 neurofibromatosis was found to be a risk factor for hearing loss and peripheral tumor dose was a risk factor for seventh and fifth cranial nerve injuries. These risk factors corresponded to those reported at other institutions. At the present time, controversy exists regarding history of prior surgical resection and tumor size as risk factors for cranial nerve complications. OBJECTIVES: To identify more precisely the risk factors for neurological complications after stereotactic radiosurgery (SRS) based on long-term follow-up. PATIENTS AND METHODS: Between June 1990 and September 1998, 138 patients with acoustic neurinomas had SRS at Tokyo University Hospital. Of these, the 125 patients who were followed up for at least 6 months were entered into the present study. The patients' ages ranged from 13 to 77 years (median 53 years). The average tumor diameter ranged from 6.7 to 25.4 mm (mean 13.9 mm). The maximum tumor doses ranged from 20 to 40 Gy (mean 29.8 Gy), and the peripheral doses ranged from 12 to 25 Gy (mean 15.4 Gy). One to 12 isocenters were used (median 4). The follow-up period ranged from 6 to 191 months (median 60 months). The potential risk factors for neurological complications were analyzed using two univariate actuarial analyses. The neurological complications studied included hearing loss, facial palsy, and trigeminal nerve dysfunction. The variables analyzed were age, gender, prior operation, neurofibromatosis type 2 (NF2), tumor diameter, maximum tumor dose, peripheral tumor irradiation dose, and the number of isocenters. Variables with significant p values (<0.05) on both actuarial analyses were considered risk factors. RESULTS: NF2 was significantly correlated with both total hearing loss and pure tone threshold (PTA) elevation; a history of prior surgical resection, tumor size, and the peripheral tumor dose were significantly correlated with facial palsy; and the peripheral tumor dose was significantly correlated with trigeminal neuropathy.

Neurofibromatosis tipo 1 (NF1) revisión y presentación de un caso clínico con manifestaciones bucofaciales / Neurofibromatosis type 1 (NF1) review and report of a case with buccofacial manifestation

La neurofibromatosis es una enfermedad hereditaria de transmisión autosómica dominante que compromete el desarrollo de las células de la cresta neural. Las manifestaciones bucofaciales de la neurofibromatosis tipo 1 (NF1) son muy escasas, presentando una prevalencia de 1:16.000.El caso que se presenta es de un paciente varón de 10 años de edad, de raza negra, que acudió al Servicio de Cirugía Oral y Maxilofacial del Hospital Universitario de Cartagena de Indias (Colombia) por presentar un nódulo en el suelo de la boca y una ligera asimetría facial provocada por una hipertrofia fibrosa que comprometía el maxilar superior y el cuerpo mandibular izquierdo. En el examen físico se encontraron, a nivel cutáneo, numerosas manchas café con leche dispersas por todo el cuerpo, mientras que la exploración oftalmológica reveló múltiples nódulos de Lisch (hamartomas del iris). Las imágenes radiográficas mostraron una compresión extra ósea y la tomografía computadorizada (TC) descartó la presencia de glioma de los nervios ópticos. Como antecedentes familiares, el padre, una hermana y una tía del paciente presentaban una NF1 confirmada clínicamente. De acuerdo con la determinación de los criterios diagnósticos de la NF1 establecidos en 1987 por el “National institut of health concensus development conference on neurofibromatosis”, esos tres hallazgos permitieron hacer un diagnóstico de NF1 y orientar la impresión clínica de las lesiones bucofaciales hacia neurofibromas, lo que fue confirmado histológicamente. El manejo de los pacientes con NF1 es difícil, como también lo es el tratamiento de las complicaciones que pueden producir las lesiones tales como deformidades (con el consiguiente problema psicológico), gliomas de los nervios ópticos (ceguera) o un alto riesgo de malignización. La ayuda del consejo genético, el aislamiento del gen implicado y los últimos avances en el campo de la genética, son muy esperanzadoras en cuanto al diagnóstico prenatal

Neurofibromatosis is a hereditary illness of dominant autosomic transmission which cope with cell development in the neural creek. Mouth-face manifestations caused by neurofibromatosis type 1 (NF1) are scarce, showing a dominance of 1 among 16,000.The case shown belongs to a patient – male, aged 10, black – who went into hospital in Cartagena de Indias (Colombia) in the section of Oral and Maxilofacial Surgery Service after detecting a nodule on the mouth soil and a light facial asymmetry caused by a swelling around the upper and lower left jaw. During the medical tests, several light-brown spots were found on the skin and the ophthalmology test revealed several Lisch nodules. Radiography showed bone compression and ,later on, computer thomography discarded the existence of optic nerves glioma. In the medic reports we could see that the patient’s father, sister and aunt suffered from NF1 as well. According to the diagnostic criteria regarding NF1 established in “National Institute of Health Concensus Development. A Conference on Neurofibromatosis” (1987), the evidence found in the patient after the tests (the3 sympthoms) led us to diagnose NF1 and made us focus and re-consider the case from a former mouth-faceinjury to a later neurofibroma, which was clinically and officially confirmed. The treatment of NF1 patients is hard as well as the complications derived from deformations (and its following psychological problem), gliomas of the optic nerves (blindness) or the high-risk of malignization. The genetic Council assistance, the isolation of the gen and the latest developments in the field of Genetics allowus to have great expectations in the pre-birth diagnostic

Role of the neurofibromatosis type 2 gene in the development of tumors of the nervous system.

Germ line and somatic mutations in the neurofibromatosis Type 2 (NF2) tumor suppressor gene predispose individuals to tumors of the nervous system, including schwannomas and meningiomas. Since identification of the NF2 gene more than a decade ago, a large body of information has been collected on the nature and consequences of these alterations in patients with NF2 and in individuals in whom sporadic tumors associated with NF2 develop. The catalog of mutations identified thus far has facilitated extensive genetic analysis, including studies of patients with mosaicism and phenotype-genotype correlations, and has also led to experiments that have begun to unravel the molecular biology of the NF2 gene and its role in tumorigenesis. The authors describe some of the most significant findings in NF2 genetics and biology over the last decade.

Neurofibromatosis type II presenting as vertical diplopia.

Neurofibromatosis type II (NF II) is rare and most commonly presents with hearing loss, tinnitus and/or vestibular disturbance in the third decade of life. The authors describe a rare case presenting with NF II with vertical diplopia due to IV(th) nerve palsy. The patient was otherwise asymptomatic despite multiple extensive lesions on MRI.

NF2: the wizardry of merlin.

Neurofibromatosis type II (NF2) is an autosomal dominant cancer syndrome characterized by the formation of tumors of the nervous system, particularly schwannomas and meningiomas. The NF2 gene is also implicated in the development of sporadic schwannomas and meningiomas, as well as tumor types seemingly unrelated to the NF2 disorder, such as malignant mesotheliomas. Inactivation of NF2 occurs by a "two-hit" mechanism, as proposed by Al Knudson, and the NF2 gene behaves as a classical tumor suppressor gene. The NF2 gene product, merlin, exhibits homology with the ezrin-radixin-moesin family of membrane-cytoskeleton-linking proteins. During the past several years, there has been intensive investigation aimed at elucidating the mechanisms underlying merlin's functions. In this review, we summarize the involvement of NF2 inactivation in tumorigenesis. We also discuss observations implicating merlin in cell motility and cell proliferation, with a focus on recent findings linking merlin to Rac signaling.

Tumorigenesis in neurofibromatosis: new insights and potential therapies.

The neurofibromatoses NF1 and NF2 are inherited cancer predisposition syndromes in which affected individuals are prone to development of mostly benign, but occasionally malignant, tumors. The NF1 and NF2 genes function as tumor suppressor genes (negative growth regulators), such that their loss of expression predisposes to tumor formation. Neurofibromin, the protein product of the NF1 gene, acts as a negative regulator of the ras proto-oncogene, to reduce cell growth. Merlin, the NF2 gene product, is involved in regulating cell proliferation and motility, and probably plays a role in integrating multiple cell-signaling pathways. By understanding the function of these tumor suppressors, we have a unique opportunity to develop targeted pharmacotherapeutic interventions for these disorders.

Neurofibromatosis: a propósito de un caso / Neurofibromatosis: a proposal of a case

La neurofibromatosis (NF) forma parte de los síndromes neurocutáneos que presentan manifestaciones clínicas multisistémicas. Se describen ocho entidades, de las cuales las más frecuentes (98 por ciento-99 por ciento) corresponden a la NF tipo I y II, ambas enfermedades de herencia autosómica dominante, localizadas en los cromosomas 17 y 22, respectivamente. Específicamente, la NF tipo I se caracteriza por la presencia de manchas café con leche, seudoefélides inguinales y axilares, schwannomas y neurofibromas plexiformes. Además, se asocia compromiso de tipo neurológico (50 por ciento), con retraso del desarrollo psicomotor (10 por ciento-20 por ciento) y convulsiones (8 por ciento-13 por ciento) y compromiso óseo (50 por ciento), con escoliosis (20 por ciento), talla baja (10 por ciento) y pseudoartrosis (8 por ciento). A modo de ejemplo se describe el caso de un paciente portador de NF tipo I que presentó un neurofibroma plexiforme, cuyo diagnóstico diferencial era neurofibrosarcoma, el cual presentó una evolución benigna satisfactoria