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.

Natural history of peripheral nerve schwannomas.

BACKGROUND: Little information about the natural history of peripheral nerve schwannomas exists in the literature. The aim of this study was to determine the natural history of those tumors both in sporadic and schwannomatosis cases to determine their growth rates and patterns. METHODS: In 44 patients from 3 surgical centers, hospital charts, follow-up records, and imaging studies were reviewed. Of these patients, 7 had sporadic schwannomatosis. Histological diagnosis was obtained in 37 patients (84%). Tumor growth rates were determined by calculating the absolute and relative growth rates. RESULTS: On the 47 tumors analyzed, the median tumor size at diagnosis was 1.8 cm3, and the majority of tumors were located in the lower limb (62%). The absolute growth rate ranged from - 1.13 to 23.17 cm3/year (mean, 1.69 cm3/year). Relative annual growth rates ranged from - 9 to 166%/year (mean, 33.9%/year). There was no clear correlation between initial tumor size, age at diagnosis, and tumor growth rate. Six patients (13%) harbored "fast-growing" tumors (absolute growth rate > 2 cm3/year and relative growth rate > 35%/year) while 19% of tumors demonstrate no growth or negative growth. In schwannomatosis patients, each tumor displayed a distinct growth pattern. CONCLUSION: This study confirms the slow-growing nature of most, but not all, peripheral nerve schwannomas. Additional studies are mandatory to explore the environmental factors influencing growth in sporadic cases and the precise growth patterns in schwannomatosis cases to detect the rare cases of malignant transformation and pave the way to the evaluation of future clinical trials.

[Surgery treatment of neurofibromatosis associated severe cervical kyphotic deformity: mid- and long-term follow-up and efficacy analysis].

Objective: To investigate the surgical strategy and mid-and long-term outcomes of neurofibromatosis associated cervical kyphotic deformity. Methods: Thirteen patients with neurofibromatosis associated cervical kyphotic deformity operated in Shanghai Changzheng Hospital from January 1998 to December 2015 were analyzed retrospectively. There were 7 males and 6 females in this group, aged from 12 to 61 years, with an average age of (28±15) years. Eight patients were treated with anterior surgery (Group A) and 5 patients were treated with combined anterior and posterior surgery (Group A+P). Cobb angle correction of cervical kyphosis and improvement of clinical symptoms were followed up. Clinical efficacy between the two groups was compared and analyzed. Chi-square test, Fisher exact test and independent sample t test were used for comparative analysis between the two groups. Results: All patients were operated successfully and finished follow up. The follow-up period was from 42 to 128 months ((80±22) months). After the surgery, neurological symptoms and pain were significantly improved in all patients. Compared with preoperative values, Japanese Orthopedic Association (JOA) score and visual analogue scale (VAS) score for pain at the last follow-up were significantly improved (t=7.63, -5.19, 8.63, -4.75, all P<0.01). Cervical kyphosis was significantly improved in all patients after surgery. In group A, the Cobb angle was improved from 64°±24° preoperatively to 12°±11° at the last follow-up, and the average correction rate of Cobb angle was 82.6%. In group A+P, the Cobb angle was improved from 55°±10° preoperatively to 7°±9° at the last follow-up, and the average correction rate of Cobb angle was 88.3%. The operation time, intraoperative blood loss and length of stay in group A were all significantly lower than those in group A+P (t=-6.32, -11.92, -6.52, all P<0.01). At the last follow-up, there was no significant difference in Cobb angle, JOA score and VAS score between the two groups (t=0.89, 0.94, 1.02, all P>0.05). Conclusions: Mid-and long-term results of anterior and combined anterior and posterior surgery for neurofibromatosis associated severe cervical kyphosis are satisfactory. Moderate correction strategy for cervical kyphosis is safe and effective. The incidence of complications of nerve injury can be reduced.

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.

First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and advances of new therapeutics.

The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, capillary malformation arterio-venous malformation syndrome, and SYNGAP1 autism. Due to their common underlying pathogenetic etiology, all these syndromes have significant phenotypic overlap of which one common feature include a predisposition to tumors, which may be benign or malignant. Together as a group, they represent one of the most common multiple congenital anomaly syndromes estimating to affect approximately one in 1000 individuals worldwide. The subcontinent of India represents one of the largest populations in the world, yet remains underserved from an aspect of clinical genetics services. In an effort to bridge this gap, the First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics was held in Kochi, Kerala, India. These proceedings chronicle this timely and topical international symposium directed at discussing the best practices and therapies for individuals with neurofibromatoses and RASopathies.

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.

Hemidiaphragmatic palsy following excision of cervical dumbbell neurofibroma in a patient with neurofibromatosis: Importance of assessing functional status of "non-limb" roots.

A 27-year-old male patient with neurofibromatosis type 1 who was operated on for a dumbbell neurofibroma of the cervical spine developed transient respiratory difficulty due to postoperative unilateral diaphragmatic palsy. This report emphasizes the need for preoperative assessment of residual function in involved non-limb roots, the role of intraoperative monitoring to take a decision on root sacrifice, and the need for optimizing respiratory function preoperatively, and describes a complication rarely reported in literature.

Anaplastic pilocytic astrocytoma.

This clinical series examines the presentation of three adult patients who were found to have de novo anaplastic pilocytic astrocytoma. Initial imaging demonstrated an intracranial mass with histological analysis diagnostic of pilocytic astrocytoma with anaplastic features including necrosis, marked nuclear pleomorphism and a very high mitotic rate leading to the diagnosis of anaplastic pilocytic astrocytoma. We discuss the clinical pitfalls, treatment and implications when managing this condition.

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.

Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms.

Neurofibromas, schwannomas and malignant peripheral nerve sheath tumors (MPNSTs) all arise from the Schwann cell lineage. Despite their common origin, these tumor types have distinct pathologies and clinical behaviors; a growing body of evidence indicates that they also arise via distinct pathogenic mechanisms. Identification of the genes that are mutated in genetic diseases characterized by the development of either neurofibromas and MPNSTs [neurofibromatosis type 1 (NF1)] or schwannomas [neurofibromatosis type 2 (NF2), schwannomatosis and Carney complex type 1] has greatly advanced our understanding of these mechanisms. The development of genetically engineered mice with ablation of NF1, NF2, SMARCB1/INI1 or PRKAR1A has confirmed the key role these genes play in peripheral nerve sheath tumorigenesis. Establishing the functions of the NF1, NF2, SMARCB1/INI1 and PRKAR1A gene products has led to the identification of key cytoplasmic signaling pathways promoting Schwann cell neoplasia and identified new therapeutic targets. Analyses of human neoplasms and genetically engineered mouse models have established that interactions with other tumor suppressors such as TP53 and CDKN2A promote neurofibroma-MPNST progression and indicate that intratumoral interactions between neoplastic and non-neoplastic cell types play an essential role in peripheral nerve sheath tumorigenesis. Recent advances have also provided new insights into the identity of the neural crest-derived populations that give rise to different types of peripheral nerve sheath tumors. Based on these findings, we now have an initial outline of the molecular mechanisms driving the pathogenesis of neurofibromas, MPNSTs and schwannomas. However, this improved understanding in turn raises a host of intriguing new questions.

Syndrome of early onset colon cancers, hematologic malignancies & features of neurofibromatosis in HNPCC families with homozygous mismatch repair gene mutations.

Hereditary nonpolyposis colon cancer (HNPCC) is the most common hereditary colon cancer syndrome. It is characterized by multiple colon as well as extracolonic cancers such as endometrial, ovarian and urinary tract cancers. In addition, it is well known that some cases of HNPCC can present with unique tumor spectrums such as sebaceous tumors, which is often referred to as the 'Muir-Torre' syndrome. In recent years there have been a few reports of families presenting with early onset of colon tumors along with café-au-lait spots and/or hematologic malignancies often associated with homozygous mutations involving one of the mismatch repair genes. In this article we have performed a comprehensive review of the entire medical literature to identify all cases with similar presentations reported in the literature and have summarized the clinical features and genetic test results of the same. The available data clearly highlight such presentations as a distinct clinical entity characterized by early onset of gastrointestinal tumors, hematologic malignancies as well as features of neurofibromatosis (easily remembered by the acronym ;CoLoN'; Colon tumors or/and Leukemia/Lymphoma or/and Neurofibromatosis features). Furthermore, there has also been some evidence that the neurofibromatosis type-1 gene is a mutational target of the mismatch repair deficiency that is seen in families with HNPCC, and that mlh1 deficiency can accelerate the development of leukemia in neurofibromatosis (Nf1) heterozygous mice. Recognition of this syndrome has significant importance in terms of earlier detection of cancers, cancer screening recommendations as well as genetic counseling offered to such families.

Neurocutaneous syndromes: behavioral features.

Neurocutaneous syndromes are disorders characterized by a neurological abnormality and cutaneous manifestations. Three of the more common neurocutaneous syndromes are Sturge-Weber syndrome, tuberous sclerosis, and neurofibromatosis. This review focuses on the cognitive and behavioral features of these syndromes.

[Peripheral, central neurofibromatosis and multiplex meningiomas (a historical review)]. / TT

Despite that the neurofibromatosis and the multiplex meningiomas have been known for centuries, it is hardly during the last decade that a significant progress has been achieved in the understanding of their etiology and pathogenesis. The development of the concept for NF is being followed from the time of the first descriptions till today.

Glomus tumors.

The authors report a series of 12 consecutive patients with 13 glomus tumors operated from July 1991 until February 1999. Symptoms were present for an average of 1.9 years before surgery. Women were more frequently affected. The mean age was 44 years. In 12 of the 13, the tumor was located in the distal phalanx and one patient had a glomus tumor on the dorsum of the hand. One glomus tumor was found in the right hallux of a two-year-old child. Both hands and all fingers were equally involved. One bilateral glomus tumor was associated with neurofibromatosis. All tumors were resected and histology confirmed the diagnosis. The result was good with immediate pain relief. No recurrence has been noted to date.

Multiple bilateral thoracic meningoceles without neurofibromatosis: a case report.

Lateral thoracic meningoceles are rare and, in most cases, they are associated with neurofibromatosis. We report a case in which computerized tomography (CT)-myelography established the diagnosis of multiple, bilateral, lateral, thoracic meningoceles without neurofibromatosis. Plain film radiographs are necessary to evaluate any associated kyphoscoliosis and its progression. CT and magnetic resonance imaging demonstrate the extent of bony erosion, and the size and number of lateral thoracic meningoceles. CT-myelography reveals contrast medium in the meningoceles and is the major diagnostic imaging modality.

Mid-aortic syndrome presenting in childhood.

Mid-aortic syndrome (MAS) is an uncommon condition characterized by segmental narrowing of the proximal abdominal aorta and ostial stenosis of its major branches. It is usually diagnosed in young adults, but may present in childhood as a challenging problem. Over the past 20 years 13 patients with MAS have presented to this institution. All had hypertension, four had associated neurofibromatosis, three persistent eosinophilia and three had Williams syndrome. In all cases arteriography showed a smooth segmental narrowing of the abdominal aorta with concomitant stenosis at the origins of the renal arteries. Six children were successfully treated with antihypertensive medication alone. Percutaneous transluminal angioplasty was attempted in two cases with poor result. Surgery was indicated in seven children with refractory hypertension and progressive renal impairment. Techniques used to revascularize the kidneys included thoracoabdominal to infrarenal aortic bypass with renal artery reimplantation, splenorenal bypass, gastroduodenal to renal bypass, aortorenal bypass and autotransplantation.