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Concept: Neurofibromatosis type I

156

A 62-year-old female with neurofibromatosis type 1 (NF1; also von Recklinghausen’s disease) was diagnosed with a giant, thick-walled tubular mass, mainly located in the right abdominal area on computed tomography, following an examination for intermittent abdominal pain and increasing abdominal distension. According to the clinical manifestations and imaging features, the giant tubular mass was considered most likely to be a dilated fallopian tube associated with infection, while the possibility of obstructed bowel loops was excluded. However, the subsequent laparotomy revealed a giant appendix, caused by a large neurofibroma in the root region of the appendix, which occluded the lumen. Neurofibroma of the appendix is extremely rare, even in patients with NF1. To the best of our knowledge, only three such cases have previously been reported in the English literature to date.

Concepts: Neurology, Abdominal pain, Bowel obstruction, Neurofibromatosis type I, Neurofibromatosis, Abdominal distension, Friedrich Daniel von Recklinghausen, Café au lait spot

148

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment.

Concepts: Nervous system, Cancer, Oncology, Evolution, Brain tumor, Anatomical pathology, Neurology, Neurofibromatosis type I

28

Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes 30-50 % of affected individuals to develop plexiform neurofibromas. We found that macrophage infiltration of both mouse and human neurofibromas correlates with disease progression. Macrophages accounted for almost half of neurofibroma cells, leading us to hypothesize that nerve macrophages are inflammatory effectors in neurofibroma development and/or growth. We tested the effects of PLX3397, a dual kit/fms kinase inhibitor that blocks macrophage infiltration, in the Dhh-Cre; Nf1 ( flox/flox ) mouse model of GEM grade I neurofibroma. In mice aged 1-4 months, prior to development of nerve pathology and neurofibroma formation, PLX3397 did not impair tumor initiation and increased tumor volume compared to controls. However, in mice aged 7-9 months, after tumor establishment, a subset of mice demonstrating the largest reductions in macrophages after PLX3397 exhibited cell death and tumor volume regression. Macrophages are likely to provide an initial line of defense against developing tumors. Once tumors are established, they become tumor permissive. Macrophage depletion may result in impaired tumor maintenance and represent a therapeutic strategy for neurofibroma therapy.

Concepts: Cancer, Death, Effect, Apoptosis, Neurology, Neurofibromatosis type I, Neurofibromatosis, Neurofibroma

28

Malignant peripheral nerve sheath tumors (MPNSTs) occur sporadically, after prior radiation therapy (RT), or in association with neurofibromatosis type 1 (NF1). It is controversial whether patients with NF1-associated MPNST have worse outcomes. We investigated the prognostic significance of sporadic, NF1-associated, and RT-induced MPNST.

Concepts: Medicine, Cancer, Oncology, Medical terms, Action potential, Neurofibromatosis type I, Malignant peripheral nerve sheath tumor, Nerve sheath tumor

27

Defects in the RAS small G protein or its associated network of regulatory proteins that disrupt GTPase cycling are a major cause of cancer and developmental RASopathy disorders. Lack of robust functional assays has been a major hurdle in RAS pathway-targeted drug development. We used NMR to obtain detailed mechanistic data on RAS cycling defects conferred by oncogenic mutations, or full-length RASopathy-derived regulatory proteins. By monitoring the conformation of wild-type and oncogenic RAS in real-time, we show that opposing properties integrate with regulators to hyperactivate oncogenic RAS mutants. Q61L and G13D exhibited rapid nucleotide exchange and an unexpected susceptibility to GAP-mediated hydrolysis, in direct contrast with G12V, indicating different approaches must be taken to inhibit these oncoproteins. An NMR methodology was established to directly monitor RAS cycling by intact, multidomain proteins encoded by RASopathy genes in mammalian cell extracts. By measuring GAP activity from tumor cells, we demonstrate how loss of neurofibromatosis type 1 (NF1) increases RAS-GTP levels in NF1-derived cells. We further applied this methodology to profile Noonan Syndrome (NS)-derived SOS1 mutants. Combining NMR with cell-based assays allowed us to differentiate defects in catalysis, allosteric regulation, and membrane targeting of individual mutants, while revealing a membrane-dependent compensatory effect that attenuates dramatic increases in RAS activation shown by Y337C, L550P, and I252T. Our NMR method presents a precise and robust measure of RAS activity, providing mechanistic insights that facilitate discovery of therapeutics targeted against the RAS signaling network.

Concepts: DNA, Protein, Gene, Cancer, Signal transduction, Cell membrane, Regulation, Neurofibromatosis type I

25

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.

Concepts: Neurofibromatosis type I, Café au lait spot

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BACKGROUND Pancreatic endocrine tumors (PETs) are rare and can occur as part of neurofibromatosis type 1 (NF1). Gastrinomas are functional PETs that are rarely associated with NF1. Only two cases of their occurrence have been reported in the literature. CASE REPORT A 28-year-old woman was admitted for further evaluation of epigastric soreness, heartburn, nausea, vomiting, diarrhea, and a significant weight loss. Physical examination was remarkable for cutaneous findings (axillary freckling and multiple café-au-lait spots) as well as neurofibromas (dermal, plexiform). A diagnosis of NF1 was confirmed. Esophagogastroduodenoscopy (EGD) revealed multiple ulcers in the duodenum and the upper jejunum. A fasting gastrin level exceeded ten times the normal limit. An abdominal multi-slice 128 computed tomography (CT) scan revealed an oval mass of 26 mm in diameter adjacent to the second section of the duodenum. The patient was examined carefully to rule out multiple endocrine neoplasia type 1 (MEN1). Surgical resection was performed and a gastrinoma, causing Zollinger-Ellison syndrome (ZES), was diagnosed by histological examinations of the extirpated mass. The serum gastrin level decreased to normal limits shortly after surgery. Continuous follow-up revealed that the symptoms and the EGD findings completely resolved without recurrences. CONCLUSIONS Although NF1 has common skeletal, visual, neurological, and cardiovascular complications, it also has a rare association with duodenal or pancreatic gastrinomas. Vigilance for this possible association is important to promote timely and careful management to help eliminate serious and potentially life-threatening complications.

Concepts: Cancer, Endocrinology, Neurofibromatosis type I, Multiple endocrine neoplasia, Neurofibromatosis, Zollinger-Ellison syndrome, Gastrin, Gastrinoma

23

The earliest examples of neurofibromatosis (in this case type 1, NF1) can be traced in the Ebers Papyrus (Ancient Egypt, 1.500 B.C.), in a Hellenistic statuette (Smyrna, 323 B.C.), in the coinage of the Parthians kings (247 B.C.) and in some 13th century monks' drawings. These earlier examples are somewhat less well defined as compared to the most recent better defined reports credited as having NF1 including an Inca child mummy (1480-1650 AD), Ulisse Aldrovandi’s homuncio (“Monstrorum Historia”, 1592 A.D.) with mosaic NF1 or the illustrations seen in the 18th century “Buffon’s Histoire Naturelle” and “Cruveilhier’s Anatomie Pathologique du Corps Human”. The first English language report on NF1 was made by Akenside in 1768 and the first systematic review by Robert William Smith in 1849, while Virchow’s pupil, Friedrich Daniel von Recklinghausen, in 1882, was the first to understand the origin of skin tumors and to name them neurofibromas. The touching story of Joseph C. Merrick (the “Elephant man,” (who had Proteus syndrome and not NF1), in 1884, played an important role in the later misconception of NF1, as did the novel by Vicotr Hugo on the hunchback Quasimodo. The studies by van der Hoeve (1921), Yakovlev and Guthrie (1931), and Van Bogaert (1935), categorized “von Recklinghausen’s” neurofibromatosis among the phakomatoses and the neurocutaneous syndromes. The first known mention of an acoustic neuroma (at autopsy) is attributed to Eduard Sandifort (1777 AD) while John H. Wishart made the earliest autoptic description of neurofibromatosis type 2 (NF2), in 1822, in a 21-year-old man with bilateral acoustic neuromas, who manifested signs since his infancy (Wishart subtype NF2). Smith likely described the first case of schwannomatosis in 1849. Older, Virchow, von Recklinghausen, and Verocay first classified “neuromas” and Masson and Penfield first used the word “schwannoma” taking it from Theodore Schwann’s works. In 1903 Henneberg and Koch described NF2 in detail. Young, Eldridge, and Gardner, in the late ‘70, established NF2 as a distinct familial entity (Gardner subtype NF2). Schwannomatosis, the late entry of the different forms of neurofibromatosis, was credited in the middle '90.

Concepts: Neurology, Neurofibromatosis type I, Ancient Egypt, Neurofibromatosis, Schwannoma, Friedrich Daniel von Recklinghausen, Joseph Merrick, Ulisse Aldrovandi

8

Neurofibromatosis 1 (NF1) is a complex and multifaceted neurocutaneous syndrome with many and varied comorbidities. The literature about the prevalence and degree of maternal stress and the impact of NF1 in the parent-child interaction is still scant. The aim of this study was to evaluate the prevalence of maternal stress in a large pediatric sample of individuals affected by NF1.

Concepts: Neurofibromatosis type I

7

The current study was designed to determine the risk of cancer in patients with neurofibromatosis type 1 (NF1) by cancer type, age, and sex with unprecedented accuracy to be achieved by combining two total population-based registers.

Concepts: The Current, Neurofibromatosis type I, Neurofibromatosis, Café au lait spot