Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (cafe-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.

Neurofibromatosis type 1.

Noonan syndrome and clinically related disorders

In 5-10% of patients, neurofibromatosis type 1 (NF1) results from microdeletions that encompass the entire NF1 gene and a variable number of flanking genes. Two recurrent microdeletion types are found in most cases, with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP–c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion). A more severe phenotype is usually associated with NF1 microdeletion patients than in those with intragenic mutations. We characterized NF1 microdeletions in 70 unrelated NF1 microdeleted patients using a high-resolution NF1 custom array comparative genomic hybridization (CGH). Genotype-phenotype correlations were studied in 58 of these microdeletion patients and compared to 389 patients with intragenic truncating NF1 mutations and phenotyped in the same standardized way. Our results confirmed in an unbiased manner the existence of a contiguous gene syndrome with a significantly higher incidence of learning disabilities and facial dysmorphism in microdeleted patients compared to patients with intragenic NF1 mutations. Microdeleted NF1 patients also showed a trend toward significance for childhood overgrowth. High-resolution array-CGH identified a new recurrent ∼1.0 Mb microdeletion type, designated as type-3, with breakpoints in the paralogous regions middle NF1-REP-b and distal NF1-REP–c.

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NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype†

Neurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS. NF1 exhibits variable clinical expression and is characterized by benign cutaneous lesions including neurofibromas and cafe-au-lait macules, as well as a predisposition to various types of malignancy, such as breast cancer and leukaemia. However, acquired somatic mutations in NF1 are also found in a wide variety of malignant neoplasms that are not associated with NF1. Capitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context. As neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma. Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1. Somatic NF1 mutations may be critical drivers in multiple cancers. The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer. The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1.

/pdf/the-nf1-somatic-mutational-landscape-in-sporadic-human-ev6grz5ddm.pdf

The NF1 somatic mutational landscape in sporadic human cancers

RAS GTPases control a major signaling network implicated in several cellular functions, including cell fate determination, proliferation, survival, differentiation, migration, and senescence. Within this network, signal flow through the RAF-MEK-ERK pathway, the first identified mitogen-associated protein kinase (MAPK) cascade, mediates early and late developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Signaling through the RAS-MAPK cascade is tightly controlled, and its enhanced activation represents a well-known event in oncogenesis. Unexpectedly, in the past few years, inherited dysregulation of this pathway has been recognized as the cause underlying a group of clinically related disorders sharing facial dysmorphism, cardiac defects, reduced postnatal growth, ectodermal anomalies, variable cognitive deficits and susceptibility to certain malignancies as major features. These disorders are caused by heterozygosity for mutations in genes encoding RAS proteins, regulators of RAS function, modulators of RAS interaction with effectors or downstream signal transducers. Here, we provide an overview of the phenotypic spectrum associated with germline mutations perturbing RAS-MAPK signaling, the unpredicted molecular mechanisms converging towards the dysregulation of this signaling cascade, and major genotype-phenotype correlations.

/pdf/disorders-of-dysregulated-signal-traffic-through-the-ras-3y72biwucz.pdf

Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms

Context Autosomal dominant inactivating sprouty-related EVH1 domain–containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with cafe au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation. Objective To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1–like syndrome (NFLS) in a large cohort of patients. Design, Setting, and Participants In a cross-sectional study, 22 unrelated probands carrying a SPRED1 loss-of-function (LOF) mutation identified through clinical testing participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1318 unrelated anonymous samples collected in 2003-2007 from patients with a broad range of signs typically found in neurofibromatosis type 1 (NF1) but no detectable NF1 germline mutation underwent SPRED1 mutation analysis. Main Outcome Measures Comparison of aggregated clinical features in patients with or without a SPRED1 or NF1 mutation. Functional assays were used to evaluate the pathogenicity of missense mutations. Results Among 40 SPRED1 LOF-positive individuals from the clinical cohort, 20 (50%; 95% confidence interval [CI], 34%-66%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. None of the 40 SPRED1 LOF-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas. In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 26 pathogenic mutations in 33 probands and 8 probable nonpathogenic missense or silent mutations in 10 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73%; 95% CI, 63%-80%) had an NF1 mutation and 18 (19%; 95% CI, 12%-29%) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS. Conclusions A high SPRED1 mutation detection rate was found in NF1 mutation–negative families with an autosomal dominant phenotype of CALMs with or without freckling and no other NF1 features. Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1.

https://jamanetwork.com/journals/jama/articlepdf/184897/joc90124_2111_2118.pdf

Robert Pedersen

Papers

Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome.