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Central nervous system: Paediatric and neurodevelopmental disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
A more severe phenotype is often found in those whose mutation is a whole gene deletion of NF1. A milder variant is caused by a specific 3 bp deletion and typically causes cafe-au-lait patches but very few tumours. NF1 is also milder when it is segmental, arising by somatic mutation, but any affected children of such a parent will be fully affected. An important differential diagnosis of NF1 is Legius syndrome, caused by mutations in SPRED1, in which skin pigmentation and other features are found but in which Lisch nodules and tumours are unlikely to develop.
Genodermatoses
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
In Legius syndrome (NF1-like syndrome), a heterozygous mutation in the SPRED1 gene is responsible for the phenotype. Individuals with Legius syndrome present with multiple café-au-lait spots with or without freckling. Diagnosis based on clinical features alone is not possible, because of the important clinical overlap with NF1. Learning disabilities, developmental delay, hyperactivity, autistic behavior, and concentration problems are frequently reported in children with Legius syndrome. On the other hand, patients do not show some associations with NF1 tumors, such as optic pathway gliomas and neurofibromas, bone abnormalities, or Lisch nodules. The intense medical surveillance that is needed for NF1 is not required in this syndrome.10
CBL Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
As the most common RASopathy (NCFCS), Noonan syndrome in its classic form is characterized by facial dysmorphism (broad forehead, hypertelorism, down-slanting palpebral fissures, low-set-posteriorly rotated ears), congenital heart defect, postnatal growth retardation, ectodermal and skeletal defects (webbed and/or short neck), variable cognitive deficits, cryptorchidism, lymphatic dysplasias, bleeding tendency, and occasionally childhood hematologic malignancies (particularly JMML); with germline mutations in the PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11), SOS1 (son of sevenless homolog 1), RAF1, KRAS, NRAS, LZTR1 and A2ML1 genes underpinning its molecular pathogenesis (see Chapter 93 in this book for further details) [5–7]. Variants of Noonan syndrome include Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome, which is characterized by lentigines (dark spots on the skin), electrocardiographic conduction defects (abnormalities of the electrical activity of the heart), ocular hypertelorism (widely spaced eyes), pulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart), abnormalities of the genitalia, retarded/slowed growth resulting in short stature, and deafness (due to mutations in the PTPN11, RAF1 and BRAF genes), Noonan-like syndrome with loose anagen hair (NS/LAH, due to mutation in the SHOC2 gene) [8], and CBL syndrome (Noonan syndrome-like disorder with or without JMML, due to mutation in the CBL gene). Other related disorders include cardio-facio-cutaneous syndrome (CFCS, due to gain of function mutations in the BRAF, MAP2K1 [mitogen activated protein kinase 1], MAP2K2, and KRAS genes), Costello syndrome (due to activating mutations in the HRAS gene), Legius syndrome (due to inactivating mutations in the SPRED1 gene), neurofibromatosis type 1 (NF1, due to loss of function mutations in the NF1 gene encoding neurofibromin), and capillary malformation–arteriovenous malformation syndrome (CM-AVM, due to loss of function mutations in the RASA1 gene) (Table 87.1) [9–11].
A RAS inhibitor reduces allergic airway remodeling via regulating IL-33-derived type 2 innate lymphoid cells
Published in Experimental Lung Research, 2021
Toshifumi Tezuka, Masahiko Azuma, Hirohisa Ogawa, Mayo Kondo, Hisanori Uehara, Yoshinori Aono, Masaki Hanibuchi, Yasuhiko Nishioka
Corticosteroid resistance of ILC2s was induced by IL-7 and TSLP by a mitogen-activated protein kinase kinase (MEK), which belongs to the RAS-ERK pathway, and was STAT5-dependent.8 IL-33/ST2 signaling patterns are similar to IL-1 stimulation through IL-1R, which induces IκB phosphorylation and the activation of mitogen-activated kinases (MAPK), such as ERK 1/2, p38 and JNK.11 In the case of ILC2 activation by IL-33, the ERK signaling pathway plays an essential role for IL-5 and IL-13 production, although NF-κB and JNK are not deeply involved.11,12 Sprouty-related Ena/VASP homology 1 domain-containing protein (Spred1) negatively regulates lung inflammation by inhibition of IL-33-induced activation of the RAS-ERK signaling pathway.12 Spred1 also suppresses ILC2s proliferation and cytokine production. However, it is unknown if the RAS signal pathway in ILC2s activated by IL-33 is involved in corticosteroid resistance in allergic asthma.
Mucosal melanoma: current strategies and future directions
Published in Expert Opinion on Orphan Drugs, 2019
Shaheer Khan, Richard D. Carvajal
Another study extracted DNA from 43 patients with MM and performed targeted sequencing, which also demonstrated relatively low somatic mutation burden with increased genomic instability [64]. This study identified a frequently deleted region at chromosome band 15q14, which occurred in 21% of cases and included the SPRED1 locus, which is a negative regulator of the Ras-MAPK pathways [65]. Overall, 37% of the samples exhibited evidence of SPRED1 loss of function. Using a zebrafish genotype model and a clustered regularly interspaced short palindromic repeats (CRISPR) technique to inactivate spred1, the investigators found that SPRED1 functioned as a tumor suppressor in patients with KIT mutations and conferred resistance to KIT inhibition. These findings suggest a rationale for MAPK co-inhibition in patients being treated for KIT-mutated MM.
Emerging therapeutic targets for neurofibromatosis type 1
Published in Expert Opinion on Therapeutic Targets, 2018
James A. Walker, Meena Upadhyaya
The most common nonneoplastic manifestations in NF1 are pigmentary features, including CALMs which are dense populations of melanocytes observed in 99% of NF1 patients and are used in early childhood diagnosis. Cognitive and behavioral deficits occur in 65–80% of children with NF1. Specific learning disabilities affecting performance in visuospatial tasks, literacy skills, and oral and written expression often lead to poor academic performance [10]. Further, attention-deficit hyperactivity disorder (ADHD) symptoms such as decreased impulse control and planning ability have also been observed [11]. Other non-tumor symptoms in NF1 include skeletal abnormalities, iris hamartomas (Lisch nodules), and reduced overall growth. NF1 patients are also at increased risk of developing neurofibromatous neuropathies [12]. Cardiovascular manifestations of NF1 include vasculopathy, hypertension, and congenital heart defects. Patients with constitutional mismatch repair deficiency (CMMRD) and Legius syndrome (caused by germline SPRED1 mutation) may have overlapping clinical symptoms, underlying the need for molecular diagnosis [13].