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Disorders of Keratinization and Other Genodermatoses
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Roselyn Stanger, Nanette Silverberg
Definition: This is a very rare autosomal dominant RASopathy characterized by lax (or redundant) skin (especially over the neck, hands, and feet), internal organ involvement (primarily cardiac), increased risk of malignancies, and severe feeding difficulties. Most patients have de novo mutations.
Noonan Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Being the most common RASopathy, Noonan syndrome results from germline mutations in the PTPN11, SOS1, SOS2, KRAS, NRAS, RIT1, RAF1, LZTR1, and A2ML1 genes, all of which encode key components of the RAS/MAPK pathway, profoundly affecting multisystem development (Table 93.1) [3].
Haematology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
JMML is a heterogeneous myeloproliferative disorder. Germline or somatic mutations of four genes of the RAS signal transduction pathway (Rasopathy), namely: PTPN11, CBL, NF1 and RAS play a pivitol role in its pathogenesis. These RAS pathway mutations represent major somatic events that contribute to oncogenesis. In addition, monosomy occurs frequently in JMML but its significance is not known.
Emerging therapeutic targets for neurofibromatosis type 1
Published in Expert Opinion on Therapeutic Targets, 2018
James A. Walker, Meena Upadhyaya
The NF1 gene encodes neurofibromin, a ubiquitously expressed protein, which functions as a RAS-GTPase-activating protein (RAS-GAP), a negative regulator of RAS activity. Consequently, neurofibromin deficiency leads to increased RAS signaling which is assumed to be the root cause of NF1 pathology. NF1 is classified as a RASopathy – a group of clinically related disorders which include Noonan syndrome, Noonan with multiple lentigines, Costello, cardiofacio-cutaneous, capillary malformation-arteriovenous malformation, gingival fibromatosis, and autoimmune lymphoproliferative syndrome that arise due to mutations in multiple genes encoding components of the RAS-MEK-ERK pathway [6].
A case of Costello syndrome diagnosed by trio whole exome sequencing
Published in Journal of Obstetrics and Gynaecology, 2022
Helen McDermott, Pallavi Karkhanis, Samantha Doyle, Harsha Gowda
Phenotypic variation is wide, from mild to severe lethal forms. RASopathies have overlapping features, caused by changes disrupting the Ras-MAPK pathway, affecting growth and development. Postnatal phenotypes overlap with Noonan, cardiofaciocutaneous (CFC), Beckwith-Wiedemann, Noonan syndrome with multiple lentigines and Simpson-Golabi-Behmel syndromes. The prenatal phenotype is less well-described. Analysis of causative genes as a Rasopathy panel or exome sequencing allows a definitive molecular diagnosis (Gripp and Rauen 2006).
Recent advances in genetic predisposition to pediatric acute lymphoblastic leukemia
Published in Expert Review of Hematology, 2020
Mackenzie Bloom, Jamie L. Maciaszek, Mary Egan Clark, Ching-Hon Pui, Kim E. Nichols
Given the increasing number, as well as the phenotypic and genotypic heterogeneity of leukemia predisposing conditions, it is highly recommended that genetic evaluations be completed in consultation with providers who are familiar with these disorders. Generally, these providers include oncologists, geneticists, and genetic counselors who will: 1) collect a medical history of the patient to assess for features such as easy bruising or bleeding (an indicator of possible thrombocytopenia or platelet functional defects as in ETV6-related predisposition to ALL or FPDMM) and developmental delays/behavioral problems (as can be seen in NF1); 2) gather family history information about close blood relatives (first or second degree) who may have also developed leukemia or other cancers, or exhibited evidence of cytopenias; 3) complete a physical examination to look for syndrome-specific features such as CALMs (NF1/RASopathy, CMMRD), axillary/inguinal freckling (NF1), and typical facial and other physical features (RASopathy); and 4) review tumor data focusing on findings such as low hypodiploidy (LFS), isochromosome or dicentric chromosome 9q (PAX5), hypermutator phenotype (CMMRD), and presence of somatic variants within genes indicative of a possible predisposition [165]. Clinical germline testing should be considered for any individual with leukemia who exhibits one or more concerning features, such as: 1) a personal history of multiple cancers; 2) a strong family history of cancers, especially those developing at earlier than expected ages; 3) hematopoietic malignancies diagnosed in two individuals within a three-generation pedigree; 4) a personal history or close relative with one or more cytopenias; and 5) a personal history or close relative with physical findings associated with a known predisposition syndrome. Genetic testing of leukemic blasts can also provide clues to an underlying leukemia predisposition, such as presence of pathogenic variants affecting PAX5 (with isochromosome or dicentric chromosome 9q), ETV6, IKZF1, NF1, PTPN11, or TP53 at an allele frequency of ~30–50%. Such cases suggest the possibility of germline heterozygosity and should prompt genetic testing, as discussed below (Section 5.2 Genetic testing for germline predisposition to ALL).