The RASopathies: Genetic Syndromes of the RAS/MAPK Pathway

Preface
Contents
Contributors
What Is a RASopathy?
	Introduction
	Clinical Aspects of the RASopathies
	RASopathies Are Cancer Predisposition Syndromes
	Modeling RASopathies and Small Molecule Inhibitor Treatment
	Defining a RASopathy
	Summary
	References
Neurofibromatosis Type 1
	Introduction
	History
	Diagnosis
		Clinical Manifestations
	Natural History
	Management
	Genetics of NF1
		Pipeline of NF1 Genetic Testing
	Molecular Genetics of NF1: Disease Mechanisms
		NF1 Signaling Pathways: RAS, cAMP, ERa, and Other Interacting Proteins
		Additional NF1 Interacting Proteins
		Cellular Localization Is Critical for NF1 Functions
		NF1 and the Tumor Microenvironment (TME)
	MEK Inhibitors in the Treatment of NF1
		MEKi in Plexiform Neurofibromas
		MEKi in Atypical Neurofibromas and Malignant Peripheral Nerve Sheath Tumors
		MEKi in Low-Grade Gliomas
		MEKi and Neurocognitive Outcomes
		Other MEKi Clinical Trials
		MEKi Side Effects
	Conclusion
	References
Legius Syndrome
	Introduction
		Legius Syndrome: Clinical Features
	When to Expect a SPRED1 Pathogenic Variant?
	Diagnostic Criteria
	Differential Diagnosis
	How to Discriminate Between NF1 and Legius Syndrome?
	Neurocognitive Aspects
	Predisposition to Malignancies and Vascular Abnormalities
		Legius Syndrome: Molecular Features
		Legius Syndrome: Animal Models
	Conclusions
	References
Noonan Syndrome
	Overview of Noonan Syndrome
	Epidemiology of Noonan Syndrome
	RAS/MAPK Pathway
	Inheritance
	Prenatal Findings
	Diagnosis
	Growth
	Gastrointestinal Complications
		Feeding
		Growth Delay and Nutrition
		Upper GI Issues
		Lower GI Issues
	Cardiovascular Features
		Congenital Heart Disease
		Cardiomyopathy
		Novel Cardiac Management
	Orthopedic and Musculoskeletal Issues
	Dermatologic Complications
	Lymphatic Disorders
		Pulmonary Lymphangiectasia
		Intestinal Lymphangiectasia
	Neurodevelopmental Features
	Ophthalmologic Complications
	Audiological Complications
	Pulmonary Complications
	Autoimmune Complications
	Genitourinary Features
	Hematologic Issues
	Cancer Incidence and Screening
	CNS Complications
	Conclusions
	References
Noonan Syndrome with Multiple Lentigines
	History
	Clinical Features of NSML
	Diagnosis
	Molecular Biology of NSML
	Current Therapeutic Approaches for Treatment of NSML
	Future Perspectives
	Summary
	References
Costello Syndrome
	Identification of the Causative Gene of Costello Syndrome
	Clinical Features
	Phenotype of Adult Individuals
	Prevalence
	Molecular Genetics and Genotype–Phenotype Correlation
	Diagnosis and Treatment
	Molecular Pathogenesis
	Animal Models
	Summary and Future Perspectives
	References
Cardio-Facio-Cutaneous Syndrome
	Early History of Cardio-Facio-Cutaneous Syndrome
	Clinical Phenotype of Cardio-Facio-Cutaneous Syndrome
	Genes Associated with Cardio-Facio-Cutaneous Syndrome
		BRAF Gene
		MAP2K1 and MAP2K2 Genes
		KRAS Gene
		YWHAZ Gene
	Diagnosing CFC
	Mouse Models for CFC
	Future Aspects and Treatment for CFC
	Summary
	References
Capillary Malformation-Arteriovenous Malformation Syndrome
	Introduction
	Prevalence and Clinical Presentation
	Genetics and Molecular Function
		RASA1
		EPHB4
		Genetic Counseling
	CM-AVM Clinical Phenotype
		Cutaneous Lesions
		Epistaxis
		Fast-Flow Lesions
			Intracranial
				Pial AVFs
				Vein of Galen Aneurysmal Malformations
			Extracranial
				Spinal AVMs
				Visceral AVMs
				Peripheral AVMs
				Parkes–Weber Syndrome
			Central Nervous System Fast-Flow Lesion Screening
	Treatment
	Differential Diagnosis
		Sporadic CMs and AVMs
		Hereditary Benign Telangiectasia
		Arterial Metameric Syndromes
		Hereditary Hemorrhagic Telangiectasia
		Sturge–Weber Syndrome
	Conclusion
	References
SYNGAP1: The Gene and Syndrome
	Introduction
	The Gene SYNGAP1
		Molecular Structure and Patterns of Expression
	Cellular and Molecular Function
		Neuronal Development: Dendritic Spine Formation and Synapse Maturation
		Synaptic Plasticity
	Neuronal Networks
		E/I Balance, Circuits, and Critical Period Plasticity
		EEG Signatures
	SYNGAP1-ID the Syndrome
		Genotype–Phenotype Correlations
		Developmental Delay and Cognition
		Epilepsy
		Sleep
		Behavior
		Other Features
		Routine Care
	Translational Biomarkers
	Conclusion
	References
Central Conducting Lymphatic Anomalies
	Central Conducting Lymphatic Anomaly (CCLA) Within Complex Lymphatic Anomalies (CLAs)
		CCLA
		Other Types of CLAs
		Different Types, the Same Disease Spectrum
	Lymphatic Development and the PI3K/AKT/mTOR and RAS/MAPK Signaling Pathways
		Lymphatic Development
		The PI3K/AKT/mTOR Signaling Pathway
		The RAS/MAPK Signaling Pathway
	Genetics of CCLAs
		Somatic ARAF Variant
		Somatic PIK3CA Variants
		Somatic KRAS Variants
		Germline EPHB4 Variant
		Germline MDFIC Variants
		Germine RASA1 Variants
		Other Germline Variants of RASopathies Genes in CCLA
	Diagnosis and Differential Diagnosis of CCLA
		Clinical Findings
		Imaging
		Laboratory Investigation
	Therapeutic Strategies for CCLA
		Potential Etiological Medications
		Comprehensive Management
	Challenges and Future Directions
	References
Defining Pathogenic Variants in RASopathies
	Introduction
	Gain-of-Function Pathogenic Variation
	Loss-of-Function Pathogenic Variation
	Variant Classification Guidelines and Recommendations
	Assessment of Evidence from Normal Population Data
	Assessment of Evidence from Gene-Centric Knowledge
	Assessment of Evidence from Case-Centric Knowledge
	Impact of Clinical Data and Other Findings
	Examples of Classifying Variants in Association with a RASopathy
		Autosomal-Dominant GOF Case Example (Table 2): MAP2K2 c.169T>G (p.Phe57Val) and CFC
		Autosomal-Dominant LOF Case Example (Table 3): NF1 c.31C>T (p.Gln11Ter) and NF1
		Autosomal Recessive LOF Case Example (Table 4): LZTR1 (NM_006767.4):c.1943-256C>T; p.Thr648fs*36 and NS
		Dominant-Negative Case Example (Table 5): PTPN11 (NM_030662.4):c.836A>G; p.Tyr279Cys and NSML
		Analogous Gene Grouping Example (Table 6): RRAS2 (NM_012250.6):c.68G>T; p.Gly23Val and NS
	Discussion
	References
Molecular Genetics of Noonan Syndrome and Other RASopathies
	Introduction
	RAS/MAPK Signaling
	Upregulated Activity of Various GTPases of the RAS Family
		HRAS, KRAS, and NRAS
		RRAS, RRAS2, and MRAS
		RIT1
	Increased Function of Signal Transducers That Positively Control RAS Activity
		PTPN11
		SOS1 and SOS2
	Enhanced Function of Proteins That Mediate RAS Interactions with RAF Kinases
		SHOC2 and PPP1CB
		YWHAZ
	Functional Upregulation of Proteins Belonging to the MAPK Cascade
		RAF1 and BRAF
		MAP2K1 and MAP2K2
		MAPK1
	Inefficient Signaling Switch-Off Operated by Feedback Mechanisms Acting at Different Levels
		NF1 and SYNGAP 1
		SPRED1 and SPRED2
		LZTR1
		CBL
	Other Pathways
		CDC42
	Closing Remarks
	References
Comprehensive Care for Patients with RASopathies
	Introduction
	Fetal and Neonatal Period
	Infancy and Early Childhood
	Preschool and Early School Age
	Adolescence
	Transition of Care and Adulthood
	Discussion
	References
Precision Medicine in RASopathies: Tailored Disease Management Through Enhanced Approaches, Disease Delineation, and Pathway-Specific Therapies
	The Essence of Precision Medicine
	RASopathies: Genetic Diversity and Tailored Clinical Management
	References
Genetic Counseling and the RASopathies
	Introduction
	Genetic Counseling: Before the Diagnosis
		Test Selection
		Laboratory Selection
		Pretest Genetic Counseling
	Genetic Counseling: Diagnosis Disclosure
		Variant Interpretation
		Psychosocial Support
		Anticipatory Guidance and Management
		Support and Resources
	Genetic Counseling: Inheritance and Reproductive Risks
		Neurofibromatosis Type 1
		Legius Syndrome
		Noonan syndrome (NS) and Noonan Syndrome with Multiple Lentigines (NSML)
		LZTR1-Related NS
		Costello Syndrome
		CFC Syndrome
		SYNGAP1-Related Intellectual Disability (SYNGAP1)
		Congenital Malformation-Arteriovenous Malformation Syndrome (CM-AVM)
	Reproductive Risks and Screening Options
	Conclusion
	References
The Importance of Advocacy in the RASopathies
	Introduction
	Seeds of Advocacy
	Engaging with Clinicians and Researchers
		Clinician Engagement
		Clinical Researchers’ Affinity
		“Big Sister” Resources
	RASopathies Network Incorporation Story
	The Value of Research Conferences for the Advocacy Mission
	Collaborations and Successes
		Expanding Scope: Getting the Attention of Cancer Researchers
		Funding RASopathies Research
	Summary and Conclusion
	References
The RAS Signaling Network and Cancer
	Introduction
	RAS Protein Structure and Biochemistry
		RAS GDP-GTP Regulation
		RAS Membrane Association
		RAS Activation by Diverse Extracellular Stimuli
	Aberrant RAS Activation in Cancer
		RAS Mutations in Cancer
		Other Mechanisms of RAS Activation in Cancer
		RAS and Cancer Progression
		RAS and Other Diseases
	The RAS Effector Signaling Network
		TIAM1-RAC1 Small GTPase Effector Signaling
		RALGEF-RAL Small GTPase Effector Signaling
		PI3K-AKT-mTORC1 Effector Signaling
		RAF-MEK-ERK Mitogen-Activated Protein Kinase Cascade
	ERK Regulation of a Complex Phosphoproteome and Transcriptome
		ERK Substrates
		ERK Inhibitory Feedback Signaling Mechanisms
		MYC: A Key Driver of ERK-Dependent Cancer Growth
	RAS Therapeutics
	Concluding Remarks
	References
The RAS-Regulated RAF-MEK1/2-ERK1/2 Protein Kinase Pathway: The Path Most Traveled in RASopathies
	Introduction
	A Short Overview of the RAS-RAF-MEK1/2-ERK1/2 Pathway
	Growth Factor-Dependent Activation of RAS
	RAS-Dependent Activation of the ERK1/2 Pathway
	Inactivation of RAS
	ERK1/2 Signal Duration and Magnitude Are Critical Arbiters of Cell Fate
	Feedback Control and Fine-Tuning of the ERK1/2 Pathway
	Translating ERK1/2 Pathway Cancer Therapeutics to RASopathies
	References
The Noncanonical RAS/MAPK Pathway and the RASopathies
	Introduction
	The Canonical RAS/MAPK Pathway
	Noncanonical RAS/MAPK Pathway
	RIT1: An Atypical GTPase of the RAS Family
	LZTR1: An Adaptor Protein That Facilitates the Ubiquitination of RAS GTPases
	MRAS/SHOC2/PP1: A Phosphatase Complex That Regulates RAF Activation
	CBL: A Ligase Involved in the Control of RTK Ubiquitination
	RRAS and RRAS2: Two Members Closely Related to Classical RAS GTPases
	Other RASopathy Genes of the Noncanonical RAS Pathway
	Conclusions
	References
Understanding the RAS in RASopathies
	RAS Proteins that Cause RASopathies
	Regulation of RAS Proteins
	How RAS Proteins Activate RAF Kinase
	Summary
	References
RAS Family Interactions: The SHOC2-MRAS-PP1 Complex in Noonan Syndrome
	The SHOC2-MRAS-PP1 Complex
	Role of RAF “S259” Dephosphorylation in RAF Activation and ERK Pathway Regulation
	SMP Complex in Noonan Syndrome
	SHOC2
	PP1
	MRAS
	Concluding Remarks: The SMP Complex as a Therapeutic Target
	References
RASopathy Genes: Germline Risk and Somatic Cancers
	RAS/MAPK Pathway in Cancer and RASopathies
	Frequency of Somatic RAS/MAPK Mutations
	KRAS
	NRAS and BRAF
	HRAS
	Somatic RAS/MAPK Mutations in Pediatric Cancer
	Neoplasms and Cancer in RASopathies
		Costello Syndrome
		Noonan Syndrome
		CBL-Related Noonan Syndrome-Like Disorder
		Cardio-Facio-Cutaneous Syndrome (CFC)
		Legius Syndrome
	Conclusions
	References
Cancer in Neurofibromatosis Type 1
	Introduction
	Common Cancer Predisposition
		Breast Cancer
			Contralateral Risk and Survival
			Screening Implications
			Treatment of NF1 Breast Cancers
		Other Common Cancer Risk
	Rare Cancers
		Soft Tissue Sarcomas
			Malignant Peripheral Nerve Sheath Tumors
				Molecular Pathology
				Treatment
			Gastrointestinal Stromal Tumors
			Rhabdomyosarcoma
	Central Nervous System Tumors
		Optic Pathway Glioma
		Other Central Nervous System (CNS) Tumors
		Endocrine Tumors
		Hematological and Other Malignancy
	Conclusion
	References
Prenatal Manifestations of the RASopathies
	Introduction
	Preconception and Prenatal Diagnosis
		Phenotypes by Trimester
			First Trimester
			Second Trimester
			Third Trimester
		Phenotypes by Organ System
			Cardiac
			Lymphatic
			Renal
			Polyhydramnios
			Growth Parameters
			Gastrointestinal (GI) Abnormalities
		Syndrome Specific Phenotype
			Costello Syndrome (CS)
			Neurofibromatosis Type 1 (NF1)
			Legius Syndrome (LS)
			Noonan Syndrome (NS)
			Noonan Syndrome with Multiple Lentigines (NSML)
			Cardio-Facio-Cutaneous Syndrome (CFC)
			Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM)
			SYNGAP1 Syndrome
			Central Conducting Lymphatic Anomalies
	Obstetrical Management of RASopathies
		Affected Fetus
		Affected Pregnant Individual
	Conclusion
	References
Cardiovascular Disease in the RASopathies
	Introduction
	Congenital Heart Disease in RASopathies
	Cardiomyopathy in RASopathies
	Arrhythmia and Electrocardiographic Features in the RASopathies
	Cardiovascular Outcomes in RASopathies
	Summary and Conclusions
	References
Cognitive Development and Learning in RASopathies
	Introduction
	Epidemiology of Intellectual and Learning Disabilities in RASopathies
	Cognition and Learning in Specific RASopathies
		Neurofibromatosis Type 1 (NF1)
	Legius Syndrome (LGSS)
	Noonan Syndrome (NS) and Noonan-Like Conditions
	Costello Syndrome (CS)
	Cardio-facio-cutaneous Syndrome (CFC)
	Impact of Medical Comorbidities on Cognition and Learning in RASopathies
	Considerations for Clinical Care of Individuals with RASopathies
	Supporting Educational Needs
	Clinical Trials to Improve Cognitive and Learning Outcomes
	Future Directions
	References
Behavioral Profile in RASopathies
	Introduction
		Neurofibromatosis Type 1 (NF1)
		Legius Syndrome
		Noonan Syndrome
		Costello Syndrome
		Cardio-Facio-Cutaneous Syndrome (CFC)
		SYNGAP1 Syndrome
	Conclusions
	Future Work
	References
Autism and Social Behavior in RASopathies
	Introduction
	Epidemiology of Autism Spectrum Disorder in RASopathies
	Variability in Social Behavior in RASopathies
	Conceptual and Diagnostic Considerations
	Biopsychosocial Underpinnings of Social Behavior in RASopathies
	Autism Spectrum Disorder and Social Functioning in Each RASopathy Syndrome
		Cardio-Facio-Cutaneous Syndrome (CFC)
		Costello Syndrome (CS)
		Neurofibromatosis Type 1 (NF1)
	Noonan Syndrome (NS) and Noonan Syndrome-Like Conditions
	Cross-Syndrome Comparisons in RASopathies
	Implications for Assessment
	Intervention for Autism and Social Challenges in RASopathies
	Future Research Directions
	References
Epilepsy in the RASopathies
	Introduction
	Mechanisms of Epileptogenesis in the RASopathies
		Overview of RAS/MAPK Pathways in Epilepsy
		Role of BRAF
		Role of Extracellular Signal-Regulated Kinases (ERKs) and Mitogen-Activated Protein Kinase Kinase (MEKs)
		RAS-GRF1 Interface with NMDA Receptor Function
		HRAS Interface with NMDA Receptor Function
		SYNGAP Interface with RAS/MAPK
	Clinical, Diagnostic, and Therapeutic Considerations for RASopathy-Associated Epilepsy
		General Diagnostic Considerations
		Neurofibromatosis Type 1 (NF1)
			MEK1 Inhibitor Therapy in NF1
		Noonan Syndrome (NS)
		Cardio-Facio-Cutaneous Syndrome (CFC)
		Costello Syndrome (CS)
		Noonan Syndrome with Multiple Lentigines (NSML)
		SYNGAP1 Syndrome
		Somatic Mutation-Associated Brain Malformations
	Future Directions
	References
Speech-Language Pathology in the RASopathies
	Overview of the Field of Speech-Language Pathology
	Speech-Language Pathology in RAS/Mitogen-Activated Protein Kinase (MAPK) Disorders
	Speech-Language Pathology in Cardio-Facio-Cutaneous Syndrome (CFC)
	Speech-Language Pathology in Costello Syndrome
	Speech-Language Pathology in Neurofibromatosis Type 1
	Speech-Language Pathology in Legius Syndrome (LS)
	Speech-Language Pathology in Noonan Syndrome
	Speech and Language Assessment for Individuals with RASopathies
	Assessment of Feeding and Swallowing
	Intervention for Speech and Language for Individuals with RASopathies
	Intervention for Feeding and Swallowing Concerns for Individuals with RASopathies
	Resources for Speech-Language Services
	Conclusion
	References
Ophthalmic Manifestations in RASopathies
	Introduction
	Role of RAS Pathway in Ocular Development
	Noonan Syndrome (NS)
		Periorbital, Orbital, and Ocular Adnexal
		Ocular Alignment and Motility
		Refractive Errors
		Anterior Segment
		Posterior Segment
		Visual Function
		Genotype-Phenotype Correlation
	Noonan Syndrome with Multiple Lentigines (NSML)
		Periorbital, Orbital, and Ocular Adnexal
		Ocular Alignment and Motility
		Refractive Errors
		Anterior Segment
		Posterior Segment
		Visual Function
		Genotype-Phenotype Correlation
	Neurofibromatosis Type 1 (NF1)
		Periorbital, Orbital, and Ocular Adnexal
		Ocular Alignment and Motility
		Refractive Errors
		Anterior Segment
		Posterior Segment
		Optic Pathway Gliomas (OPGs)
		Visual Function
		Genotype-Phenotype Correlation
	Legius Syndrome (LS)
	Cardio-Facio-Cutaneous Syndrome (CFC)
		Periorbital, Orbital, and Ocular Adnexal
		Ocular Alignment and Motility
		Refractive Errors
		Anterior Segment
		Posterior Segment
		Visual Function
		Genotype/Phenotype Correlation
	Costello Syndrome (CS)
		Periorbital, Orbital, and Ocular Adnexal
		Ocular Alignment and Motility
		Refractive Errors
		Anterior Segment
		Posterior Segment
		Visual Function
		Genotype/Phenotype Correlation
	Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM)
		Periorbital, Orbital, and Ocular Adnexal
		Ocular Alignment and Motility
		Refractive Errors
		Anterior Segment
		Posterior Segment
		Visual Function
		Genotype/Phenotype Correlation
	SYNGAP1 Syndrome
	Treatment and Management
	Emerging Molecular-Based Therapies
	Summary
	References
Dermatological Associations in the RASopathies
	Neurofibromatosis 1 (NF1)
		Pigmentary
			Café-Au-Lait Macules
			Freckling
			Management
		Tumors
			Cutaneous Neurofibromas
			Plexiform Neurofibromas
		Other Findings
			Juvenile Xanthogranulomas
			Nevus Anemicus
			Glomus Tumors
	Cardio-Facio-Cutaneous Syndrome
		Hair Abnormalities
		Ulerythema Ophryogenes
		Keratosis Pilaris
		Numerous Melanocytic Nevi
		Infantile Hemangioma
		Other Skin Findings
		Management
	Noonan Syndrome
		PTPN11 Variants—Easy Bruising and Hair Abnormalities
		SOS1 and SHOC2 Variants—Keratinization Disorders and Hair Abnormalities
		SOS1
		SHOC2
		Management
	Noonan Syndrome with Multiple Lentigines
		Multiple Lentigines
		Multiple Café-Au-Lait Macules
			Management
	Costello Syndrome
		Hand, Foot, and Nail Changes
		Cutaneous Papillomatosis
		Acanthosis Nigricans
		Hair Abnormalities
		Melanocytic Neoplasms
		Pigmentary Changes
		Other Cutaneous Features
	Capillary Malformation-Arteriovenous Malformation Syndrome
		Capillary Malformations
		Fast-Flow Vascular Malformations
		Lymphatic Malformations
		Parkes-Weber Syndrome Phenotype
		Other Mucocutaneous Manifestations
	Summary
	References
Mosaic RASopathies
	Introduction
	Isolated Mosaic RASopathies
		Epidermal Nevi
		RAS-Associated Autoimmune Leukoproliferative Disorder
	Mosaic RASopathies Involving Multiple Organs (True Mosaic RASopathies)
		Linear Nevus Sebaceous Syndrome
		Keratinocytic Epidermal Nevus Syndrome
		Cutaneous Skeletal Hypophosphatemia Syndrome
		Phacomatosis Pigmentokeratotica
		Encephalocraniocutaneous Lipomatosis and Oculoectodermal Syndrome
	Mosaic Forms of Germline RASopathies
		Mosaic Neurofibromatosis Type 1
		Mosaic Legius Syndrome
		Mosaic Noonan Syndrome
		Mosaic Cardio-Facio-Cutaneous Syndrome
		Mosaic Costello Syndrome
		Mosaic Capillary Malformation-Arteriovenous Malformation Syndrome
	Other Considerations
		Histiocytic Disorders
	Cancer Risk, Diagnosis, and Therapeutics of the Mosaic RASopathies
		Cancer Risk
		Diagnosis
		Therapeutics
	Conclusion
	References
Craniofacial and Dental Development in the RASopathies
	Introduction
	Effects of the RAS Pathway on Craniofacial and Dental Development
	Neurofibromatosis 1 (NF1)
	Noonan Syndrome (NS)
	Noonan Syndrome with Multiple Lentigines (NSML or LEOPARD Syndrome)
	Cardio-Facio-Cutaneous Syndrome (CFC)
	Costello Syndrome (CS)
	Phenotypic Summary of Craniofacial Dysmorphia in the RASopathies
	Oral Health Recommendations for the Provider
	References
Skeletal Muscle Development in the RASopathies
	Introduction
	Skeletal Muscle Phenotype in RASopathies
	Skeletal Muscle Histology in RASopathies
	RASopathy Mouse Models
	Dysregulation of Multiple Intracellular Pathways in CS HrasG12V and the CFC Braf L597V Skeletal Muscle
	Summary
	References
Orthopedic Issues of the RASopathies
	Introduction
	Skeletal Abnormalities and Posture
		Axial Skeleton (Thorax-Spine)
			Neurofibromatosis Type 1 (NF1)
			Noonan Syndrome (NS)
			Noonan Syndrome with Multiple Lentigines (NSML)
			Costello Syndrome (CS)
			Cardio-facio-cutaneous Syndrome (CFC)
		Appendicular Skeleton
			NF1
			NS
			CS
			CFC
	Other Bone Abnormalities
		Skull Abnormalities
		Impaired Bone Homeostasis and Risk of Fractures
	Muscle Pathology
	Functional Impairment
	Management and Treatment Strategies
	Conclusions
	References
Drosophila Models of RASopathies
	Introduction
	Misexpression Studies Reveal That Pathogenic Variants Are More Sensitive to Extracellular Signals
	Gene-Edited Flies Reveal Stochastic Contributions to Variable Phenotypes Caused by Disease Mutations
	Discussion
	References
Neurofibromatosis Type 1 Mouse Models
	Introduction to NF1
	Genetics of NF1
	Function of the NF1 Protein, Neurofibromin
	Neurodevelopmental Disorders
	Bone Defects
	Optic Gliomas
	Malignant Glioma
	Dermal Neurofibromas
	Plexiform Neurofibromas
	Malignant Peripheral Nerve Sheath Tumors
	Lessons Learned from Nf1 Mouse Modeling
	Future Directions
	References
Glossary
Neurofibromatosis Type I: Preclinical Modeling
	Introduction
		NF1 and Nerve Tumors
		NF1 and the RAS/MAPK Pathway
		Neurofibromas and the Microenvironment
	Modeling Neurofibromas
		Cell Culture/In Vitro Models
		Mouse Models of Neurofibroma
			Mouse Models
		Swine Models of NF1
	PNF Models for Preclinical Drug Testing
		Methods for Efficacy Evaluation
	Conclusions and Future Perspectives
	References
Modeling the Non-NF1 RASopathies
	Introduction
	Drosophila Melanogaster Models
	Danio Rerio (Zebrafish) Models
	Xenopus Laevis Models
	Mus Musculus Models
	iPSC Models
	Animal Models of Legius Syndrome
	Models of Emerging RASopathy-Associated Variants
	Models of Other Syndromes Involving Alterations of the RAS/MAPK Pathway
	Conclusions
	References
Clinical Studies and Small Molecule Inhibitors for RASopathy Treatment
	Introduction
	The Path to the First Approved Medical Therapy for NF1
	Targeted Therapies for Non-NF1 RASopathies
	General Considerations for Future RASopathy Trials
	Conclusions
	References
Index