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RASopathy

RASopathies are a group of developmental disorders caused by germline pathogenic variants in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway, leading to its hyperactivation and dysregulation.^[1] These syndromes, first unified under the term "RASopathies" in the early 2000s, represent one of the largest classes of congenital anomaly disorders, affecting multiple organ systems through disrupted cell signaling that influences growth, differentiation, and proliferation.^[2] The clinical spectrum of RASopathies is broad yet overlapping, featuring characteristic craniofacial dysmorphisms (such as hypertelorism, low-set ears, and a short neck), congenital heart defects (including pulmonary valve stenosis and hypertrophic cardiomyopathy), short stature, cutaneous abnormalities (like café-au-lait spots or lentigines), lymphatic and vascular malformations, neurodevelopmental delays, and an elevated predisposition to certain cancers, such as leukemias and neurofibromas.^[1] Phenotypic variability arises from the specific gene affected, the nature of the mutation (gain-of-function or loss-of-function), and factors like mosaicism or inheritance patterns, which can be autosomal dominant, with many cases occurring de novo.^[3] The major syndromes classified as RASopathies include Noonan syndrome (prevalence approximately 1 in 1,000–2,500 births), cardio-facio-cutaneous syndrome, Costello syndrome (rarer, about 1 in 1,290,000), neurofibromatosis type 1 (prevalence 1 in 2,500–3,000), Noonan syndrome with multiple lentigines, Legius syndrome, and others like capillary malformation–arteriovenous malformation syndrome.^[3] These conditions collectively highlight the pathway's critical role in embryonic development and postnatal growth, with recent advances emphasizing immune dysregulation and potential for targeted therapies, such as MEK inhibitors, to mitigate symptoms like hypertrophic cardiomyopathy.^[3] Diagnosis typically involves genetic testing, and management requires multidisciplinary care addressing cardiac, endocrine, and oncologic risks across the lifespan.^[1]

Definition and Overview

Definition

RASopathies are a clinically defined group of developmental disorders caused by germline mutations in genes encoding components or regulators of the RAS/MAPK signaling pathway. These mutations typically represent gain-of-function alterations that lead to hyperactivation of the pathway, resulting in overlapping multisystem phenotypes across affected individuals. The term "RASopathy" derives from the RAS proto-oncogene family and the suffix "-pathy," denoting disease, and was coined in 2009 to unify this spectrum of syndromes under a shared molecular etiology. As one of the most common groups of malformation syndromes, RASopathies collectively affect approximately 1 in 1,000 individuals, based on the combined frequencies of the constituent disorders.^[2]

Historical Development

The recognition of RASopathies began with the clinical description of individual syndromes in the mid-20th century. Noonan syndrome was first delineated in 1963 by pediatric cardiologist Jacqueline Noonan, who reported a series of patients with characteristic facial features, short stature, and congenital heart defects, particularly pulmonic stenosis.^[4] Neurofibromatosis type 1 (NF1), another key disorder later grouped within RASopathies, had been clinically observed since the 19th century, but its genetic basis was mapped to the pericentromeric region of chromosome 17 in 1987 through linkage analysis in affected families.^[5] The molecular era of RASopathies emerged in the early 2000s with the identification of germline mutations in genes encoding components of the RAS/MAPK signaling pathway. In 2001, mutations in PTPN11, which encodes the protein tyrosine phosphatase SHP-2, were discovered as the primary cause of Noonan syndrome, accounting for approximately 50% of cases and revealing hyperactivation of the pathway as a unifying mechanism. This was followed by the finding of HRAS mutations in Costello syndrome in 2005, further linking the pathway to a spectrum of overlapping developmental disorders. The term "RASopathies" was formally coined in 2009 by Tidyman and Rauen to encompass this group of syndromes unified by germline variants leading to dysregulated RAS/MAPK signaling, including Noonan, Costello, cardio-facio-cutaneous, and NF1 syndromes.^[6] By the 2010s, the classification evolved from phenotypic similarities to a pathway-based framework, with additional genes identified through next-generation sequencing. Influential reviews, such as those in 2013, solidified the RASopathies as a distinct category of developmental disorders predisposing to cancer.^[7] Post-2020 advancements have expanded the spectrum to include mosaic and somatic variants, recognizing conditions like oculoectodermal syndrome as mosaic RASopathies, and incorporating new causative genes such as RIT1 (identified in 2013) and SOS2 (2015).^[8]

Pathophysiology

The RAS/MAPK Signaling Pathway

The RAS/MAPK signaling pathway serves as a critical intracellular cascade that transduces extracellular signals, such as those from growth factors, into coordinated cellular responses, primarily regulating processes like cell proliferation, differentiation, and survival.^[9] Upon binding of ligands like epidermal growth factor (EGF) to receptor tyrosine kinases (RTKs) such as the EGF receptor (EGFR), the pathway is initiated through receptor dimerization and autophosphorylation, which recruits adaptor proteins.^[9] These adaptors, including growth factor receptor-bound protein 2 (GRB2) and son of sevenless (SOS), facilitate the activation of downstream effectors, ensuring precise signal propagation from the cell membrane to the nucleus.^[9] Key components of the pathway include the RAS family of small GTPases (HRAS, KRAS, and NRAS), which act as molecular switches; RAF serine/threonine kinases (ARAF, BRAF, and CRAF); mitogen-activated protein kinase kinases (MEK1/2); and extracellular signal-regulated kinases (ERK1/2). RAS is activated by guanine nucleotide exchange factors (GEFs) like SOS, which promote the exchange of GDP for GTP, transitioning RAS to its active GTP-bound conformation that recruits and activates RAF at the plasma membrane.^[9] Activated RAF then phosphorylates and activates MEK1/2, which in turn phosphorylates ERK1/2; the latter translocates to the nucleus to modulate transcription factors such as ELK1, influencing gene expression programs for cellular growth and adaptation. The activation cycle of RAS is tightly regulated to prevent aberrant signaling: in its inactive GDP-bound state, RAS is maintained by GTPase-activating proteins (GAPs) that accelerate GTP hydrolysis to GDP, while GEFs drive activation during signaling events.^[9] Normal feedback inhibition mechanisms, such as ERK-mediated phosphorylation of SOS to attenuate GEF activity or induction of dual-specificity phosphatases (DUSPs) and Sprouty (SPRY) proteins, ensure transient pathway activation and return to baseline, safeguarding against prolonged stimulation.^[9] This dynamic regulation underscores the pathway's role in maintaining signaling fidelity. Physiologically, the RAS/MAPK pathway is indispensable for embryonic development, where it orchestrates cell proliferation, differentiation, and tissue patterning—for instance, fibroblast growth factor receptor (FGFR) signaling via RAS/MAPK is essential for neural and lens formation in mammalian embryos.^[10] In adult tissues, it supports homeostasis by balancing cell growth, survival, and apoptosis in response to mitogenic cues, as exemplified by its role in maintaining epidermal and hematopoietic tissue integrity.^[10] Dysregulation of this pathway through somatic mutations is commonly associated with cancers, whereas germline alterations contribute to developmental disorders.^[11] The pathway's architecture can be described as a predominantly linear kinase cascade with notable branching and feedback elements: signals flow from RTKs through adaptors to RAS-GTP, which scaffolds RAF-MEK complexes for sequential activation, culminating in ERK-dependent transcriptional outputs, while negative feedback loops at multiple nodes (e.g., from ERK back to SOS or RTKs) provide robustness and prevent overactivation.^[9]

Mechanisms of Dysregulation in RASopathies

RASopathies arise from germline mutations—often gain-of-function in positive regulators or loss-of-function in negative regulators—of genes encoding components of the RAS/MAPK signaling pathway, resulting in increased pathway flux and constitutive signaling that occurs independently of upstream stimuli such as growth factors. For instance, loss-of-function mutations in GAPs like neurofibromin (NF1) or phosphatases like SHP2 (PTPN11) impair negative regulation, while gain-of-function in RAS or GEFs like SOS1 enhances activation.^[12]^[1] These mutations disrupt the tightly regulated cycling between inactive GDP-bound and active GTP-bound states of RAS proteins, leading to persistent activation of downstream effectors like RAF, MEK, and ERK.^[13] This hyperactivation is milder compared to oncogenic alterations, allowing embryonic viability while causing developmental perturbations.^[14] Dysregulation manifests through several mechanisms that shift the equilibrium toward the active GTP-bound state of RAS. One common type involves impaired GTP hydrolysis, where mutations lock RAS proteins in their GTP-bound conformation, reducing intrinsic GTPase activity by ~2- to 10-fold and preventing timely inactivation.^[15]^[16] Another mechanism is reduced activity of GTPase-activating proteins (GAPs), which normally accelerate GTP hydrolysis; loss of GAP function elevates GTP-bound RAS levels, often by 2- to 10-fold depending on the extent of impairment.^[12] Enhanced guanine nucleotide exchange factor (GEF) activity promotes faster GDP-to-GTP exchange, increasing the active RAS fraction by 2- to 8-fold.^[15] Additionally, hypersensitivity of upstream receptors or adapters can amplify initial signals, further sustaining pathway flux.^[13] At the cellular level, these dysregulations drive increased cell proliferation through sustained ERK-mediated transcription of growth-related genes, altered cell migration via disrupted cytoskeletal dynamics, and impaired apoptosis due to anti-apoptotic signaling.^[14] Dosage effects during critical developmental windows exacerbate these changes, leading to congenital anomalies as the hyperactive pathway influences tissue patterning and organogenesis in a temporally sensitive manner.^[12] Overall, mutations typically elevate GTP-bound RAS levels by 2- to 10-fold relative to wild-type conditions, establishing a new signaling baseline that propagates through development, milder than in many cancers.^[15]^[16] In contrast to cancers, where somatic mutations often cause aggressive, high-level pathway activation in differentiated tissues, RASopathies involve germline mutations that exert effects from embryonic stages onward, resulting in multisystem developmental phenotypes rather than localized tumors.^[14] This early timing modulates the severity, with partial hyperactivation permitting survival but yielding pleiotropic traits, unlike the potent oncogenic shifts that prioritize proliferation over development.^[13]

Genetics

Inheritance Patterns and Prevalence

RASopathies are primarily inherited in an autosomal dominant manner, characterized by high or complete penetrance and variable expressivity, meaning that affected individuals almost invariably exhibit some clinical features, though the severity and specific manifestations can differ widely even within families.^[17] This pattern arises from germline heterozygous mutations in genes encoding components of the RAS/MAPK pathway, leading to gain-of-function effects that dysregulate signaling. Rare cases of autosomal recessive inheritance have been reported, such as Noonan syndrome associated with biallelic variants in LZTR1.^[18] A significant proportion of RASopathy cases, approximately 30-50%, result from de novo mutations that occur sporadically in the parental germline, rather than being inherited. These mutations are particularly prevalent due to elevated mutation rates during spermatogenesis, where errors in DNA replication and repair accumulate in aging germ cells. For instance, in neurofibromatosis type 1 (NF1), about half of cases are de novo, while Noonan syndrome also shows a high rate of sporadic occurrences.^[2]^[19] Advanced paternal age is a key risk factor, as it correlates with an increased likelihood of de novo mutations in offspring, with studies demonstrating a gradual rise in sporadic NF1 and Noonan syndrome cases as paternal age advances.^[20]^[21] The collective incidence of RASopathies is estimated at approximately 1 in 1,000 live births, making them one of the most common groups of genetic developmental disorders. Among individual syndromes, NF1 has a prevalence of 1 in 2,500 to 3,000 individuals, while Noonan syndrome affects 1 in 1,000 to 2,500 live births; other RASopathies like cardiofaciocutaneous and Costello syndromes are rarer. Geographic variations in prevalence appear minimal, with consistent rates reported across diverse populations. RASopathies exhibit genetic heterogeneity, with mutations in more than 20 genes implicated across the group, including PTPN11, SOS1, RAF1, HRAS, KRAS, BRAF, NF1, RIT1, NRAS, SHOC2, and MAP2K1/2, though most defined syndromes are monogenic in nature, often involving a primary causative gene alongside occasional contributions from others.^[22]^[11]^[19]

Specific Gene Mutations

RASopathies are caused by germline mutations in genes encoding components of the RAS/MAPK signaling pathway, with the majority being heterozygous missense variants that result in gain-of-function effects, leading to pathway hyperactivation.^[8] The most frequently mutated gene is PTPN11, accounting for approximately 50% of Noonan syndrome (NS) cases, where mutations are predominantly missense and cluster in the SH2 or PTP domains, such as at residues D62, Y63, Q79, and N308, enhancing phosphatase activity.^[8] SOS1 mutations occur in 10-15% of NS, typically affecting the guanine nucleotide exchange factor (GEF) domain, including hotspots like M269R and R552, which increase GEF activity toward RAS.^[8] RAF1 variants, found in 5-15% of NS, are missense mutations in the kinase domain, often around S259 (e.g., S257L), promoting constitutive kinase activation.^[8] In Costello syndrome, HRAS mutations predominate, with about 80% being the G12S missense variant and rarer ones like G12V at codon 12, which impair GTP hydrolysis and prolong RAS activation.^[8] KRAS mutations contribute to NS and cardio-facio-cutaneous (CFC) syndrome overlap, featuring gain-of-function missense changes such as V14I, G60R, or T58I that stabilize the GTP-bound state.^[8] BRAF mutations are characteristic of CFC syndrome, primarily missense in the kinase domain (e.g., Q257R), resulting in elevated pathway signaling.^[8] NF1 mutations underlie neurofibromatosis type 1, typically loss-of-function truncations or frameshifts that eliminate neurofibromin GAP activity, leading to unchecked RAS signaling.^[8] The mutation spectrum across RASopathies is dominated by gain-of-function missense variants, with hotspots like PTPN11 exons 3 and 8, HRAS codon 12, and RAF1 kinase domain regions; rare copy number variants such as deletions or duplications occur but are less common.^[8] Genotype-phenotype correlations reveal that KRAS mutations often associate with more severe manifestations compared to milder phenotypes from PTPN11 variants in NS.^[8] Somatic mosaicism, detected in 5-10% of cases, can modify disease severity by limiting variant distribution to certain tissues.^[23] Targeted next-generation sequencing panels for RASopathy genes yield causative variants in 70-95% of clinically suspected cases, with rates around 78% in comprehensive cohorts.^[24] Discoveries in the 2010s, such as activating SOS2 mutations in NS-like phenotypes and RASA2 loss-of-function variants contributing to milder Noonan-like disorders, have expanded the genetic spectrum, identified through whole-exome sequencing in undiagnosed patients.^[25]^[19]

Clinical Features

Shared Phenotypic Traits

RASopathies are characterized by multisystem involvement, with overlapping clinical features stemming from dysregulation of the RAS/MAPK pathway. These shared traits, often resembling those seen in Noonan syndrome, include distinctive craniofacial, cardiac, growth, neurological, and other anomalies that affect multiple organ systems.^[14]^[18] Craniofacial features are prominent and characteristic, manifesting as facial dysmorphism such as hypertelorism (widely spaced eyes), low-set ears, ptosis, downslanting palpebral fissures, and a short or webbed neck.^[14]^[26] These traits contribute to a recognizable gestalt across the spectrum of disorders, though they may coarsen with age.^[18] Cardiac anomalies occur in 50-80% of individuals, with congenital heart defects like pulmonary valve stenosis and hypertrophic cardiomyopathy being the most frequent.^[14]^[26] The prevalence is highest in Noonan syndrome, affecting approximately 70% of cases.^[14] Growth disturbances are nearly universal, featuring postnatal short stature with final adult height typically 10-20 cm below the population mean, corresponding to a height standard deviation score (SDS) of -2 to -3, alongside feeding difficulties in infancy that exacerbate growth failure.^[14]^[26]^[27] Relative macrocephaly and delayed puberty are also common components of this phenotype.^[18] Neurological and developmental issues affect 30-50% of individuals, often presenting as mild intellectual disability with IQ scores in the 70-85 range, hypotonia, and motor delays.^[14]^[26] Learning difficulties, attention deficits, and behavioral challenges further contribute to the neurodevelopmental profile.^[18] Additional shared traits include an elevated lifetime cancer risk of 5-10%, particularly for hematologic malignancies like leukemia, as well as skin and hair anomalies such as curly or slow-growing hair and café-au-lait spots.^[14]^[26] Skeletal abnormalities, notably pectus excavatum or carinatum deformities, are also prevalent.^[18]^[26] Lymphatic abnormalities, such as congenital lymphedema and lymphatic dysplasia, are common, affecting up to 60% in syndromes like Noonan.^[1]

Variations by Syndrome

While all RASopathies share core phenotypic traits such as facial dysmorphology, cardiac anomalies, and growth delays, individual syndromes display unique clinical distinctions that aid in differentiation.^[2] Noonan syndrome is characterized by a webbed neck and congenital lymphedema, particularly affecting the hands and feet in infancy, alongside a predisposition to bleeding diathesis manifested as easy bruising or prolonged bleeding after minor trauma.^[28] These features often become more prominent during childhood, with lymphedema resolving in some cases but neck webbing persisting.^[2] Cardiofaciocutaneous syndrome stands out with its ectodermal abnormalities, including sparse, curly or brittle hair, dry and hyperkeratotic skin resembling ichthyosis, and frequent nevi or keratosis pilaris, which contribute to a more severe dermatological burden than in other RASopathies.^[29] Intellectual disability in this syndrome tends to be more profound, often requiring significant educational support, and is accompanied by feeding difficulties leading to marked failure to thrive.^[28] Costello syndrome features a distinctive coarse facial appearance with full lips, loose skin folds, and papillomatous lesions around the mouth and nose, coupled with severe failure to thrive that persists into adolescence despite nutritional interventions.^[2] Individuals face an elevated risk of rhabdomyosarcoma, with tumors often presenting in early childhood, necessitating vigilant oncologic surveillance.^[28] Neurofibromatosis type 1 is defined by the development of cutaneous and plexiform neurofibromas, which increase in number and size during puberty and adulthood, iris hamartomas known as Lisch nodules visible on slit-lamp examination, and a risk for optic pathway gliomas that typically emerge in the first decade of life.^[2] Among other variants, Legius syndrome presents a milder phenotype resembling neurofibromatosis type 1, with multiple café-au-lait spots and axillary freckling but notably absent tumors or neurofibromas, resulting in fewer complications overall.^[30] Noonan syndrome with multiple lentigines is marked by widespread brown lentigines appearing in late childhood or adolescence, primarily on the face and upper trunk, along with electrocardiographic abnormalities such as conduction defects that may predispose to arrhythmias.^[28] An overlap spectrum exists in some cases, where individuals exhibit features blending multiple syndromes, such as the combination of cardiofaciocutaneous-like ectodermal dysplasia with Noonan syndrome's cardiac and neck anomalies.^[2] Clinical manifestations in RASopathies often evolve with age; for instance, cardiac defects like pulmonary stenosis or hypertrophic cardiomyopathy are most critical in infancy, while dermatologic and neoplastic risks may intensify later in life.^[28]

Diagnosis

Clinical Criteria

The diagnosis of RASopathies relies on a multidisciplinary assessment involving clinical geneticists, cardiologists, endocrinologists, and other specialists to evaluate phenotypic features such as facial dysmorphology, cardiac anomalies, and growth patterns. This approach includes a detailed dysmorphology examination to identify characteristic facial traits, echocardiography to detect congenital heart defects like pulmonic stenosis or hypertrophic cardiomyopathy, and serial monitoring using syndrome-specific growth charts to assess short stature.^[31]^[32] For Noonan syndrome, clinical suspicion is guided by adapted criteria from the van der Burgt system, which categorizes features as major or minor. Major criteria include typical facial dysmorphology (e.g., hypertelorism, low-set posteriorly rotated ears, and ptosis) and congenital heart defects such as pulmonic valve stenosis or hypertrophic cardiomyopathy; minor criteria encompass short stature below the third percentile, chest deformities like pectus excavatum or carinatum, broad or webbed neck, and mild intellectual disability. Definitive diagnosis requires typical facial features plus at least one major criterion, or two major criteria plus three minor criteria; a suggestive diagnosis, warranting further evaluation, is indicated by suggestive facial features plus two minor criteria or one major and two minor criteria.^[33]^[31] In neurofibromatosis type 1 (NF1), the National Institutes of Health consensus criteria require the presence of two or more of the following clinical features for diagnosis: six or more café-au-lait macules greater than 5 mm in prepubertal individuals or greater than 15 mm in postpubertal individuals; two or more neurofibromas of any type or one plexiform neurofibroma; axillary or inguinal freckling; an optic pathway glioma; two or more Lisch nodules (iris hamartomas); a distinctive osseous lesion such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudarthrosis; or a first-degree relative with NF1 by the above criteria.^[34] For Costello syndrome, clinical diagnosis is based on a constellation of suggestive features including severe failure to thrive, coarse facial features (e.g., full lips, large ears, and depressed nasal bridge), congenital heart defects such as hypertrophic cardiomyopathy, developmental delay, and skin abnormalities like loose skin and deep palmar creases, without formal scoring criteria. Similarly, cardiofaciocutaneous (CFC) syndrome is suspected clinically through multiple major features such as bitemporal constriction with sparse, curly hair, congenital heart disease (e.g., pulmonic stenosis), dermatologic issues including eczema and keratosis pilaris, relative macrocephaly, and postnatal growth failure, often accompanied by hypotonia and intellectual disability.^[35]^[36] Differential diagnosis involves excluding chromosomal disorders with overlapping features, such as Turner syndrome, which shares short stature, cardiac defects, and neck webbing; this is achieved through karyotype analysis to rule out X chromosome monosomy or mosaicism. Prenatally, increased nuchal translucency on first-trimester ultrasound serves as a key indicator for RASopathies, particularly Noonan syndrome, often exceeding 3.5 mm and often associated with cystic hygroma (in approximately 50% of cases) or hydrops fetalis (rarer).^[37]^[38]^[39]

Molecular Testing

Molecular testing for RASopathies is initiated following clinical suspicion to confirm a diagnosis through identification of pathogenic variants in genes of the RAS/MAPK pathway. The primary approach involves targeted next-generation sequencing (NGS) panels that interrogate 10-20 key genes, including PTPN11, SOS1, RAF1, BRAF, KRAS, and NRAS, focusing on gain-of-function mutations characteristic of these disorders. These panels achieve diagnostic yields of 70-95% in patients with suggestive phenotypes, such as those with Noonan syndrome or cardiofaciocutaneous syndrome.^[40] If the targeted panel is negative, whole-exome sequencing (WES) is pursued to broaden the search for variants in less common genes or novel loci, enhancing overall diagnostic sensitivity.^[40] Specific laboratory methods complement NGS for comprehensive analysis. Sanger sequencing is employed to validate variants identified at mutational hotspots, such as in PTPN11 exon 3 or 8, ensuring accuracy in heterozygous calls.^[40] For structural variants like large deletions or duplications, which account for a subset of cases (e.g., in NF1), multiplex ligation-dependent probe amplification (MLPA) provides targeted detection.^[41] RNA-based analysis, including reverse transcription PCR and sequencing, is utilized to evaluate splicing variants that may not be apparent from genomic DNA alone, particularly in genes like NF1 where aberrant splicing disrupts protein function.^[42] Variant interpretation adheres to the American College of Medical Genetics and Genomics (ACMG) guidelines, with disease-specific modifications developed by the ClinGen RASopathy Expert Panel to account for the gain-of-function mechanisms predominant in these disorders. These adaptations include adjusted minor allele frequency thresholds (e.g., benign if ≥0.0005 in population databases) and criteria for hotspot residues (PM1), enabling classification of variants as pathogenic, likely pathogenic, or benign.^[43] In silico prediction tools, such as PolyPhen-2, support the PP3 criterion by forecasting deleterious effects on protein structure or function, particularly for missense changes predicted to enhance pathway activation.^[43] Challenges in interpretation arise with mosaicism, prevalent in up to 20-30% of sporadic cases, requiring deep NGS coverage (e.g., >1,000x) to detect low-level variants at 10-20% allele frequencies; failure to do so can lead to false negatives.^[44]^[45] Incidental findings in asymptomatic family members, such as carriers of de novo variants, also complicate counseling and may prompt cascade testing.^[40] Prenatal and postnatal testing options extend diagnostic capabilities for at-risk families. Postnatally, blood or saliva samples suffice for standard panels, while prenatal diagnosis in confirmed familial cases uses amniocentesis or chorionic villus sampling (CVS) at 10-16 weeks gestation to analyze fetal DNA via the same NGS methods, yielding results comparable to postnatal testing.^[46] Non-invasive prenatal testing (NIPT) is emerging as of 2025, with targeted panels analyzing cell-free fetal DNA from maternal blood to detect monogenic RASopathy variants (e.g., in PTPN11), offering >90% sensitivity for high-risk pregnancies without procedural risks.^[47] The cost of targeted RASopathy panels ranges from $500 to $1,000 per test, depending on the laboratory and inclusions like confirmatory Sanger, rendering it cost-effective; professional guidelines from bodies like ACMG endorse molecular testing for all clinically suspected cases to guide management.^[48]^[40]

Management

Supportive Interventions

Supportive interventions for RASopathies primarily address symptom management and complications through multidisciplinary, non-pharmacologic approaches tailored to individual needs. These strategies focus on mitigating the impact of common features such as cardiac defects, growth delays, developmental challenges, and cancer risks, emphasizing regular monitoring and timely interventions to improve quality of life.^[38] Cardiac management involves routine surveillance and corrective procedures for congenital heart defects prevalent in RASopathies like Noonan syndrome, where pulmonary valve stenosis affects up to 50-60% of individuals. Mild cases may require only periodic echocardiograms, but moderate to severe stenosis often necessitates percutaneous balloon valvuloplasty or surgical repair, such as pulmonary valvotomy, to alleviate obstruction and prevent right ventricular hypertrophy.^[38]^[49] For hypertrophic cardiomyopathy, seen in 20-30% of Noonan syndrome cases and higher rates in Costello syndrome, beta-blockers like propranolol are used as first-line therapy to reduce outflow tract obstruction and improve symptoms, with surgical myectomy reserved for refractory cases. Annual cardiology evaluations are recommended until age 5, followed by assessments every 3-5 years or as clinically indicated to monitor progression.^[50]^[38] Growth and endocrine support targets short stature and hormonal imbalances, with recombinant human growth hormone (GH) therapy approved for children with Noonan syndrome who have growth velocity below the third percentile. GH treatment accelerates linear growth in approximately 70-80% of responsive patients, enabling many to achieve final heights within the normal range, though monitoring for potential cardiac effects is essential. Thyroid function and pubertal development should be assessed annually, with hormone replacement initiated for hypothyroidism or precocious puberty as needed to support overall development.^[51]^[27]^[38] Developmental interventions emphasize early and ongoing therapies to address motor, speech, and cognitive delays common across RASopathies, including learning disabilities in up to 50% of Noonan syndrome cases. Early intervention programs, such as physical therapy (PT), occupational therapy (OT), and speech-language therapy, are initiated in infancy to enhance milestones and independence; educational accommodations, including individualized education plans (IEPs), provide academic support for school-aged children. Regular neurodevelopmental assessments guide these therapies, promoting optimal cognitive and social outcomes.^[38]^[52] Cancer surveillance protocols are critical, particularly for neurofibromatosis type 1 (NF1), where annual comprehensive ophthalmologic exams starting in early childhood detect optic pathway gliomas in 15-20% of cases, often managed conservatively unless symptomatic. For high-risk features like PTPN11 mutations in Noonan syndrome, complete blood counts (CBCs) every 3-6 months until age 5 screen for juvenile myelomonocytic leukemia (JMML), which occurs in 2-5% of cases; in NF1, women begin annual breast MRI or mammography at age 30 due to elevated breast cancer risk. Whole-body MRI may be used periodically in NF1 for plexiform neurofibroma monitoring, with prompt referral to oncology for suspicious findings.^[53]^[38]^[54] Multidisciplinary care coordinates specialists including cardiologists, endocrinologists, geneticists, and therapists through RASopathy networks and clinics, following guidelines that recommend centralized care plans to streamline appointments and family support. Genetic counseling addresses inheritance risks and psychosocial needs, fostering informed family decision-making.^[32]^[31]^[38] Lifespan management ensures seamless transition from pediatric to adult care, with structured handoffs around age 18 to maintain surveillance for cardiac function, endocrine issues, and neurodevelopmental support in adulthood, where complications like arrhythmias or malignancies may emerge. Ongoing monitoring adapts to evolving needs, emphasizing self-management education for patients.^[32]^[38]^[55]

Targeted Pharmacotherapies

Targeted pharmacotherapies for RASopathies primarily focus on modulating the dysregulated RAS/MAPK signaling pathway, which is central to the pathogenesis of these disorders. MEK inhibitors represent the most advanced class of agents, with selumetinib and mirdametinib receiving FDA approval for specific manifestations. Selumetinib, approved in 2020 for pediatric patients aged 2 years and older with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas, has demonstrated significant tumor volume reductions, with approximately 70% of treated children achieving at least a 20% decrease in neurofibroma size in phase II trials. The recommended dosing for selumetinib in children is 25 mg/m² orally twice daily, adjusted based on body surface area and rounded to the nearest 5-mg or 10-mg capsule strength. Mirdametinib, approved in February 2025 for adult and pediatric patients aged 2 years and older with NF1 and symptomatic, inoperable plexiform neurofibromas, offers another oral MEK inhibitor option with similar efficacy profiles in reducing tumor burden.^[56] Trametinib, another MEK inhibitor, has shown promise in NF1 plexiform neurofibromas, with studies reporting comparable efficacy to selumetinib in reducing tumor burden by 20-50% in responsive cases. In Noonan syndrome, MEK inhibitors are being investigated for hypertrophic cardiomyopathy, a common and severe complication. Retrospective analyses of 61 children with RASopathy-associated hypertrophic cardiomyopathy treated with MEK inhibitors, including trametinib, indicate improved cardiac function, reduced left ventricular mass, and decreased mortality and morbidity. Phase II trials, such as NCT06555237 evaluating trametinib in patients with genetic RASopathies and hypertrophic cardiomyopathy, are ongoing (estimated completion November 2026), with evidence from related studies and retrospective data suggesting stabilization or regression of cardiac hypertrophy. For Costello syndrome, trametinib has improved cardiomyopathy symptoms in small cohorts of five children, highlighting mutation-specific responses, particularly for HRAS variants. mTOR inhibitors, such as sirolimus, have been used off-label for lymphatic anomalies in Noonan syndrome. Case series report that sirolimus leads to substantial reductions in lymphatic malformation volume, with improvements in clinical symptoms and quality of life in refractory cases, though exact reductions vary (e.g., up to 40% in some reports). BRAF inhibitors like vemurafenib are generally not recommended for RASopathies due to risks of paradoxical pathway activation and induction of RASopathy-like cutaneous side effects. SOS1 inhibitors remain in preclinical stages, with ongoing development of novel compounds demonstrating targeted RAS suppression in models, though applications to SOS1-mutated Noonan syndrome are investigational. Efficacy of these therapies includes tumor shrinkage and functional improvements, but side effects such as rash, diarrhea, vomiting, and potential impacts on growth and bone development necessitate careful monitoring, particularly in children. Dosing is personalized based on mutation type, with KRAS-specific approaches in trials showing enhanced responses. Ongoing clinical trials, including MEK inhibitors for Costello syndrome (e.g., trametinib expansions under NCT06555237 protocols), emphasize genotype-guided therapy. Future directions include early-stage gene therapy concepts, such as CRISPR-Cas9 editing of RAS hotspots, which have shown preclinical efficacy in correcting mutant KRAS in models, though applications to germline RASopathies remain investigational as of 2025.

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A class of developmental disorders, the “RASopathies”, is caused by germline mutations in genes that encode protein components of the Ras/MAPK pathway.Missing: definition | Show results with:definition
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The molecular genetics of RASopathies: An update on novel ...
Nature Reviews. Cancer, 11(11), 761–774. 10.1038/nrc3106 [DOI] [PMC free article] [PubMed] [Google Scholar]; Rauen, K. A. (2013). The RASopathies. Annual ...
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Defining RASopathy | Disease Models & Mechanisms
Feb 1, 2022 · RASopathy germline mutations ... However, each syndrome results from mutations in different genes associated with the RAS/MAPK pathway.
[15]
NMR-based functional profiling of RASopathies and oncogenic RAS ...
Mar 4, 2013 · Exchange activation was decreased by the allosteric mutation, but augmented by single DH or Link mutations, while increasing synergistically in ...Sign Up For Pnas Alerts · Results · Inhibition Of Ras Exchange...
[16]
Comprehensive Genetic Analysis of RASopathy in the Era of Next ...
Jan 7, 2022 · Although the majority of the pathogenic variants are dominant gain-of-function mutations with complete penetrance and variable expressivity, ...
[17]
Clinical overview on RASopathies - Zenker - Wiley Online Library
Nov 25, 2022 · The term “RASopathies” was coined in 2009 (Tidyman & Rauen, 2009). ... No generally accepted definition and definitive delineation of RASopathies ...
[18]
Recent advances in RASopathies | Journal of Human Genetics
Oct 8, 2015 · ... germline mutations that encode components of the RAS/MAPK signaling pathway. These disorders include neurofibromatosis type I, Legius ...
[19]
The effect of parental age on the presence of de novo mutations ...
Jun 16, 2016 · The risk for sporadic NF1 was lower when the fathers were younger at the time of the affected child's birth, and gradually increased with paternal age.
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Molecular and environmental characterization of Noonan syndrome ...
Feb 18, 2020 · These findings confirm, on the one hand, the association of advanced paternal age to higher risk of Noonan syndrome occurrence among offspring ...Genetic Screening · Molecular Finding · Clinical Findings
[21]
RASopathies: the Musculoskeletal Consequences and their Etiology ...
This review focuses on germline mutations and provides an overview of each RASopathy, specifically concentrating on the musculoskeletal abnormalities.
[22]
Mosaic RASopathies - PMC - NIH
RASopathies” are a group of developmental syndromes with partly overlapping clinical symptoms that are caused by germline mutations of genes within the ...
[23]
Expanding the Genetic Landscape of RASopathies: Significance of ...
Mar 18, 2025 · Noonan syndrome, the most prevalent among RASopathies, occurs in roughly 1 in 1,000 to 1 in 2,500 live births. ... The detection rate of ...
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https://karger.com/msy/article/doi/10.1159/000545192/923880/Expanding-the-Genetic-Landscape-of-RASopathies
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https://www.frontiersin.org/articles/10.3389/fgene.2025.1677143/full
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RASopathies and cardiac manifestations - PMC - NIH
Jul 17, 2023 · Current observations indicate that there may be some sex differences in the prevalence or severity of cardiac manifestations in RASopathies.
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The RASopathies: from pathogenetics to therapeutics - PMC
Feb 18, 2022 · The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway.
[28]
Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis ...
The major features of CFC include characteristic craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and ...
[29]
Recent Developments in Neurofibromatoses and RASopathies
The RASopathies include NF1, Noonan syndrome (NS), NS with multiple lentigines ... clinical overviews were provided on Costello syndrome and Legius syndrome ...
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[PDF] Noonan Syndrome Guideline Development Group
The guidelines are divided into recommendations for four age groups: Page 4 contains an overview of the diagnostic criteria and clinical features of NS, and ...
[31]
Multidisciplinary Treatment of Patients With Noonan Syndrome
Oct 15, 2025 · A multidisciplinary approach is essential, with continuous care required from infancy through adulthood; however, there is a lack of updated and ...
[32]
Noonan Syndrome | AAFP
Jan 1, 2014 · Diagnostic Criteria for Noonan Syndrome ; 2. Cardiac, Pulmonary valve stenosis, hypertrophic cardiomyopathy, and/or electrocardiographic results ...
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Revised diagnostic criteria for neurofibromatosis type 1 and Legius ...
May 19, 2021 · The NIH criteria include the most frequent disease manifestations (CALMs, freckling, neurofibromas, and Lisch nodules) alongside disease ...
[34]
HRAS-Related Costello Syndrome - GeneReviews® - NCBI Bookshelf
Aug 29, 2006 · EEG abnormalities are seen in approximately one third of individuals; between 20% and 50% have seizures [Delrue et al 2003, Kawame et al 2003].
[35]
[PDF] Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis ...
Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies that bears many clinical features in common with the other syndromes in.
[36]
Turner syndrome - Orphanet
Differential diagnosis includes Noonan syndrome; 46,XX gonadal dysgenesis; 46,XY complete gonadal dysgenesis, SHOX-related short stature, as well as a single ...
[37]
Prenatal Diagnosis of Euploid Increased Nuchal Translucency on ...
Prenatal diagnosis of euploid increased NT should include a differential diagnosis of pathogenetic copy number variants, Noonan syndrome (NS), and/or RASopathy ...
[38]
Expanding the Genetic Landscape of RASopathies - PMC - NIH
In our study, a 14-gene panel was applied to cases suspected of RASopathy, and the variant detection rate was found to be 78%. In five cases suspected of Noonan ...
[39]
[PDF] Mutational spectrum by phenotype: panel-based NGS testing of ...
. Implementation of I2HCP into routine genetic testing for RASopathies ... MLPA analysis identified two further cases and RNA analysis was required to identify ...<|control11|><|separator|>
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RNA for NF1 only | Genetics
The RNA-based NF1 testing on blood requires a fresh EDTA blood sample, to arrive in the lab <60-70 hours after blood draw. DNA is extracted.Missing: molecular | Show results with:molecular
[41]
ClinGen's RASopathy Expert Panel Consensus Methods for Variant ...
Mar 1, 2018 · Due to variable expressivity and severity, individuals must be well-phenotyped. ≥7 meioses (PP1_Strong), 5–6 meioses (PP1_moderate), 3–4 meioses.
[42]
Systematic detection of mosaicism by using digital NGS ... - PMC
Oct 14, 2022 · NGS offers the possibility of detecting mosaic variants using DNA from blood (7, 8, 14, 16, 17). The challenge is to lower the threshold of ...<|separator|>
[43]
A clinical survey of mosaic single nucleotide variants in disease ...
Jul 26, 2019 · We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples.
[44]
[PDF] Genetic Testing: Prenatal Diagnosis (Via Amniocentesis, CVS, or ...
Feb 1, 2023 · Prenatal diagnosis for Noonan spectrum disorders/RASopathies, via amniocentesis, CVS, or. PUBS, using a Noonan syndrome panel (81404, 81405 ...
[45]
Advancing Non-Invasive Prenatal Screening: A Targeted 1069 ...
We introduce an innovative, non-invasive prenatal screening approach for detecting fetal monogenic alterations and copy number variations (CNVs) from maternal ...
[46]
Gene Panels - Molecular Vision Laboratory
$$650.00$650. Updated: May 2024. Order Test. Pricing. Pricing is for institutional clients only. Contact us to learn more about self-pay discounts. Genetic Testing.
[47]
Noonan Syndrome - GeneReviews® - NCBI Bookshelf - NIH
Nov 15, 2001 · Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree.<|control11|><|separator|>
[48]
Management of Cardiovascular Disorders in Patients with Noonan ...
A combination of pulmonary valve stenosis, a usual cardiac sign in the Noonan syndrome, and HCM rendered the management of this patient very difficult.
[49]
Hypertrophic Cardiomyopathy in RASopathies: Diagnosis, Clinical ...
Medical therapy remains the first-line option in patients with R-HCM. Nonvasodilating beta blockers should be titrated to the maximum tolerated dose in patients ...
[50]
Growth hormone therapy in patients with Noonan syndrome - PMC
Dec 31, 2018 · GH therapy in NS patients is effective for improving height and GV, enabling them to reach normal final height regardless of clinical severity ...
[51]
Etiology and Treatment of Growth Delay in Noonan Syndrome
Jun 3, 2021 · Treatment with recombinant human growth hormone (rhGH) has been shown to accelerate growth in patients with NS, but the benefit of long-term ...Abstract · Growth Delay in Noonan... · Growth Hormone Treatment for...
[52]
Neuropsychological Functioning in Individuals with Noonan Syndrome
Sep 1, 2015 · In early development, a number of rehabilitation therapies may be needed to address developmental delays and support progress. Due to the ...<|separator|>
[53]
Health Supervision for Children With Neurofibromatosis Type 1
May 1, 2019 · Children with known or suspected NF1 should undergo screening and surveillance ophthalmologic examinations at least annually from the time of ...
[54]
ERN GENTURIS tumour surveillance guidelines for individuals with ...
Jan 13, 2023 · Annual screening for breast cancer in females with NF1 is advised to start at the age of 30 years preferably by breast MRI (Table 1, Table 11).
[55]
NF/Ras Pathway Genomic Medicine Clinic | UC Davis MIND Institute
Multidisciplinary care and management of individuals with genetic disorders, including those of the Ras pathway, can be challenging for the family, the primary ...