Noonan Syndrome and RASopathies

Literature and regulatory information updated: 6 October 2026. Integration of the French National Diagnosis and Care Protocols (PNDS): 6 November 2026.

Noonan syndrome, Noonan syndrome with multiple lentigines (formerly LEOPARD), Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with loose anagen hair and an overview of RASopathies

0. Initial Reference Table

Scope note: neurofibromatosis type 1 (NF1) and Legius syndrome (SPRED1) belong to the RASopathy group but are mentioned here only in the differential diagnosis.

French organisation: NS, its variants (NSML, NS-LAH and CBL syndrome) and CFC are covered by a 2021 National Diagnosis and Care Protocol (PNDS) of the Haute Autorité de Santé (HAS), and Costello syndrome by a separate PNDS (2024 update, published in 2025); both were prepared by reference centres for developmental anomalies of the AnDDI-Rares rare disease network, which is linked to ERN ITHACA [1, 2].

1. Introduction

RASopathies form a family of developmental syndromes caused by germline variants in genes encoding components or regulators of the RAS–mitogen-activated protein kinase (MAPK) signalling pathway. Collectively, they affect more than 1 in every 1,000 individuals, with Noonan syndrome the most frequent, at an estimated prevalence between 1:1,000 and 1:2,500 [3, 4]. Their phenotypes share short stature, congenital heart disease (particularly pulmonary valve stenosis and hypertrophic cardiomyopathy), neurodevelopmental abnormalities, pigmentary anomalies, common facial and skeletal traits and tumour predisposition, explaining the clinical overlap that historically hindered their nosological separation [3, 5, 6]. Reference books also designate this group as neuro-cardio-facio-cutaneous syndromes [7].

The first complete description of the phenotype now known as Noonan syndrome is attributed to Weissenberg in 1928; in 1963, Jacqueline Noonan and D. A. Ehmke delineated the clinical presentation while studying non-cardiac malformations in children with congenital heart disease and documented the association with pulmonary stenosis [3]. In 1968, Noonan published the series consolidating the entity as “hypertelorism with Turner phenotype”, emphasising that it affected both sexes and had a normal karyotype [8]. In 1949, Otto Ullrich had noted the similarity of these patients to a mouse strain described by Bonnevie (webbed neck and lymphoedema), leading to the name “Bonnevie–Ullrich syndrome”, popular in Europe; the term “male Turner” was abandoned because it incorrectly suggested that the condition did not occur in women [4]. Allanson and colleagues showed in 1985 that facial appearance changes with age, with direct implications for recognising affected parents [9].

The other entities were described during the same period. Gorlin, Anderson and Blaw (1969) recognised the multisystem nature of multiple lentigines syndrome and coined the acronym LEOPARD (lentigines, ECG abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, deafness) [10, 11]. In 1971 and 1977, Costello published reports of patients with intellectual impairment and nasal papillomas, and Der Kaloustian applied the eponym in 1991; before then, the same condition had been reported as AMICABLE syndrome and faciocutaneous–skeletal syndrome [12, 13]. In 1986, Reynolds and colleagues described eight patients with cardiac, facial and cutaneous involvement and named cardiofaciocutaneous syndrome, after Blumberg had presented the first three cases in 1979 [14, 15].

The molecular era began in 2001 when Tartaglia and colleagues identified gain-of-function variants in PTPN11, encoding the SHP-2 phosphatase, in approximately half of patients with Noonan syndrome [16]. These were followed by KRAS (2006) [17], HRAS in Costello syndrome (2005) [18], BRAF, MAP2K1 and MAP2K2 in CFC syndrome (2006) [19, 20], SOS1 (2007) [21, 22], RAF1 (2007) [23], SHOC2 (2009) [24], RIT1 (2013) [25], PPP1CB (2016) [26], the autosomal recessive LZTR1 form (2018) [27] and MAPK1 (2020) [28]. The observation that children with Costello syndrome had an increased malignancy risk contributed to identification of candidate genes in the RAS pathway [7], and some germline variants in these syndromes are the same as somatic variants arising in cancer [7, 13].

2. Molecular Genetics and Pathophysiology

2.1 The RAS-MAPK pathway

The RAS-MAPK pathway transduces signals from the extracellular environment to the nucleus, where it activates genes involved in cell growth, division and differentiation [3]. Growth factors, cytokines and hormones bind to tyrosine kinase receptors; adaptor proteins (GRB2, SHP-2) recruit guanine nucleotide exchange factors (SOS1, SOS2) that convert RAS from the inactive guanosine diphosphate (GDP)-bound form to the active guanosine triphosphate (GTP)-bound form; RAS-GTP sequentially activates RAF (BRAF, CRAF/RAF1), MEK1/MEK2 (encoded by MAP2K1 and MAP2K2) and ERK1/ERK2, which enters the nucleus and alters transcription [4, 15]. RAS proteins (HRAS, KRAS, NRAS, encoded as 21 kDa p21RAS) have low intrinsic GTPase activity, accelerated by GTPase-activating proteins (GAP), including neurofibromin; under basal conditions, most RAS is inactive [13]. The vast majority of RASopathy-causing variants increase signalling flux through the pathway [4, 7].

Table sources: [4, 7, 13, 15, 24, 27–31].

2.2 Noonan syndrome: genes, variants and genotype–phenotype correlations

PTPN11 accounts for approximately 50% of cases (40–50% according to Smith's; 50–70% according to the Oxford Desk Reference) [3, 4, 7]. All NS-associated variants are missense, and the vast majority lie in five of the 15 exons; they promote the active protein conformation and hyperactive RAS signalling [7]. PTPN11 variant carriers are more likely to have pulmonary stenosis, short stature, chest deformity, easy bruising, cryptorchidism and a characteristic face, but less likely to have hypertrophic cardiomyopathy (HCM) than patients with other genotypes [3, 4]. Germline variants at codons 61, 71, 72 and 76 are significantly associated with leukaemogenesis and identify the subgroup at risk of juvenile myelomonocytic leukaemia (JMML); among patients with a variant at codon Asp61, 20.8% developed myeloproliferative disease or JMML [3, 4]. The NM_002834.5:c.922A>G p.(Asn308Asp) variant is associated with a greater likelihood of mainstream schooling [4]. The in-frame deletion NP_002825.3:p.(Gly60del) (published protein designation) was described in a female infant with hydrops fetalis and JMML, whereas NP_002825.3:p.(Asp61del) was reported in a child with a typical phenotype [4]. Somatic PTPN11 variants found in sporadic JMML differ from NS germline variants and, when present in the germline, are associated with neonatally lethal NS [4].

SOS1 accounts for 10–13% of cases (10–20% according to Smith's) and 16–20% of patients with a clinical diagnosis without a PTPN11 variant [3, 4, 21, 22]. The SOS1 subtype is associated with more frequently normal stature, a lower likelihood of intellectual impairment, and more frequent septal defects and CFC-like ectodermal findings [4, 7]; three embryonal rhabdomyosarcomas have been described in germline SOS1 variant carriers (biliary ampulla/duodenum, bladder and urachus), as have multiple giant-cell lesions [4]. SOS2 (~4%) is associated with infrequent short stature and lymphatic anomalies in more than 50% [4].

RAF1 (approximately 5%; 3–17% according to Smith's) is strongly associated with HCM: approximately 85% of patients with RAF1-related NS have HCM, compared with 18% in NS overall; one-third have multiple naevi, lentigines or café-au-lait macules [4, 23]. The NM_002880.4:c.770C>T p.(Ser257Leu) variant was described in two patients with fatal pulmonary hypertension in childhood [4]. RIT1 (approximately 5%) is associated with HCM in 70–75% of cases, a lower likelihood of short stature, chest deformity and intellectual disability, and a higher likelihood of perinatal abnormalities, high birth weight and relative macrocephaly, as well as curly hair, hyperpigmentation and palmoplantar creases [4, 25, 32]. MRAS was associated with HCM in six of six initially reported patients [4]. KRAS (less than 5%) confers the broadest clinical spectrum and a higher likelihood and severity of intellectual disability, with phenotypes overlapping CFC; craniosynostosis was described in two patients [4, 7, 17]. BRAF and MAP2K1 are associated with ectodermal findings and NRAS with cardiomyopathy and pigmentary anomalies [3, 4]. No correlations are known for RASA2 and RRAS2 [4].

LZTR1 (approximately 8%) is the first gene associated with an autosomal recessive form of NS [3, 27]. In the dominant form (NS10), missense variants cluster on the substrate-recognition surface of the Kelch domain and have a gain-of-function effect; in the recessive form (NS2), biallelic variants impair protein synthesis, stability or localisation [4]. HCM was observed in 5 of 26 heterozygous patients and 19 of 26 patients with biallelic variants, so the recessive form has a greater cardiac burden [4]. Heterozygotes may be asymptomatic or have mild traits [4]. Heterozygous loss-of-function LZTR1 variants also cause schwannomatosis and isolated multiple café-au-lait macules, a distinct clinical entity with its own surveillance programme [4].

There are no clinically useful genotype–phenotype correlations within any of the genes BRAF, KRAS, LZTR1, MAP2K1, MRAS, NRAS, RAF1, RASA2, RIT1, RRAS2, SOS1 and SOS2, and the facial phenotype is insufficient to predict genotype because each gene is associated with typical and atypical faces [3, 4]. Up to 20% of patients meeting clinical criteria have no identifiable molecular cause [4]. RRAS and A2ML1 have each been implicated in fewer than ten individuals, and SPRED2 in a recessive form [4, 29].

The 2021 French PNDS gives a slightly different distribution: PTPN11 in 40–50%, SOS1 in approximately 15%, KRAS, RAF1, RIT1 and LZTR1 in 3–5% each, and SHOC2, PPP1CB, MAP2K1, MRAS, NRAS, RRAS2, CBL, SOS2 and RASA2 more rarely, with PTPN11 duplications in isolated cases and 10–20% of patients without an identified cause; overall, molecular testing confirms the clinical diagnosis in 80–90% of cases [1]. In its correlation table, two variants account for approximately 25% of PTPN11 carriers: NM_002834.5:c.922A>G p.(Asn308Asp) and NM_002834.5:c.923A>G p.(Asn308Ser) [1]. KRAS-related NS more often shows xerosis or ichthyosis, brain anomalies and intellectual disability, and isolated hydrocephalus is more common with this gene; RIT1 is associated with normal stature, few cutaneous signs and cardiomyopathy in more than one-third; SOS1 with less growth and intellectual impairment, xerosis or ichthyosis and multiple giant cell lesions of the jaws, with some patients showing severe cutaneous signs suggestive of CFC; SOS2 with frequent lymphoedema; and CBL with an attenuated phenotype, more common microcephaly, immunological complications and vasculitis [1]. Rare patients with BRAF, MAP2K1 or MAP2K2 variants have an NS phenotype without intellectual disability, rare HRAS variants different from those of Costello syndrome have been described in phenotypes close to CFC and, according to the same document, PTPN11 variants never produce the severe CFC phenotype [1].

Adapted from GeneReviews, table 3 [4]. +, ++, +++: increasing likelihood; −: less likely.

2.3 Noonan syndrome with multiple lentigines

PTPN11 variants causing NSML (more than 95% of cases) are missense variants distinct from NS variants, concentrated in exons 7, 12 and 13 (85% according to Oxford), the most frequent being NM_002834.5:c.836A>G p.(Tyr279Cys) and c.1403C>T p.(Thr468Met); others include c.1381G>A p.(Ala461Thr), NP_002825.3:p.(Gly503Arg) (published protein designation), c.1510A>G p.(Met504Val), c.1517A>C p.(Gln506Pro) and c.1529A>C p.(Gln510Pro) [7, 29, 33, 34]. Unlike NS variants, altered SHP-2 proteins have reduced, but not abolished, phosphatase activity; biochemical studies suggest dominant-negative effects and also gain of function through liquid–liquid phase separation, with differing effects on the MAPK and PI3K-AKT-mTOR pathways, which explains the strong association with HCM [7, 29]. Exon 13 variants are associated with severe biventricular obstructive HCM [7]. RAF1 (<3%; NM_002880.4:c.770C>T p.(Ser257Leu), c.1837C>G p.(Leu613Val)), BRAF (NM_004333.6:c.721A>C p.(Thr241Pro), NP_004324.2:p.(Leu245Phe); two patients) and MAP2K1 (NM_002755.4:c.199G>A p.(Asp67Asn), c.305A>G p.(Glu102Gly); one patient) explain the remaining cases [23, 29]. Smith's states that molecular testing identifies variants in approximately 95% of patients [10]. The French PNDS attributes more than 90% of cases to PTPN11 and describes NSML as an allelic variant of NS [1].

2.4 Costello syndrome

Costello syndrome results from activating germline variants in the proto-oncogene HRAS (11p15.5) [18, 35]. More than 95% of variants affect residues p.Gly12 or p.Gly13 (NP_005334.1), with NM_005343.4:c.34G>A p.(Gly12Ser) accounting for more than 80% of cases; sequencing detects approximately 99% of pathogenic variants, and intragenic duplications of the switch II region have been described [7, 13, 35]. The 2024 French PNDS attributes approximately 90% of cases to p.(Gly12Ser), with a very homogeneous phenotype, cites NM_005343.4:c.37G>T p.(Gly13Cys) as the second variant and associates the remaining, exceptional, variants with attenuated or atypical phenotypes [2]. These variants are identical to somatic variants observed in sporadic tumours: substitutions at amino acids 12, 13, 59, 61 or 63 reduce GTPase activity and lock RAS in the active state; substitutions at 116, 117, 119 or 146 reduce nucleotide affinity and increase GDP-to-GTP exchange. The result is constitutive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways [13]. Rhabdomyosarcomas in patients with Costello syndrome have shown loss of heterozygosity at 11p15.5 through paternal uniparental disomy (complete chromosome 11 disomy in eight of eleven tumours), suggesting that loss of the wild-type allele is the second event [13].

Most variants arise de novo on the paternal allele (14 of 16 in one series), and there is an association with advanced paternal age [13, 36]. The mechanism is positive clonal selection of spermatogonia carrying the activating variant (“selfish selection”), the same mechanism operating in FGFR2 (Apert, Crouzon, Pfeiffer), FGFR3 (achondroplasia, thanatophoric dysplasia), PTPN11 (NS) and RET (MEN2) [36, 37].

2.5 Cardiofaciocutaneous syndrome

CFC is caused by heterozygous variants in BRAF (approximately 75%; 70% according to Oxford), MAP2K1 or MAP2K2 (approximately 25%) and KRAS (less than 2%) [7, 15, 38]. The variants are gain-of-function missense variants or small in-frame deletions that increase ERK1/ERK2 phosphorylation; the most frequent are BRAF NM_004333.6:c.770A>G p.(Gln257Arg), MAP2K1 NM_002755.4:c.389A>G p.(Tyr130Cys) and MAP2K2 NM_030662.4:c.401A>G p.(Tyr134Cys) [15, 19, 20]. Germline KRAS variants in CFC do not coincide with those at codons 12, 13 and 61 typical of cancer, and the oncogenic substitution BRAF NM_004333.6:c.1799T>A p.(Val600Glu) has never been documented as a germline event [7, 15, 29]. MAP2K2 deletions have been described in a CFC-like phenotype, but their causality is disputed, and YWHAZ variants have been reported in patients with CFC traits [15]. PTPN11 is not implicated in CFC [39].

2.6 Noonan syndrome with loose anagen hair

The recurrent SHOC2 NM_007373.4:c.4A>G p.(Ser2Gly) variant creates an N-myristoylation site that relocates SHOC2 to the plasma membrane, where the protein acts as a positive regulator of RAF activation [7, 24]. PPP1CB encodes the beta catalytic subunit of protein phosphatase 1, a component of this complex; in a systematic review of 30 patients, the NM_002709.3:c.146C>G p.(Pro49Arg) variant was present in 56.7%, followed by c.545T>A p.(Met182Lys) (13.3%) and c.548A>C p.(Glu183Ala) (10%), with 86.7% de novo [26, 40].

2.7 Tissue and systemic pathophysiology

Constitutive pathway activation affects tissues of mesodermal and neuroectodermal origin. In the heart, RAS-MAPK hyperactivation leads to myocyte hypertrophy with myofibrillar disarray (pathological disarray in 70% of hearts studied in Costello syndrome) and valve dysplasia, particularly of the pulmonary valve [13, 41]. In the lymphatic system, abnormal signalling disrupts lymphangiogenesis, producing nuchal oedema, cystic hygroma, chylothorax, lymphangiectasia and lymphoedema; many NS facial traits are attributed to oedema that regresses in utero [4, 42]. In the somatotrophic axis, low IGF-I and IGFBP-3 and reduced responses to stimulation tests reflect mild growth hormone resistance due to a post-receptor signalling defect in PTPN11 carriers [4, 43]. In the haematopoietic system, activating variants confer increased proliferation and cytokine-independent growth on myeloid progenitors, underpinning myeloproliferative disease and JMML [4, 30]. In Costello syndrome, postnatal cerebellar overgrowth, probably due to abnormal cellular differentiation, causes progressive posterior fossa crowding [13].

3. Clinical Spectrum and Manifestations by System

3.1 Noonan syndrome

Several thousand individuals with clinically or molecularly diagnosed NS have been identified [4]. The following table summarises the frequency of the main manifestations.

Sources: [3, 4, 7].

Prenatal phase. Perinatal findings include polyhydramnios, lymphatic dysplasia (distended jugular lymphatic sacs, increased nuchal translucency, cystic hygroma, pleural effusion, ascites), relative macrocephaly and cardiac and renal anomalies [4]. Among fetuses with increased nuchal translucency and normal chromosomes, an estimated 3–15% have PTPN11-associated NS [4], and increased translucency may represent NS in chromosomally normal fetuses [3]. Birth weight is usually normal or increased by oedema [7].

Growth. Birth length is normal; postnatal growth failure is evident in the first year, mean height follows the 3rd centile from ages two to four until puberty, with an attenuated pubertal growth spurt; because bone maturation is delayed (approximately 2 years), growth may extend into the third decade [4, 7]. Final height is 161–167 cm in men and 150–155 cm in women (means of 162.5 cm and 151 cm, both at the 2nd centile, according to Oxford); more than half of women and approximately 40% of men have adult height below the 3rd centile [4, 7, 43]. Infant feeding difficulties (vomiting, constipation, abdominal pain and distension) cause poor weight gain that may require nasogastric tube feeding in the first year and persist until 18 months; patients with more severe feeding problems and a more marked physical phenotype have more cognitive deficits [3, 4]. The French PNDS adds that approximately one-quarter of newborns have reduced birth length, that feeding difficulties with poor weight gain affect approximately 75% of infants, that body mass index remains in the lower half of the normal range in children and adults, and that NS may be associated with glucose intolerance and insulin resistance, not yet characterised in prospective studies [1]. According to the same document, bone age is delayed by 1–2 years, allowing growth until about 18 years, and the predominant mechanism of short stature is relative insensitivity to growth hormone (normal secretion with low IGF-I) with a growth plate abnormality, true deficiency being rare except in the SHOC2 form; the adult heights of approximately 162 cm in men and 152 cm in women come from small, old series with clinical diagnosis, which probably excluded mildly symptomatic carriers [1].

Face. Facial appearance changes with age, being more evident in childhood and subtle in adults [4, 9]. In newborns: high forehead, widely spaced eyes with downslanting palpebral fissures, low-set posteriorly rotated ears with a thickened helix, a deep philtrum with high broad peaks of the upper lip vermilion, a short neck with excess nuchal skin and a low posterior hairline. In infants: prominent eyes, thick or ptotic upper eyelids, a nose with a depressed root, broad base and bulbous tip. In childhood, the face may appear expressionless, as in myopathy. In adolescence, the face takes on an inverted triangular shape, with a pointed chin and neck elongation accentuating the webbing. In older adults, nasolabial folds are prominent and the skin appears transparent and wrinkled [4, 7]. Irides are frequently bright blue or blue-green, and epicanthic folds, anterior dental malocclusion, a wide mouth and moderate retrognathia form part of the presentation [3, 4]. NHGRI maintains a photographic atlas of patients of diverse ethnic origins [4]. In the French PNDS, the reported frequencies are hypertelorism in 75%, prominent ear lobule in 90%, very marked philtral columns in 95%, micrognathia in 50% and short neck with excess skin in 55%; the median age at diagnosis is 4 years, which reflects how subtle many forms are [1].

Cardiovascular system. The frequency of congenital heart disease (50–80%) may be overestimated because heart disease was historically required for diagnosis [4]. Pulmonary valve stenosis, frequently with a dysplastic valve, is the most common defect; two-thirds of patients with pulmonary stenosis do not require surgery [3, 4]. According to Oxford, a stenotic, frequently dysplastic, pulmonary valve is present in 20–50% of those affected, and approximately 7% of children with pulmonary stenosis have NS [44]. Other defects include atrial septal defect (4–57%), ventricular septal defect (1–14%), atrioventricular septal defect (1–13%), mitral valve anomalies (2–17%), coarctation of the aorta (2–9%), patent ductus arteriosus (1–6%), tetralogy of Fallot (1–4%) and pulmonary artery branch stenosis [4, 45]. Electrocardiography shows extreme right axis deviation with a superior anticlockwise frontal QRS loop, left or superior axis deviation, left anterior hemiblock or an RSR' pattern in V1 (the latter without clinical consequence) [4]. HCM occurs in 10–29% (20% according to Oxford; 14% in a long-term series, frequently stable), with a median age at diagnosis of five months; it is the most serious cardiac problem, presents early and can be fatal [3, 4, 7, 46]. Infants presenting before six months with congestive heart failure have the worst prognosis, with two-year survival of approximately 30% [4, 47]. Left ventricular non-compaction (hypertrabeculation) is also part of the syndromic cardiac spectrum: in the Clinical Cardiogenetics table of syndromes associated with non-compaction, NS is listed with PTPN11 (the most frequently involved gene), KRAS, SOS1 and RAF1, and LEOPARD syndrome (NSML) with PTPN11 and RAF1; when non-compaction occurs with dysmorphism or other congenital malformations, these syndromes enter the differential diagnosis [48]. The French PNDS estimates cardiac anomalies at 65–80% and HCM at approximately 20%; HCM may appear late in childhood or adulthood and, rarely, attenuate or disappear, and rhythm disturbances, rare in children, may appear with ageing [1]. Aneurysmal dilatation of the coronary arteries and secondary dilatation of the ascending aorta have been described in adults, and cerebral artery anomalies at any age, with stroke or moyamoya syndrome sometimes from childhood; the incidence of these complications has not been established [1].

Psychomotor development and cognition. Motor milestone acquisition is delayed by the combination of hypotonia and hyperextensibility: unsupported sitting at around 10 months, walking at 21 months, first words at 15 months and two-word phrases at 31–32 months [4, 7]. Approximately 50% of school-age children meet criteria for developmental coordination disorder, and 72% have an articulation disorder that responds well to speech therapy; 70% receive speech and language therapy [4]. IQ is usually in the low-normal range; one-quarter have mild intellectual disability (less than one-third according to Allanson) [3, 7]. Data on the difference between verbal and performance IQ are contradictory: Oxford reports frequently lower verbal IQ, Smith's reports the opposite, and GeneReviews concludes that no consistent pattern emerges [3, 4, 7]. Attention and executive-function deficits are among the most common neuropsychological problems, and autism spectrum disorder is reported in up to 30% [3, 4]. According to the French PNDS, hypotonia with motor delay occurs in approximately 25%, language delay in 20% (with a persistent relative deficit in verbal skills and articulation disorders), IQ ranges from 50 to 120, intellectual disability (IQ <70) affects approximately 20% and learning difficulties 30–40%; deficits of auditory-verbal and visual memory, emotional regulation disorders and difficulty recognising other people's emotions (alexithymia) are also described, and performance IQ is usually higher than verbal IQ, the opposite of the Oxford position, which reinforces the absence of a consistent pattern [1].

Psychological health. There is no specific psychopathological profile, and self-esteem is comparable to that of peers; a study of 37 molecularly diagnosed patients observed greater emotional dysregulation, irritability and anxiety, and in an adult group 49% reported diagnosis and treatment of depression and/or anxiety [4]. In a cohort of 51 adults, Noonan recorded depression in 23%, a finding not replicated in a large British cohort followed for several years [4, 49].

Genitourinary system and fertility. Cryptorchidism occurs in 60–80% of boys; Sertoli cell dysfunction, also present with descended testes, suggests an intrinsic defect with hypergonadotrophic hypogonadism [3, 4]. Female fertility is usually normal; menarche occurs at a mean age of 14.6 ± 1.17 years (14.5 years according to Oxford) [4, 7]. Renal anomalies (11%) include renal pelvic dilatation, duplication of the collecting system, rotational anomalies, distal ureteric stenosis, hypoplasia, unilateral renal agenesis or ectopia and bilateral cysts [4]. According to the French PNDS, cryptorchidism affects approximately 80% of boys, the mean age at menarche is 14 years, male subfertility results from cryptorchidism and from testicular insufficiency that is mainly Sertolian (oligoazoospermia with hypergonadotrophic hypogonadism), and urinary tract and renal malformations occur in approximately 10% [1].

Endocrinology and immunology. Hypothyroidism, of autoimmune mechanism, appears late in approximately 5% of patients, and antithyroid autoantibodies are present in approximately 30%; other autoimmune diseases have been described, including systemic lupus erythematosus, of unknown incidence and apparently more frequent in CBL syndrome [1].

Bleeding diathesis. Two-thirds of patients report abnormal bleeding or bruising; defects include thrombocytopenia, platelet dysfunction, von Willebrand disease and partial deficiencies of factors V, VIII, XI and XII and of protein C, isolated or combined, in approximately 50% [3, 4, 7]. Although 50–89% have a bleeding history and/or abnormal tests, only 10–42% have both; in a study of 70 patients without preoperative assessment, the risk of perioperative bleeding complications was 6.2% [4]. The French PNDS estimates the bleeding diathesis at approximately 50%, severe in only 3%, with easy bruising (more marked in infants) and epistaxis possibly more frequent with PTPN11; factor XI deficiency is the most common coagulation abnormality, isolated factor XII deficiency confers no bleeding risk, and thrombopathy (prolonged platelet closure time, abnormal aggregation, defective activation on flow cytometry), with or without thrombocytopenia, is the predominant platelet abnormality [1].

Lymphatic system. Dorsal lymphoedema of the hands and feet is the most common form; intestinal, pulmonary or testicular lymphangiectasia, chylous pleural or peritoneal effusions and scrotal or vulval lymphoedema also occur [4]. In the Oxford table of lymphatic anomaly genes, lymphoedema is recorded in 54% of patients with PTPN11-related NS and 63% of patients with SOS1-related NS, with chylothorax described in KRAS and lymphangiectasia in RAF1 [42]. Limb lymphoedema, present at birth or of late onset, may extend to the genitalia and the gastrointestinal tract, and fetal lymphatic effusions (pleural, pericardial, ascites) may cause severe neonatal respiratory distress or perinatal death, regress and recur in childhood [1]. Syndromic central conducting lymphatic anomaly and the other complex lymphatic anomalies enter the differential diagnosis.

Eyes, hearing and skin. More than 50% have strabismus and/or a refractive error; keratoconus, Axenfeld anomaly, iridoretinal colobomas and prominent corneal nerves have been described [3, 4, 7]. Chronic serous otitis affects approximately 30% in childhood [7]. The skin may show follicular keratosis on extensor surfaces and the face, sometimes as marked as in CFC; café-au-lait macules and lentigines are more frequent than in the general population [4]. The French PNDS describes an ophthalmological problem in 95%: amblyopia due to ptosis or strabismus in one-third, refractive error (mainly myopia and astigmatism) in 50%, epicanthic folds in 80%, hypertelorism in 70%, ptosis in 60%, lower eyelid retraction in 60%, strabismus in 40%, limitation of eye movements in 40% (usually without functional impact), posterior embryotoxon in 30% and a cup-to-disc ratio greater than 0.5 without glaucoma in 20%; bilateral optic nerve hypoplasia is exceptional in NS, unlike CFC, and incomplete eyelid closure, present in 28%, may worsen with ptosis surgery [1]. The same document reports sensorineural hearing loss in 10% in one section and in 25% in another, much more frequent in NSML, as well as conductive hearing loss due to chronic otitis, narrow canals and earwax impaction; the skin is usually dry, with keratosis pilaris of the face and limbs in 15%, palmar hyperkeratosis, progressive lentiginosis in 3% (characteristic of NSML), curly and brittle hair, sparse eyebrows and frequent ulerythema ophryogenes [1].

Skeleton. Thoracic scoliosis occurs in 13–30% (mean age at diagnosis 9 years) and characteristic chest deformity in 28–95%, with vertebral anomalies (including hemivertebrae), cubitus valgus, radioulnar synostosis, brachydactyly, micrognathia, a high palate and dental crowding; reduced bone mineral density has been suggested [3, 4]. Multiple giant cell lesions of the jaw, joints (pigmented villonodular synovitis) and soft tissues, formerly designated Noonan-like syndrome/multiple giant cell lesions, are now considered part of the spectrum (PTPN11, SOS1, RAF1; also in BRAF- and MAP2K1-related CFC) [4]. The French PNDS estimates scoliosis at 25%, mainly in adolescence, and clubfoot at 5%; it describes reduced bone mass in children without a demonstrated increase in fracture risk (no data in adults), diffuse musculoskeletal pain and stiffness of the large joints and, rarely, multiple erosive pigmented villonodular synovitis [1]. Oral manifestations include mandibular underdevelopment, a deep and narrow palate, transverse maxillary deficiency, posterior crossbite, anterior open bite, class II malocclusion, dental agenesis and supernumerary teeth, macrodontia, taurodontism, delayed eruption, impacted or ankylosed teeth, enamel defects, susceptibility to caries and periodontal disease, odontomas and keratocysts; giant cell lesions of the jaws (central giant cell granuloma, with a pseudocherubism appearance) usually appear before the age of 20 [1].

Nervous system. A total of 11 cases of Chiari I malformation have been published, without a known true incidence; cerebral arteriovenous malformations and, occasionally, malignant hyperthermia also occur [3, 4]. The French PNDS estimates Chiari I malformation at less than 5%, developing progressively through late cerebellar hypertrophy in older children or young adults, with headaches, signs of spinal cord compression or syringomyelia; epilepsy is occasional [1].

Haematology and oncology. Hepatosplenomegaly is frequent and attributed to subclinical myelodysplasia [4]. The most common haematological disorder is transient neonatal myeloproliferative disease, which progresses to JMML in approximately 10%; JMML in NS generally follows a more benign course than sporadic JMML [4]. Smith's reports JMML in 3% and JMML-like myeloproliferative disease in 5.6%, with JMML the leading cause of death in these patients (50% died in the first month), five-year event-free survival below 50% and allogeneic haematopoietic stem cell transplantation as the only curative option in most [3]. In a study of patients with PTPN11, the overall risk of malignancy was three times that of the population [50]. Acute lymphoblastic leukaemia, acute myeloid leukaemia, embryonal rhabdomyosarcoma and neuroblastoma have been described, and a review of 30 patients with PTPN11 brought together 28 brain tumours, 24 of them low-grade gliomas and glioneuronal tumours [4]. In the German registry, 632 patients with NS (including NSML) had a standardised incidence ratio for childhood cancer of 8.1, and the cumulative risk by age 20 is estimated at 4% [4, 51]. The French PNDS estimates hyperleucocytosis in 2–3% of patients with NS, in a spectrum ranging from mildly symptomatic transient myeloproliferation to JMML, with monocytosis above 1×10⁹/L, circulating immature myeloid cells, circulating blasts and hepatosplenomegaly; it reports an excess of B-cell acute lymphoblastic leukaemia, the occurrence of most cancers before the age of 5 and an unknown, apparently low, risk of cancer in adults [1]. Schwannomas, mainly of the pelvic nerves, are observed mainly with LZTR1, and dysembryoplastic neuroepithelial tumours (DNET), benign and with exceptional malignant progression, have been reported in children with NS whether or not treated with growth hormone [1].

3.2 Noonan syndrome with multiple lentigines

More than 150 patients have been described [29]. The cardinal features are lentigines, HCM, short stature, chest deformity and facial dysmorphism similar to that of NS, usually milder [29]. The French PNDS recommends abandoning the designation LEOPARD, which it considers demeaning, and stresses that NSML is distinguished mainly by profuse lentiginosis of progressive onset and by the higher frequency of hearing loss and cardiomyopathy; its management and follow-up do not differ from those of NS [1].

Sources: [7, 10, 29].

Lentigines are flat dark-brown to black macules measuring 1–5 mm, more numerous on the face, neck and upper trunk but potentially occurring on palms, soles, scalp and genitalia while sparing mucosae; they differ from freckles by being darker and independent of sun exposure, are rarely present at birth, and increase to thousands at puberty, darkening with age [10, 29, 52]. Patients are frequently referred with a provisional NF1 diagnosis [7]. HCM mainly arises in childhood, frequently involves the interventricular septum and may be progressive; electrocardiography shows prolonged PR and QRS and abnormal P waves [10, 29]. Non-reentrant atrial tachycardia occurs independently of HCM in RASopathies [10]. Occasional findings include colobomas, abnormalities of stereopsis and eye movements, seizures, hypospadias, urinary and ovarian anomalies, hyposmia, hypertrophic lumbar plexus neuropathy, giant-cell lesions of the mandible and maxilla, neurofibromas and craniosynostosis (sagittal with PTPN11; multisuture cloverleaf with RAF1) [10, 29]. Hypogonadism may be hypogonadotrophic, warranting adolescent surveillance [10]. Six patients with malignancy have been reported: three leukaemias with a variant at PTPN11 residue 279, one neuroblastoma and one medulloblastoma with p.Thr468Met, and one corneal choristoma; melanoma and acute myeloid leukaemia have also been reported [10, 29, 53].

3.3 Costello syndrome

The spectrum ranges from an attenuated phenotype to a severe form with early lethal complications [13]. More than 100 patients with an HRAS variant have been described [13, 35].

Sources: [13, 35, 41].

Summary of the French PNDS. The 2024 PNDS cites more than 600 published cases and the absence of prevalence data; it describes an adult height close to 140 cm without treatment, growth hormone deficiency in half of children, cardiac involvement in approximately two-thirds (HCM usually asymmetrical, chaotic or multifocal atrial tachycardia, pulmonary stenosis often moderate), malignant tumours in 13%, constant intellectual disability, mostly mild to moderate and rarely severe, osteoporosis in half of adults, myopia that is sometimes severe and should be screened for early, palmoplantar hyperkeratosis with hyperhidrosis that is sometimes disabling in adults, papillomas from the age of 3 (sometimes only at puberty) with a predominantly perioral and perinasal facial distribution, hypogonadism with frequent pubertal delay, and sleep apnoea; mortality is mainly due to cardiac and tumour complications [2]. In the prenatal period, macrosomia with relative macrocephaly contrasts with short femurs, in a context of polyhydramnios, thickened nuchal fold or fetal tachycardia [2].

Prenatal and neonatal. Increased nuchal translucency, polyhydramnios (>90%), ulnar deviation of the wrists, short humeri and femora, fetal atrial tachycardia and preterm delivery [13]. Birth weight is high in 50% because of oedema, potentially leading to incorrect classification as an overgrowth syndrome; prenatally diagnosed cases have a more severe phenotype and a high risk of intrauterine death [13, 35]. Neonatal hyperinsulinaemia and hypoglycaemia are frequent [7, 13].

Feeding and growth. Severe poor weight gain is the most difficult clinical problem; oral feeding is generally possible only between ages two and four, and gastro-oesophageal reflux and increased resting energy expenditure contribute to the weight deficit [13, 35]. Growth restriction persists even with supplementation, and aggressive high-calorie feeding is ineffective; adult height ranges from 135 to 150 cm [13].

Face, skin and appendages. Relative macrocephaly, coarse face with thick lips, a large mouth, full nasal tip, full cheeks, low-set ears with thick lobules, an aged appearance; loose, soft skin, particularly on the hands and feet, deep palmar and plantar creases, palmoplantar hyperkeratosis, acanthosis nigricans, sparse curly hair, thin deeply set nails [13, 35]. Papillomas, absent in infants, emerge between ages 2 and 15 in perinasal, perioral and perianal areas [13, 35].

Heart. Among 146 molecularly confirmed patients, 87% had a cardiovascular abnormality: congenital heart disease in 44% (mainly non-progressive pulmonary valve stenosis), HCM in 61% and histological myocardial disarray in 70% [13, 41]. HCM may be chronic, progressive (37%), stabilise (27%) or regress (14%); some patients with moderate to severe obstruction show “remodelling” over years [13, 41]. A severe neonatal form can be lethal within the first two years [13, 35]. Non-reentrant atrial tachycardias (multifocal or chaotic atrial tachycardia and ectopic atrial tachycardia) are characteristic, independent of HCM and usually self-limiting with intensive treatment, but persist or worsen in approximately one-quarter of patients and may cause sudden death [10, 13, 35]. Oxford reports that 61% of patients have chronic or progressive HCM, warranting lifelong screening [46].

Nervous system and behaviour. Progressive cerebellar overgrowth with bony posterior fossa hypoplasia causes posterior fossa crowding (27 of 28 patients in an MRI study), Chiari I malformation, syringomyelia and hydrocephalus that may require shunting; tethered cord is frequent [13, 35]. All patients have developmental delay or intellectual impairment (IQ 47–68, occasionally low-normal) [13, 35]. Personality is sociable and warm; many children under four meet autism spectrum disorder criteria, which tend to disappear after that age; separation anxiety occurs in 39% [13, 46].

Musculoskeletal system. Severe hypotonia with reduced muscle mass and a myopathic phenotype, finger hypermobility, ulnar deviation, progressively shortened Achilles tendons, hip dysplasia (sometimes acquired), kyphoscoliosis and osteoporosis in young adults; in adults aged 16–40, all eight bone density scans performed were abnormal [13, 35].

Other findings. Obstructive sleep apnoea in 7 of 10 patients investigated by polysomnography; respiratory complications in 78% of newborns; growth hormone deficiency, hypothyroidism, cortisol deficiency, dysregulated or precocious puberty, craniosynostosis, dental anomalies, retinal dystrophy and keratoconus [13, 35].

Tumours. Cumulative cancer incidence is approximately 15% by age 20: rhabdomyosarcoma (mainly abdominal and pelvic, including the umbilical ligament), followed by neuroblastoma in early childhood and transitional cell carcinoma of the bladder in adolescence (at ages 10, 11 and 16 in the three described patients, whereas in the general population 70% occur after age 65) [13, 35]. In a review of 13 cystoscopies in patients aged 10 or older, 10 had a macroscopic bladder lesion at the first examination, with low-grade epithelial dysplasia in 70% and papillary urothelial neoplasia of low malignant potential or low-grade carcinoma in 30% [13]. In a meta-analysis of 621 patients from 35 countries, more than 9% had cancer; cumulative incidence by age 20 was 13% for cancer and 11% for death without cancer, with standardised incidence ratios of 1,240 for rhabdomyosarcoma, 1,971 for bladder carcinoma and 60 for neuroblastoma, and reduced survival after cancer [54]. In the German registry, the standardised childhood cancer incidence ratio was 42.4 [51]. Tumour-specific cumulative risk estimates in the American Association for Cancer Research (AACR) update are 7% for rhabdomyosarcoma, 2% for neuroblastoma and 2.2% for transitional cell carcinoma [53].

Genotype–phenotype correlations. In a review of 146 patients, there was no correlation between variant and HCM, multifocal tachycardia or aortic dilatation [13, 41]. Tumour risk was 9.2% for NM_005343.4:c.34G>A p.(Gly12Ser), 38.7% for c.35G>C p.(Gly12Ala) and 37.5% for c.34G>T p.(Gly12Cys); mortality is higher with p.(Gly12Cys), c.35G>A p.(Gly12Asp), c.35G>T p.(Gly12Val) and c.179G>T p.(Gly60Val); p.(Gly12Ala) and p.(Gly12Cys) are associated with a severe neonatal phenotype, and p.(Gly12Val) and NP_005334.1:p.(Gly12Glu) (published protein designation) with an early lethal form (with pulmonary vascular dysplasia in p.(Gly12Glu)) [13, 35, 54, 55]. The NM_005343.4:c.37G>T p.(Gly13Cys) variant, the second most frequent, is associated with long eyelashes, loose anagen hair syndrome and absence of papillomas and multifocal tachycardia, without described malignancies; c.38G>A p.(Gly13Asp) is associated with a milder phenotype; c.173C>T p.(Thr58Ile), c.437C>T p.(Ala146Val) and c.179G>T p.(Gly60Val) with attenuated NS-like phenotypes; NP_005334.1:p.(Glu37dup) (published protein designation) with very sparse hair and a less coarse face [13, 35]. Somatic mosaicism may produce only segmental skin changes or a presentation indistinguishable from germline disease [13]. Life expectancy is reduced: reported deaths (10%) resulted from HCM, coronary fibromuscular dysplasia, multifocal tachycardia, malignancy, pulmonary causes and multiorgan failure [13].

3.4 Cardiofaciocutaneous syndrome

Hundreds of patients have been described [15]. CFC is characterised by heart disease, craniofacial dysmorphism, ectodermal abnormalities, hypotonia, ocular anomalies, gastrointestinal dysfunction, seizures and neurocognitive delay of variable degree [15, 56].

Prenatal and neonatal. Polyhydramnios in the vast majority, macrocephaly, macrosomia with relatively short femora and an increased nuchal fold; maternal hyperemesis, gestational diabetes, hypertension and pre-eclampsia; frequent operative delivery; in newborns, arrhythmia, need for intubation and tube feeding, oedema, chylothorax and hyperbilirubinaemia [15, 38].

Face. Relative macrocephaly (88%), high prominent forehead (100%), bitemporal narrowing (100%), supraorbital ridge hypoplasia (100%), downslanting palpebral fissures (71%), hypertelorism (84%), ptosis (53%), exophthalmos (55%), a short upturned nose (92%), deep philtrum with a marked Cupid's bow (82%), low-set rotated ears (95%) and a webbed neck [38]. The face is coarser than in NS but usually less so than in Costello syndrome; in adolescence it becomes less NS-like [15].

Heart. Heart disease in 75–80% (77% in Smith's): pulmonary stenosis (approximately 50% in patients with BRAF), atrial and ventricular septal defects, HCM (approximately 40% in molecularly diagnosed patients, potentially arising later), mitral and tricuspid valve dysplasia, bicuspid aortic valve and arrhythmias [13, 15, 38].

Skin, hair and nails. All patients develop skin abnormalities: xerosis, hyperkeratosis, keratosis pilaris, ichthyosis, ulerythema ophryogenes, eczema (severe atopic dermatitis), haemangiomas, café-au-lait macules, erythema, melanocytic naevi increasing in number with age, and palmoplantar hyperkeratosis at pressure sites; hair is sparse, curly, fine or thick, woolly or brittle (100%), with sparse or absent eyebrows and eyelashes; nails may be dystrophic or grow rapidly [15, 38]. Xerosis and follicular hyperkeratosis tend to improve with age, while palmoplantar hyperkeratosis and lymphoedema may worsen [15].

Nervous system. Moderate to severe intellectual impairment in more than 95% (approximately 90% according to Oxford), although some patients have normal or borderline IQ; hypotonia due to skeletal myopathy; walking at a mean age of three years in those acquiring it; many remain non-verbal [7, 15, 38]. More than 50% develop epilepsy (complex partial, generalised tonic–clonic and absence seizures, infantile spasms), usually beginning in early childhood and frequently refractory [15, 38]. MRI may show Chiari I, ventriculomegaly, hydrocephalus, cortical atrophy, frontal lobe or brainstem hypoplasia, and corpus callosum and myelination abnormalities [15, 38]. Peripheral neuropathy, musculoskeletal pain (highly prevalent in RASopathies), irritability, attention deficit, obsessive or aggressive behaviour, anxiety, tactile defensiveness and autism spectrum disorder are frequent [15, 38].

Other systems. Severe feeding difficulties with reflux, aspiration, vomiting, oral aversion, dysmotility and intestinal malrotation, frequently requiring gastrostomy; persistent constipation [15]. Strabismus, nystagmus, optic nerve hypoplasia, refractive errors, cataracts and cortical blindness [15, 38]. Reduced muscle bulk, joint laxity, progressive contractures, scoliosis, kyphosis, hip dysplasia and reduced bone mineral density [15]. Recurrent otitis media with narrow auditory canals, hyperacusis and hearing loss; urogenital anomalies in up to 33%; growth hormone deficiency, growth hormone resistance, precocious or delayed puberty and hypothyroidism; laryngotracheomalacia, laryngeal clefts and sleep disorders; rare bleeding diathesis [15]. Acute lymphoblastic leukaemia, non-Hodgkin lymphoma, large B-cell lymphoma, hepatoblastoma, chondroblastoma and giant-cell lesions have occasionally been described, without quantified risk [15, 38, 53].

Gene-specific correlations. Seizures are more frequent in BRAF- and MAP2K1-related CFC than in MAP2K2-related CFC, which is associated with a lower risk of severe neurodevelopmental delay [15]. According to Oxford, MEK1/2 variants are more associated with relative macrocephaly, chest deformity and keratosis pilaris, and BRAF variants with severe intellectual impairment, congenital heart disease, sparse curly hair, optic nerve anomalies and feeding problems [7].

Summary of the French PNDS. The 2021 PNDS describes CFC as a more pronounced form of NS, on a clinical continuum: feeding difficulties occur in more than 70%, more severe and prolonged than in NS, with enteral nasogastric tube feeding in 20% and gastrostomy in chronic situations; HCM is reported in 70% in the text and in 40% in the summary table of the same document; intellectual disability is almost constant (>95%), walking is acquired at a mean age of 3 years and some patients never achieve it, comprehension is always better than expression, relative or absolute macrocephaly is very frequent and MRI is abnormal in 50% (ventricular dilatation or hydrocephalus, cortical atrophy, white matter and brainstem abnormalities) [1]. Epilepsy affects 40–50% of children, infantile spasms are a diagnostic and therapeutic emergency, sleep disorders (night waking, apnoea) are frequent, and peripheral neuropathy with distal weakness and atrophy may appear with age [1]. Optic nerve hypoplasia or dysplasia is present in at least one-third, of variable and non-progressive severity, sometimes with low vision and nystagmus; the skin shows diffuse keratosis pilaris, ulerythema ophryogenes, palmoplantar keratoderma, deep (padded) palmoplantar creases, numerous naevi, palmoplantar hyperhidrosis and infantile haemangiomas more frequent than in the general population, and axillary and pubic hair is sparse or absent after puberty [1]. There is no bleeding diathesis, orthopaedic complications (mainly scoliosis) result from hypotonia, and the cumulative risk of cancer by age 20 is below 2% (acute lymphoblastic leukaemia, lymphoma, rhabdomyosarcoma, hepatoblastoma; no JMML described) [1].

3.5 Noonan syndrome with loose anagen hair

SHOC2 c.4A>G defines a subgroup with Noonan-like traits (or a classic phenotype in a small proportion), growth hormone deficiency, hyperactive behaviour improving with age in most, loose anagen hair (sparse, fine, slow-growing and easily plucked without pain), dark skin with eczema or ichthyosis, a hypernasal voice and overrepresentation of mitral valve dysplasia and septal defects compared with classic NS [4, 24, 29]. The skin frequently has a tanned appearance [29]. In an Italian cohort, height was approximately −3 standard deviations, with very low IGF-I and growth hormone deficiency on pharmacological testing; puberty was delayed and prolonged or rapidly progressive [57]. Oxford emphasises the lesser growth and developmental impairment in the SOS1 subtype and reserves “NS with loose anagen hair” for SHOC2 [7].

In the PPP1CB form, the systematic review of 30 patients showed universal facial dysmorphism, ectodermal anomalies in 79.3%, congenital heart disease in 75.9% (pulmonary stenosis and atrial septal defect), short stature in 69.2%, macrocephaly in 58.6%, neurodevelopmental delay in 72.4–84.6%, structural brain anomalies in 35.7%, intellectual impairment in 26.9% and epilepsy in 6.7% [40]. Complete commissural agenesis [58] and maternal transmission of p.Met182Lys to three children have been described [40].

3.6 Other entities in the spectrum

CBL syndrome. CBL-related Noonan-like syndrome with or without JMML is characterised by a high frequency of neurological manifestations, predisposition to JMML, low prevalence of heart disease, reduced growth and cryptorchidism [4, 30]. JMML results from somatic inactivation of the normal allele through acquired uniparental isodisomy of 11q; some patients with spontaneous regression of JMML later developed vasculitis, and arteritis is exclusive to this syndrome among the RASopathies [30, 53]. The French PNDS stresses the lower penetrance than in NS and the higher frequency of immuno-haematological, ophthalmological (uveitis) and vascular (arteritis, moyamoya) manifestations [1]. Most RASopathy panels include CBL sequencing and the recurrent SHOC2 variant [4].

MAPK1-related RASopathy. Neurodevelopmental disorder with developmental delay, Noonan-like facial traits, short stature and cardiac defects, without described HCM [28].

Mosaic RASopathies. Postzygotic HRAS variants cause Schimmelpenning–Feuerstein–Mims syndrome (linear sebaceous naevus, frequently NM_005343.4:c.37G>C p.(Gly13Arg)) and cutaneous–skeletal hypophosphataemia syndrome; KRAS variants cause encephalocraniocutaneous lipomatosis; NRAS variants (codon 61) cause multiple congenital melanocytic naevi and neurocutaneous melanosis [4, 13, 52]. The postzygotic HRAS p.(Gly13Arg) variant has also been described in the extensive dermal melanocytosis of phakomatosis pigmentovascularis.

4. Clinical Recognition and Warning Signs

Recognition rests on the combination of short stature, heart disease (pulmonary stenosis or HCM), a characteristic face and lymphatic, cutaneous or neurodevelopmental abnormalities. The following features should prompt consideration of a RASopathy:

Sources: [2, 4, 7, 13, 15, 29, 39, 46, 59, 60].

History-taking should include a three-generation pedigree focused on short stature, heart disease and learning difficulties; pregnancy history with exposure to alcohol and anticonvulsants (phenocopies), nuchal oedema, hygroma, pleural effusion or polyhydramnios; poor weight gain; developmental milestones; schooling; and a history of bruising or prolonged bleeding after venepuncture, dental extraction or surgery [7]. Examination assesses weight, height and head circumference (usually disproportionately higher than the height centile), face, eyes (thick eyelids, ptosis, pale irides), low posterior hairline and neck with redundant skin, widely spaced nipples, sternal deformity, murmurs, cryptorchidism (60%), hypotonia, hyperextensibility and skin (lentigines, café-au-lait macules, xerosis, eczema, keratosis pilaris); careful examination for café-au-lait macules is essential to avoid missing NF1 [7]. As facial traits become subtler with age, caution is required before considering a parent unaffected, and reviewing parents' childhood photographs is useful; several relatives are frequently diagnosed after the proband [4, 7].

When assessing an infant with HCM, NS, CFC, Costello and NSML facial appearances, lentigines and deafness should be actively sought [46]. RAS-MAPK pathway variants were found in 6.4% of HCM cases presented as non-syndromic [46], and non-sarcomeric genes such as PTPN11 are almost always associated with an extracardiac syndromic phenotype [61]. When evaluating generalised or limb oedema in a newborn, the NS face (thick eyelids, ptosis, webbed neck, low-set ears, widely spaced nipples) indicates that oedema regressed in utero, and echocardiography is indicated [42].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Noonan syndrome

There are no consensus clinical diagnostic criteria. The van der Burgt scoring system (2007), incorporated into the European DYSCERNE guidelines (2010), was proposed but has seen little use in North America [4]. Molecular diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic variant in BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1 or SOS2, or heterozygous or biallelic LZTR1 variants [4]. A variant of uncertain significance neither confirms nor excludes the diagnosis, and a negative test does not exclude clinical diagnosis because up to 20% of patients lack an identifiable cause [4]. The 2025 Italian consensus achieved complete agreement on the importance of molecular characterisation for diagnosis, prognosis and therapeutic decisions [62].

Testing strategy. When the phenotype is suggestive, the first-line test is a multigene RASopathy panel, which should include the recurrent SHOC2 variant and CBL; when a panel is unavailable, PTPN11 sequencing is the first test, with subsequent steps guided by phenotype (RIT1 if HCM is present, LZTR1 if recessive inheritance is suspected), although sequential single-gene analysis is less efficient and more expensive [4]. When the phenotype is atypical or “Noonan-like”, exome or genome sequencing is preferable [4]. Because the mechanism is gain of function, deletion/duplication analysis has minimal yield [4]. Providing detailed clinical information to the laboratory is useful [7].

Initial additional investigations. Genomic microarray in all girls with a sporadic presentation (overlap with 45,X) and all patients with developmental delay; echocardiography and electrocardiography; prothrombin time, activated partial thromboplastin time and platelet count, with measurement of factors XI, XII, IX, VIII, von Willebrand factor and platelet aggregation in collaboration with haematology (repeated after 12 months if initial screening was earlier); ophthalmological examination; audiological assessment; renal ultrasound; bone age, thyroid function (TSH, free T4) and somatotrophic-axis assessment in children with short stature (height below −2 SD or crossing two major centile lines) [4, 7].

Initial assessment according to the French PNDS. The 2021 PNDS considers the diagnosis of NS and CFC to be essentially clinical and accepts that, in infants, distinguishing between them may be impossible, in which case the term “RASopathy” should be used; it recommends molecular confirmation in all patients with suspected disease, with a RASopathy gene panel as first-line test, and points out that a sensitivity of 80–90% does not allow the diagnosis to be excluded on a negative test [1]. Parental testing is desirable even without obvious signs, because of the possibility of vascular or neurological complications in adulthood and the implications for counselling; a de novo variant of uncertain significance is a strong argument for pathogenicity, and an undescribed variant inherited from an apparently healthy parent is difficult to interpret, a plausible situation in NS but very unlikely in CFC [1]. When CFC is clinically suspected, HRAS testing is essential to exclude Costello syndrome, which requires its own tumour surveillance [1].

Source: [1].

5.2 Noonan syndrome with multiple lentigines

Clinical criteria (Voron 1976; Sarkozy 2008) establish diagnosis in the presence of multiple lentigines and two other cardinal features (cardiac anomalies; reduced linear growth/short stature; chest deformity; facial dysmorphism with hypertelorism and ptosis), or, without lentigines, three cardinal features and an affected first-degree relative [29, 63]. Molecular confirmation identifies a heterozygous variant in PTPN11, RAF1, BRAF or MAP2K1 through an NS, RASopathy or HCM panel, or exome/genome; targeted sequencing of PTPN11 exons 7, 12 and 13 and RAF1 exons 6, 13 and 16 detects almost all described variants [10, 29]. In the first year of life, before lentigines appear, the phenotype may be indistinguishable from NS, and HCM with multiple café-au-lait macules provides a clue [10, 29].

5.3 Costello syndrome

There are no consensus clinical criteria; diagnosis is suspected from clinical and neuroimaging findings and confirmed by a heterozygous pathogenic HRAS variant [13]. HRAS sequencing alone or within a panel is the first option; a p.Gly12 or p.Gly13 variant is diagnostic [7, 13]. In earlier series, the 10–15% of patients with suspected Costello without an HRAS variant proved to have CFC or KRAS-related NS [13]. In mosaicism, leucocyte DNA may be negative and buccal mucosal DNA positive [13].

The 2024 French PNDS considers a pathogenic or likely pathogenic HRAS variant sufficient, classified according to ACMG/AMP criteria and sought by targeted sequencing, panel or exome/genome, whose request should follow the advice of a reference centre for developmental anomalies linked to a reference laboratory [2, 64]. When the presentation is highly suggestive and blood testing is negative, somatic mosaicism should be sought in a buccal swab or skin fibroblasts, distinguishing it from the somatic HRAS variants of Schimmelpenning–Feuerstein–Mims syndrome, cutaneous–skeletal hypophosphataemia syndrome and sporadic tumours [2]. The recommended initial assessment varies with age:

Source: [2].

5.4 Cardiofaciocutaneous syndrome

There are no established clinical criteria; suspicion rests on dysmorphism, heart disease, severe feeding problems with relative macrocephaly, ectodermal abnormalities, lymphoedema/chylothorax, ocular anomalies, hypotonia, developmental delay, epilepsy and cryptorchidism, and confirmation requires a heterozygous variant in BRAF, MAP2K1, MAP2K2 or KRAS on a RASopathy panel or exome/genome [15]. The GeneReviews chapter author argues that a pathogenic BRAF or MAP2K1 variant molecularly defines CFC even when the phenotype approaches NS or Costello syndrome; Smith's notes that BRAF and KRAS variants have been identified in patients with NS and NSML [15, 38].

5.5 Noonan syndrome with loose anagen hair

Diagnosis is molecular (SHOC2 c.4A>G or a PPP1CB variant); no biochemical or functional examination confirms it, and hair, skin, behavioural and endocrine findings are suggestive but non-specific. Because the SHOC2 variant is included in most NS panels, it should be reported as NS-LAH rather than classic NS [4, 24].

5.6 Prenatal diagnosis

Ultrasound may show increased nuchal translucency, cystic hygroma, scalp oedema, distended jugular lymphatic sacs, pleural and pericardial effusions, ascites, hydrops, polyhydramnios, hydronephrosis and heart disease, which is diagnosed prenatally in approximately 20% of NS cases; pulmonary stenosis is difficult to detect on fetal echocardiography [4, 7]. In a series of 309 pregnancies with isolated translucency above the 99th centile, four had NS; in the HYDROPS study, four of 44 fetuses with non-immune hydrops had NS identified by trio exome sequencing [4]. The combination of severe polyhydramnios and fetal atrial tachycardia in a fetus with a normal microarray should suggest Costello syndrome [13, 59]. In CFC, polyhydramnios is present in the vast majority of cases diagnosed in utero [15]. The French PNDS reports excess amniotic fluid or polyhydramnios in approximately one-third of pregnancies with NS or CFC and usual regression of early lymphatic anomalies in utero; because the signs are non-specific, prenatal diagnosis is rarely considered without a family history, and some RASopathies probably end in spontaneous miscarriage or fetal death [1].

5.7 Practical algorithm

Sources: [4, 7, 13, 15].

5.8 Limits of genetic tests and report content

Coverage and limitations. RASopathy panels and exome primarily detect coding sequence variants and exon–intron junction variants; because the dominant mechanism is gain of function through missense variants or small in-frame deletions and duplications, copy number analysis has minimal, but non-zero, yield: intragenic HRAS duplications occur in Costello syndrome, MAP2K2 deletions of disputed causality occur in a CFC-like phenotype, and in the recessive LZTR1 form, loss-of-function alleles may include intronic or splicing variants or rearrangements detected only if the laboratory specifically analyses those classes [4, 13, 15, 27]. Microarray remains necessary to exclude 45,X in girls and chromosomal imbalances in patients with developmental delay and does not replace the panel [4, 7]. Somatic mosaicism (described in Costello syndrome and mosaic HRAS, KRAS and NRAS RASopathies) may escape leucocyte DNA testing, requiring adequate read depth and sometimes buccal mucosal or affected-tissue DNA [4, 13]. In children with myeloproliferative disease or JMML, a PTPN11, KRAS, NRAS or CBL variant found in blood may be somatic; confirming germline origin requires non-haematopoietic tissue (for example, fibroblasts or buccal mucosa), and in CBL syndrome, loss of the normal allele in leukaemia occurs through acquired 11q isodisomy [4, 30]. A negative result does not exclude clinical diagnosis because up to 20% of patients with NS lack an identified cause, and DNA should be stored for reanalysis [4].

Reference transcripts and nomenclature. The report should state the gene, versioned reference transcript, variant in HGVS nomenclature at DNA and protein levels, zygosity, classification and method. The table presents MANE (Matched Annotation from NCBI and EMBL-EBI, version 1.5) transcripts for the main genes [65]. The literature frequently uses abbreviated protein numbering (for example, “G12S”, “codon 61”, “D61”, “Y279C”, “S2G”) or older transcript versions (Andelfinger's report uses NM_006912.5 for RIT1); the corresponding standardised form is, for example, NM_005343.4(HRAS):c.34G>A p.(Gly12Ser), NM_002834.5(PTPN11):c.922A>G p.(Asn308Asp), NM_002834.5(PTPN11):c.836A>G p.(Tyr279Cys), NM_002834.5(PTPN11):c.1403C>T p.(Thr468Met), NM_007373.4(SHOC2):c.4A>G p.(Ser2Gly) and NM_006912.6(RIT1):c.246T>G p.(Phe82Leu), all classified as pathogenic (or pathogenic/likely pathogenic) in ClinVar, several by expert panels [66]. This article retains historical codon numbering when used by the source (for example, PTPN11 codons 61, 71, 72 and 76), without mixing it with DNA coordinates. In genes with two clinically relevant transcripts, the transcript must be explicit: in KRAS, MANE Select (NM_004985.5) corresponds to the KRAS4B isoform and MANE Plus Clinical (NM_033360.4) to the KRAS4A isoform, needed for variants in its isoform-specific exon; HRAS and BRAF also have MANE Plus Clinical transcripts [65].

Source: MANE GRCh38 v1.5 [65].

Classification and interpretation. Classification follows ACMG/AMP criteria with specifications from the ClinGen RASopathy expert panel, which adapted population-data, functional-hotspot, de novo occurrence and specific-phenotype criteria for these genes [64, 67]. The same panel evaluated the validity of 19 genes: 11 had a definitive association with at least one RASopathy, two a strong association, one moderate, three limited, and two were disputed for all conditions, so panel content should reflect current curation [68]. Confirmation that a variant is de novo (with confirmed parentage) is strong evidence of pathogenicity; a variant of uncertain significance does not become pathogenic because a patient responds to growth hormone or a MEK inhibitor, or because of partial segregation in a small family — segregation analysis is an additional investigation whose result must be reassessed using formal criteria [4, 64]. In LZTR1-related NS, interpreting two variants requires demonstrating that they are in trans (parental testing) and distinguishing the recessive form from the dominant form caused by Kelch-domain variants [4]. Regarding actionability, ClinGen concluded that NSML has limited actionability in paediatric and adult contexts (report AC1023), whereas the paediatric NS assessment (AC1003) does not yet have a consensus assertion; these assessments concern secondary findings and do not reduce the utility of molecular diagnosis in a symptomatic patient [69].

6. Differential Diagnosis

6.1 Differential diagnosis among RASopathies

Sources: [3, 4, 7, 10, 13, 15, 29, 35, 38, 40].

The summary table of the French PNDS compares the three main RASopathies:

Source: [1]. The HCM percentages in this table (10% in NS and 40% in CFC) differ from those in the text of the same document (20% and 70%) and from those of GeneReviews (see 7.14).

Compared with NS, CFC has similar cardiac and lymphatic findings but more severe intellectual disability with more structural anomalies of the central nervous system, more florid skin disease, more severe and prolonged gastrointestinal problems, a rare bleeding diathesis, a coarser face, more frequent dolichocephaly and absent eyebrows, and less frequent blue eyes [4, 29]. Distinguishing Costello syndrome from CFC in infants is difficult: cutis laxa, curly hair, pruritus and hyperhidrosis occur in both, whereas acanthosis nigricans, papillomas and loose, thick skin on the dorsum of the hands are characteristic of Costello syndrome; in CFC the lips are less thick, the eyebrows typically sparse, atopic dermatitis and ichthyosis more frequent, and malignancies rare [13, 35]. Non-re-entrant atrial tachycardia has been described in NS and CFC but is much more frequent in Costello syndrome [13]. The distinction between Costello syndrome and NS is clearer in older children [13]. The French PNDS stresses that there is no international consensus on clinical criteria separating NS from CFC, that genotype–phenotype correlations are imperfect and that the severity of neurological involvement is the main argument; the severity of feeding disorders, the degree of intellectual disability, optic atrophy and absent eyebrows are good clues in infants, and the literature before 2005 frequently confused CFC and Costello syndrome [1].

6.2 Other conditions

Sources: [4, 7, 13, 29, 42, 46, 52, 61].

In the HCM differential diagnosis table in Clinical Cardiogenetics, NS is distinguished from sarcomeric HCM by learning difficulties, increased right ventricular thickness and right ventricular outflow tract obstruction; malformation syndromes (NS, LEOPARD, Costello, CFC) form part of the non-sarcomeric causes of HCM [61].

According to the French PNDS, 10–15% of patients with NF1 have Noonan-like dysmorphism (the former “Noonan–NF1 syndrome”, now attributed exclusively to NF1) and some have pulmonary stenosis (Watson syndrome); the characteristic skin lesions of NF1 are rare before the age of 6, so confusion is more likely in young children, and in NSML the lentigines are smaller and more pigmented than those of NF1 [1]. In girls, Turner syndrome shares increased nuchal translucency or hygroma in the first trimester, heart disease, short stature, hearing loss, short neck, low hairline and low-set ears, broad chest and transient lymphoedema, but does not involve the RAS pathway or its neoplastic complications [1].

7. Treatments and Risk Management Strategies

7.1 General principles and guidance

There is no curative treatment; management is multidisciplinary, directed towards manifestations and anticipatory surveillance from the neonatal period to adulthood, with specific attention to transition from paediatric to adult care [4, 62]. Available NS guidance includes that of the American Academy of Pediatrics in collaboration with the Noonan Syndrome Support Group (Romano 2010), European guidance from the DYSCERNE consortium (2010), the Lancet review (Roberts 2013) and the 2025 Italian Delphi consensus (47 recommendations, with 100% agreement on the multidisciplinary approach, improving transition, increased risk in patients with HCM and monitoring growth hormone adherence) [4, 62, 70, 71]. For Costello syndrome, 2019 guidance exists (Gripp), and for CFC, 2014 consensus guidance (Pierpont); there is no published NSML guidance [29, 56, 72]. Cancer surveillance follows the 2017 AACR recommendations, updated in 2024 [53, 73].

In France, the HAS PNDS for the RASopathies (NS, variants and CFC; 2021) and for Costello syndrome (2024 update) define the care pathway: follow-up coordinated by the clinical geneticist or the paediatrician of a reference centre for developmental anomalies, in liaison with the paediatrician or general practitioner, with an annual visit to the centre during childhood and intervals of 2–5 years in adults with NS, and involvement of cardiology, gastroenterology, endocrinology, haematology, paediatric neurology, dermatology, oncology, child psychiatry, orthopaedics, otorhinolaryngology, ophthalmology, nephrology and urology, dentistry and maxillofacial surgery, physical and rehabilitation medicine, rehabilitation professions and social services [1, 2]. The 2021 PNDS states that there is no treatment that corrects pathway hyperactivation, that the toxicity of the inhibitors used in oncology is an obstacle to chronic use and that there is no systematic use of off-label medicines; the 2024 PNDS mentions trametinib only as under study in HCM with refractory heart failure [1, 2]. The divergences between these documents and the other guidance are brought together in 7.14.

7.2 Heart disease and hypertrophic cardiomyopathy

Structural heart disease is treated as in the general population [4]. Percutaneous balloon pulmonary valvuloplasty has a higher reintervention rate in NS than in non-syndromic pulmonary stenosis (because of valve dysplasia) but remains first-line [4, 45]. HCM is associated with substantial early mortality; infants with heart failure before six months have approximately 30% two-year survival [4, 47]. Conventional treatment includes high-dose beta-blockers (propranolol up to 9–10 mg/kg/day in Andelfinger's cases) and, in severe obstruction, surgical myectomy or transplantation [13, 74]. In NSML with HCM, certain physical activities may need restriction to reduce sudden death risk [29]. In Costello syndrome, atrial tachycardias may require combined antiarrhythmics, and a medical identification bracelet should be considered; general anaesthesia carries risk in patients with unrecognised HCM or atrial tachycardia predisposition, and relatively high sedative doses may be necessary [13].

French PNDS guidance. In NS without a known anomaly, echocardiography is annual in the first three years, to detect late-onset HCM, then every 2–3 years until the age of 20 and every 3–5 years in adults (the visit table of the same document indicates every 5 years), because of the risk of late HCM and coronary dilatation; ECG is performed at the first assessment and in HCM, and Holter monitoring if there is a rhythm abnormality before 1 year [1]. HCM, usually moderate, requires no treatment in most patients; in symptomatic forms beta-blockers are used, physical activity restrictions may be based on an exercise test from the age of 7–8 years, and in severe obstructive HCM myectomy or a modified Konno procedure in a specialised centre may be indicated; early obstructive forms in infants have a very guarded prognosis [1]. In pulmonary stenosis, less than half require invasive treatment: echocardiographic monitoring every six months, intervention if right ventricular pressure exceeds 80 mmHg, percutaneous valvuloplasty as first line in valvular stenosis and surgery with cardiopulmonary bypass if this fails or if the stenosis is supravalvular [1]. In arrhythmias, the antiarrhythmic drug is chosen by the cardiologist; a beta-blocker is the preferred option in HCM and amiodarone requires attention to thyroid function; in Costello syndrome, radiofrequency ablation is preferred in case of resistance or contraindication to antiarrhythmic drugs, and Morrow-type myectomy is indicated in subaortic obstructive HCM [1, 2]. Infective endocarditis prophylaxis is limited to high-risk patients and, in dental care, to procedures involving the gingiva or the periapical region or perforation of the oral mucosa, with amoxicillin, ampicillin or clindamycin [2]. In the French SmPCs, the prophylactic dose of amoxicillin (Clamoxyl®) is 2 g orally in adults and 50 mg/kg in children, as a single dose 30–60 minutes before the procedure, and that of clindamycin (Dalacine®), reserved for beta-lactam allergy, is 600 mg in adults and 15 mg/kg in children over 6 years, in the hour before the procedure [75]. Clindamycin, still listed by the 2024 PNDS and the French SmPC, is no longer recommended for this prophylaxis by the 2021 American Heart Association scientific statement, because of the risk of severe Clostridioides difficile infection, even after a single dose; in penicillin allergy, the oral alternatives in the statement are cefalexin (2 g in adults; 50 mg/kg in children, without a history of anaphylaxis, angioedema or urticaria with penicillins), azithromycin or clarithromycin (500 mg; 15 mg/kg) and doxycycline (100 mg; 2.2 mg/kg below 45 kg), and, without oral access, cefazolin or ceftriaxone (1 g; 50 mg/kg intramuscularly or intravenously) [76, 77].

MEK inhibition. The observation that RASopathy hypertrophy results from pathway hyperactivation led to off-label use of MEK1/MEK2 inhibitors. Trametinib (Mekinist®, Novartis) is a reversible, highly selective allosteric inhibitor of MEK1/MEK2 activation and activity, with exclusively oncological approved indications, limited in the FDA label to BRAF V600 tumours (melanoma, non-small-cell lung carcinoma, anaplastic thyroid carcinoma, solid tumours with BRAF V600E from age one under FDA accelerated approval, and paediatric low-grade glioma with BRAF V600E from age one); it is available as 0.5 mg and 2 mg tablets and powder for oral solution (0.05 mg/mL after reconstitution) [78]. No MEK inhibitor has an approved indication for any cardiac or lymphatic RASopathy manifestation; selumetinib (Koselugo®) and mirdametinib (Gomekli® in the United States, Ezmekly® in the European Union) are approved only for symptomatic, inoperable plexiform neurofibromas in NF1, with age limits differing between jurisdictions (see 7.12) [79–81].

Sources: [4, 74, 82–85].

The Costello syndrome GeneReviews classifies trametinib as targeted therapy to consider in HCM with heart failure refractory to standard treatment, at an oral dose of 0.02–0.04 mg/kg/day (extrapolated from Andelfinger's and Leegaard's cases) [13]. Patients with PTPN11 were excluded from Wolf's analysis, and the catalytic-loss mechanism of NSML variants makes extrapolation to this entity uncertain [29, 84]. Adverse effects described in the trametinib label include acneiform rash and severe skin toxicity, diarrhoea and colitis, lymphoedema, bleeding, venous thromboembolism, reduced left ventricular ejection fraction (assess before treatment, after one month and every 2–3 months), ocular toxicity (retinal vein occlusion, retinal pigment epithelial detachment), interstitial pneumonitis, hyperglycaemia and severe febrile reactions (mainly in combination with dabrafenib) [78]. Management includes interruption or dose reduction, skin care and serial ophthalmological and echocardiographic assessment [78]. The phase 2 NCT06555237 trial is ongoing (Medical University of Warsaw; trametinib versus standard treatment in RASopathy HCM, 40 planned patients, recruiting since August 2024, with estimated primary completion in August 2026, but no registry update since August 2024 and no published results), and the phase 3 Baby MERIT trial is registered (NCT07817186; sponsor Carelon Research), targeting severe RASopathy-associated infantile HCM, with 25 planned infants, a composite primary endpoint of time to death, cardiac transplantation or septal myectomy for left ventricular outflow tract obstruction, not yet recruiting and with an estimated start in August 2027 (registry updated on 14 September 2026) [86]. Up to 6 October 2026, we identified no results, preliminary-result communications or authorisation applications for any MEK inhibitor in cardiac or lymphatic RASopathy manifestations [80, 81, 86].

7.3 Growth and growth hormone

Short stature in NS is an FDA-approved indication for recombinant growth hormone. The current somatropin Norditropin® label (Novo Nordisk; FDA label July 2025) includes “short stature associated with Noonan syndrome” in children, at a dose up to 0.46 mg/kg/week (approximately 0.066 mg/kg/day), divided into 6–7 weekly subcutaneous administrations; in the registration trial (21 randomised and 6 non-randomised patients, ages 3–14), 0.033 or 0.066 mg/kg/day was administered, continuing until final height [4, 87]. The indication was added to the US Norditropin® label through an efficacy supplement approved on 31 May 2007 [81]; among daily somatropins, this indication is product-specific, and other somatropin labels do not include it [87]. In the European Union, SmPCs for centrally authorised somatropins (for example, Omnitrope®) do not include NS [88]; Norditropin® is authorised through decentralised/national procedures, and the national SmPC (for example, the Spanish AEMPS product information) includes “growth retardation due to Noonan syndrome”, with a recommended dose of 0.066 mg/kg/day (0.033 mg/kg/day may suffice in some cases), to be discontinued at epiphyseal closure [89]; availability of the indication should be confirmed in the approved SmPC in each Member State; the 2025 Italian consensus recommends growth hormone for short stature in NS and considers that partial growth hormone insensitivity should not exclude treatment [62].

Short- and long-term studies show a consistent increase in growth velocity, with height gains of 0.6–1.8 standard deviations, depending on age at initiation, duration, pubertal age and hormone sensitivity; earlier initiation is associated with greater final height, without an apparent correlation between dose and final height, and no standard dose is established [4, 43]. In prepubertal children with growth hormone deficiency, response is equivalent to that in girls with Turner syndrome and lower than in idiopathic deficiency [4]. Mild hormone resistance may reduce response [3]. There is no evidence of increased malignancies, cardiac complications or other comorbidities in treated patients, and the 2024 AACR update does not advise against growth hormone in RASopathies when clinically indicated or recommend prior brain MRI in asymptomatic children [4, 53]. However, the Italian consensus retains safety concerns relating to HCM and malignancy risk [62]. Oxford recommends paediatric endocrinology referral when height is below centiles 0.4–2 [7].

Long-acting (weekly) growth hormone. Somapacitan (Sogroya®, Novo Nordisk), a growth hormone analogue with reversible albumin binding, received three new paediatric FDA indications on 27 February 2026, including “growth failure associated with Noonan syndrome” from age 2.5; the label gives an initial subcutaneous dose of 0.24 mg/kg once weekly, both in previously untreated patients and when transitioning from daily somatropin (last daily dose the previous day or at least 8 hours earlier), with subsequent individualisation according to growth response [81, 90]. The basis is the NS substudy of the phase 3 basket trial REAL8 (NCT05330325), open-label with an active comparator: 77 previously untreated prepubertal children (ages 2.5–11 in boys and 2.5–10 in girls), randomised 2:1 to somapacitan 0.24 mg/kg/week or daily somatropin 0.050 mg/kg/day; annualised growth velocity at week 52 (primary endpoint) was 10.4 versus 9.2 cm/year (estimated difference 1.2 cm/year; 95% CI 0.32–2.03), with confirmed non-inferiority and statistical superiority, and change in height standard deviation score was 1.07 versus 0.75; the safety profile was similar [91]. The label itself emphasises that the comparator's daily dose (0.050 mg/kg/day) is below the maximum US-approved NS dose (0.066 mg/kg/day), so superiority does not demonstrate an advantage over somatropin at its maximum labelled dose; final height and long-term safety (including HCM and malignancies) were not assessed in the main 52-week phase, whose 104-week extension is ongoing [90, 91]. A manufacturer-sponsored pharmacokinetic/pharmacodynamic modelling analysis, including 62 children with NS from REAL8 and REAL9 (NCT05723835, a 26-week safety study), concluded that the initiation rules, dosing-day flexibility (minimum 4 days between doses) and IGF-I monitoring already established for growth hormone deficiency are applicable [92]. In the European Union, the Committee for Medicinal Products for Human Use (CHMP) issued a favourable opinion on 21 May 2026 on extending Sogroya® to NS and children born small for gestational age and, after re-examination, on 17 September 2026 also to idiopathic short stature; as of 6 October 2026, EMA's medicines data file retained only the growth hormone deficiency indication, so the European Commission decision (normally approximately 67 days after the opinion) had not been identified, and NS use in the EU remains off-label until that decision [80, 93]. Other weekly growth hormones (somatrogon, Ngenla®; lonapegsomatropin, Skytrofa®) are indicated only for growth hormone deficiency on both sides of the Atlantic, and the phase 3 lonapegsomatropin basket trial (NCT07221851, recruiting since December 2025) includes Turner syndrome, SHOX deficiency, small for gestational age and idiopathic short stature, but not NS [80, 86].

Somatropin adverse effects described in the label include intracranial hypertension (fundoscopy before and during treatment; discontinue if papilloedema occurs), slipped capital femoral epiphysis, progression of pre-existing scoliosis, glucose intolerance, hypothyroidism, hypoadrenalism, pancreatitis, hypersensitivity reactions and fluid retention; it is contraindicated in active malignancy and with closed epiphyses, and pre-existing tumours should be monitored [87].

Specific situations: in NSML there are no growth hormone data; it may be contraindicated in HCM, and prior cardiac assessment and HCM surveillance during treatment are recommended [29]. In Costello syndrome, the hormone should be used only for proven deficiency, after cardiac assessment, discussing the unproven benefit and theoretical risks: three patients with deficiency had increased growth velocity without adverse effects, but two remained short; in a series of 35 patients (16 with deficiency, 13 treated), four of seven tumours occurred in patients never treated; HCM progression after initiation has been reported in individual cases without an established causal relationship [13]. In CFC, the hormone may be considered with close HCM monitoring [15]. In SHOC2-related NS-LAH, seven children treated with 0.035 mg/kg/day for a mean of 8.5 years had increased IGF-I and growth velocity, but the three reaching final height remained at −2.34 SD, without the catch-up growth typical of isolated deficiency [57].

French guidance on growth hormone. In France, the indication for somatropin (Norditropine®) in children with NS and height below −2 SD on general population charts, even without growth hormone deficiency, was validated in 2021 with an opinion of the HAS Transparency Committee, which recommends starting treatment after feeding difficulties have resolved (efficacy data come from prepubertal children aged at least 3 years), once the genetic diagnosis has been established and at the lowest SmPC dose (0.033 mg/kg/day; the maximum labelled dose is 0.066 mg/kg/day [87, 89]), adjusted every six months according to growth velocity, height, tolerance and IGF-I; prescription is reserved for paediatric endocrinologists, follow-up is coordinated by reference or competence centres, and treatment ends at epiphyseal closure [1]. The PNDS considers the indication non-systematic, to be decided case by case according to the degree of growth delay and the psychological impact, estimates the gain in adult height at approximately 1–1.5 SD (similar to that of other indications without deficiency), greater with early initiation and highly variable, and points out that children with pre-existing HCM were excluded from the studies, so the risk in this group is unknown, and that the maximum follow-up of the trials was 4 years; in view of the cases of DNET under growth hormone, it does not recommend systematic brain MRI before treatment, maintaining the indications for untreated children (intellectual disability or neurological signs) [1]. In CFC there are no recommendations, and treatment does not seem justified in the presence of significant cognitive delay [1]. In Costello syndrome, the 2024 PNDS tests for deficiency with a stimulation test in the event of height deceleration, height below −2 SD or hypoglycaemia (together with testing for cortisol deficiency), and replacement treatment, within the somatropin marketing authorisation, requires objective information on the uncertain benefit and the tumour and cardiac risk, thoracoabdominal MRI to exclude a tumour, brain MRI to look for a hypothalamic–pituitary cause, cardiological assessment and IGF-I once or twice a year, which should remain below +2 SD [2].

Source: [1].

Investigational growth therapies. Vosoritide (Voxzogo®), a C-type natriuretic peptide analogue approved in achondroplasia, inhibits the MAPK pathway through the NPR2 receptor [79]. In a phase 2 basket trial, 30 prepubertal children aged 3 to 11 years with a RASopathy, ACAN or NPR2 deficiency and height ≤ −2.25 SD received 15 µg/kg/day subcutaneously for 12 months (fixed dose of the trial protocol; no maximum dose defined in the source): annualised growth velocity increased from 4.53 to 8.09 cm/year, with a height gain of 0.65 SD and responses in all subgroups; injection-site reactions were the most common adverse effects, but five patients discontinued because of adverse effects, including three slipped capital femoral epiphyses and four cases of genu valgum [94]. A BioMarin phase 2 trial in children with NS with inadequate growth during or after growth hormone (NCT06668805; approximately 30 patients; primary endpoint: change in annualised growth velocity) is active, not recruiting, with estimated primary completion in March 2027 (registry updated on 23 September 2026), and the academic basket trial that generated the above results (NCT04219007; 56 participants) reached primary completion in August 2025 [86]. Vosoritide has no approved indication in the RASopathies in any jurisdiction (FDA label and European SmPC limited to achondroplasia), and we identified no marketing authorisation applications for this indication [79, 80].

7.4 Feeding and nutrition

In NS, nasogastric tube feeding in infants with poor weight gain, particularly with heart disease; gastrostomy may be necessary, although the difficulties are frequently self-limiting; investigate for malrotation if vomiting persists [4]. In Costello syndrome, most infants need a nasogastric tube or gastrostomy and many require Nissen fundoplication; aggressive feeding does not improve oral intake and may cause oral aversion; blended foods through a gastrostomy may be considered [13]. In CFC, increased caloric intake, feeding therapy, gastrostomy, fundoplication for severe reflux, surgery for malrotation and treatment of constipation with fibre, osmotic laxatives or prokinetics [15]. The French PNDS adds that reflux, oral feeding disorders (poor appetite, food refusal, swallowing disorder) and constipation should be objectively assessed (pH monitoring, scintigraphy, endoscopy) with paediatric gastroenterology, and that chronic diarrhoea requires endoscopy to exclude intestinal lymphangiectasia with malabsorption; reflux is treated with H2-receptor antagonists or proton pump inhibitors and the usual dietary measures [1]. A nasogastric tube is indicated when oral feeding does not maintain nutritional status (weight deceleration or stagnation) or when meals exceed 3 hours a day; gastrostomy is discussed with tube dependence longer than 3 months, risk of aspiration due to sucking or swallowing disorders or reflux, or a need for continuous supplementation; it is placed under general anaesthesia, often as a day case, does not prevent oral feeding or oral feeding therapy, and the family receives 5–10 days of training, a written protocol and a replacement button [1]. In Costello syndrome, the 2024 PNDS includes continuous or overnight enteral feeding and antireflux surgery [2].

7.5 Haemostasis

Avoid acetylsalicylic acid in NS [4]. Before any surgery, or in the presence of bleeding, assess bleeding history, full blood count, prothrombin time, activated partial thromboplastin time, factors XI, XII, IX and VIII, von Willebrand factor and platelet aggregation in collaboration with haematology; treatment is directed towards the specific deficiency [4, 7]. Recombinant factor VIIa was used to control severe postoperative bleeding in an infant with NS and normal coagulation tests [4]. In CFC, platelet count and function should be assessed before invasive procedures [15]. According to the French PNDS, coagulation screening is performed at diagnosis and is not systematically repeated, except before any anaesthesia or surgery in NS (including invasive dental procedures and orthognathic surgery), and overt bleeding warrants platelet function studies; in patients without an identified variant, creatine kinase measurement is recommended before anaesthesia, because the Noonan-like dysmorphism of King–Denborough syndrome is associated with malignant hyperthermia, an association never described in patients with a confirmed variant in an NS gene [1].

7.6 Haematology and oncology

JMML and other malignancies are treated according to standard protocols [4]. In NS and CBL syndrome, the 2024 AACR update recommends physical examination for hepatosplenomegaly from birth or diagnosis, every 3 months until age one and then at each child health visit until age 5; full blood count only if the child is unwell or has hepatosplenomegaly, and no tests in an asymptomatic child; referral to haemato-oncology with experience in RASopathy myeloproliferative disease if abnormalities occur [53]. This recommendation replaces the 2017 recommendation, which proposed physical examination with spleen assessment and full blood count every 3–6 months until age 5 in carriers of JMML-associated PTPN11 or KRAS variants, still mentioned in GeneReviews [4, 53, 73]. Brain tumour surveillance is not recommended without symptoms; annual skin examination is recommended in NSML [53]. In germline CBL-related JMML, most patients can remain under expectant surveillance, with frequent spontaneous resolution [30, 53].

Cancer surveillance in Costello syndrome. The table summarises current recommendations.

Source: AACR 2024 [53]. GeneReviews recommends, more conservatively, abdominal and pelvic ultrasound every 3–6 months until age 8–10 and annual urinalysis from age 10, and stresses that no strategy has demonstrated benefit and that the most important factor is awareness of the risk among parents and physicians [13]. Urinary catecholamine measurement should not be used, because patients with Costello syndrome have elevated values without a tumour [13, 53]. Rhabdomyosarcomas are located in the abdomen and pelvis in 80% of cases and have not been diagnosed after the age of 14 [53]. In CFC there is no quantified tumour risk warranting specific surveillance [53]. The 2021 French PNDS recommends a full blood count every six months until the age of 5 in NS, with referral to paediatric haemato-oncology in the event of monocytosis above 1×10⁹/L in a healthy infant or hepatosplenomegaly, and no systematic test after the age of 5; the 2024 PNDS, for Costello syndrome, proposes abdominopelvic ultrasound every six months until the age of 10, an annual urine dipstick from the age of 10 with cystoscopy to be discussed every 2 years from that age (and whenever there is haematuria), mammography if there is nipple discharge, and does not recommend urinary catecholamine measurement; it acknowledges that six-monthly screening causes parental distress with repercussions on siblings, which justifies psychological support [1, 2]. These proposals are less intensive than those of the 2024 AACR (see 7.14).

7.7 Neurology, development and behaviour

Early intervention (physiotherapy, occupational therapy, speech and language therapy, feeding support), an individualised education plan, standard treatment of attention deficit hyperactivity disorder and other neuropsychiatric disorders [4]. Chiari malformation is treated neurosurgically; in Costello syndrome, posterior fossa decompression may improve hydrocephalus and syringomyelia, and tethered cord is surgically released, with a risk of retethering [13]. In CFC, epilepsy frequently requires polytherapy; cardiology should be consulted before starting corticosteroids for infantile spasms because of the baseline cardiomyopathy risk; neurotoxic drugs should be avoided in peripheral neuropathy [15]. In CFC, heat intolerance requires avoiding excessive heat exposure, intense exertion and dehydration [15]. For tone disorders (hypertonia, dystonia), baclofen, tizanidine, botulinum toxin or orthopaedic procedures may be used [15].

The French PNDS defines the neuroimaging strategy: in NS without intellectual disability, MRI is not systematic and is reserved for epilepsy, abnormal neurological examination, excessive head circumference growth, regression, repeated headaches, imbalance, neck pain, swallowing disorder or torticollis; in NS with intellectual disability and in CFC, MRI is part of the initial assessment and is repeated every 5 years until adulthood, or every 2 years if it shows a Chiari malformation [1]. In Chiari malformation, neurosurgical assessment includes MRI with a flow sequence, spinal MRI, polysomnography and somatosensory evoked potentials, with posterior fossa decompression, possibly combined with ventriculoperitoneal shunting, if there are symptoms; suspected peripheral neuropathy warrants electromyography with conduction velocities [1]. In infants with CFC, the paediatrician should watch for the clusters of flexion spasms of West syndrome, which require prompt electroencephalography, because diagnostic delay correlates with drug resistance and sequelae, and the use of corticosteroids in the presence of cardiomyopathy is decided between paediatric neurologist and cardiologist [1]. In neurodevelopment, hypotonia warrants psychomotor therapy or physiotherapy, absence of language at 18 months requires hearing impairment to be excluded, formal psychometric assessment is recommended at around 5 years and neuropsychological assessment before each change of school cycle (5 years, 10–11 years and entry into secondary school), specialised autism assessment (ADI, ADOS, CARS) if there is a communication disorder, and augmentative communication (PECS, Makaton) without waiting when oral language does not emerge after the age of 3; schooling is adapted to the functional level, from mainstream education with support to inclusion units (IQ 55–70) and special education (IQ below 50), with support until vocational integration [1].

7.8 Other manifestations

Cryptorchidism and renal anomalies: urology [4]. Vision and hearing: optical correction, strabismus treatment, hearing aids and cochlear implantation in profound NSML deafness [4, 29]. In Costello syndrome: early orthoses and occupational therapy for ulnar deviation, Achilles tendon lengthening, hip and kyphoscoliosis surgery, calcium and vitamin D for osteopenia, removal of inflamed or recurrent papillomas (cryotherapy, shaving excision), diazoxide for neonatal hyperinsulinaemia, cortisol for corticotrophic deficiency, adenotonsillectomy, mandibular distraction or tracheostomy for airway obstruction, and, according to GeneReviews, antibiotic endocarditis prophylaxis for lesions such as pulmonary valve stenosis [13]. In CFC: environmental humidification and emollients for xerosis and pruritus, antibiotics for skin infections (particularly with lymphoedema), follow-up in a vascular anomaly or lymphoedema clinic [15].

Endocrinology according to the French PNDS. Height and weight are measured at least every 3 months until the age of 2 and then every 6 months, on general population charts (NS-specific charts are of little practical use); growth deceleration, height below −2 SD or more than 1.5 SD below the familial target height warrant paediatric endocrinology referral, and absence of breast development after the age of 13 or of testicular enlargement after the age of 14 requires investigation [1]. Investigations include TSH, free T4, IGF-I and IGFBP-3 (with a stimulation test if there are signs of deficiency), LH, FSH and oestradiol or testosterone from the age of 8 in girls and 9 in boys, and inhibin B and anti-Müllerian hormone at any age; annual thyroid function with antibody testing is suggested [1]. Hypothyroidism is treated as in other causes when TSH exceeds 10 mIU/L; between 5 and 10 mIU/L it is monitored and treated if it worsens or there are symptoms; daily levothyroxine (2–5 µg/kg/day) aims at a TSH between 0.5 and 3.5 mIU/L [1]. The PNDS range does not distinguish by age: the US label for levothyroxine (Synthroid®) sets the starting dose by weight according to age, at 10–15 µg/kg/day (0–3 months), 8–10 (3–6 months), 6–8 (6–12 months), 5–6 (1–5 years), 4–5 (6–12 years) and 2–3 µg/kg/day over 12 years with incomplete growth and puberty, up to 1.6 µg/kg/day once growth is complete, with titration every 2 weeks according to TSH or free T4; the 2–5 µg/kg/day range only coincides with the labelled dose from the age of 6, so in infants and young children the label is followed [1, 95]. Pubertal delay is treated with sex steroids after assessment of the axis (used appropriately, they do not reduce adult height), cryptorchidism according to the usual protocols, and Leydig and Sertoli cell dysfunction (low inhibin B) may cause infertility; NS does not contraindicate medically assisted reproduction, with information on the 50% transmission risk and variable expressivity [1]. In Costello syndrome, hypogonadism requires hormone replacement therapy to limit osteoporosis, and vitamin D is given in children and adolescents and, in adults, according to bone densitometry [2].

Dermatology according to the French PNDS. Prolonged hot baths, perfumed soaps and dry environments are avoided; photoprotection and naevus surveillance follow the rules for the general population, because an excess of melanoma has not been demonstrated in the RASopathies [1]. Xerosis and ichthyosis are treated with emollients based on glycerol, petrolatum and paraffin or, more effectively, emollients containing 3–10% urea; topical anti-inflammatory agents (topical corticosteroids, tacrolimus) are not indicated; keratosis pilaris and ulerythema ophryogenes respond poorly, and compounded preparations of urea and lactic acid prescribed by a dermatologist may be used, with relapse on discontinuation [1]. Painful or fissured palmoplantar keratoderma may require keratolytics, topical retinoids or acitretin (Soriatane®) and podiatry; in Costello syndrome, the 2024 PNDS reserves acitretin for severe forms, with regular laboratory monitoring [1, 2]. The French SmPC for acitretin includes severe keratinisation disorders (including certain palmoplantar keratodermas) and indicates, in children, approximately 0.5 mg/kg/day (up to 1 mg/kg/day for a limited period), not exceeding 35 mg/day, and, in adults with keratinisation disorders, the minimum effective dose, ideally below 20 mg/day and never above 50 mg/day, with initial prescription by a dermatologist and mandatory pregnancy prevention because of the teratogenic risk [75]. Palmar hyperhidrosis is treated with aluminium salt antiperspirants, iontophoresis and, if these fail, oral oxybutynin (Ditropan®) off label [1]; by extrapolation from the SmPC (urological indication), the paediatric dose from the age of 5 starts at 2.5 mg twice daily, up to 0.3–0.4 mg/kg/day, with maximums of 2.5 mg three times daily from 5 to 9 years, 5 mg twice daily from 9 to 12 years and 5 mg three times daily from 12 years, and in adults it starts at 2.5 mg three times daily, with a maximum of 5 mg four times daily; it is not recommended before the age of 5 [75]. In hypotrichosis, topical minoxidil 2% or 5%, started by a dermatologist, may increase hair density, without an approved indication in this situation or in children; the adult SmPC indicates 1 mL twice daily, not exceeding 2 mL/day [1, 75]. In Costello syndrome, papillomas are treated by cryotherapy or electrocoagulation [2].

Lymphoedema and effusions. In lower limb lymphoedema, the main risk is infection: careful hygiene of the feet and interdigital folds, drying after bathing, prompt treatment of bacterial or fungal infections and compression stockings; in recurrent infections, long-term prophylaxis with phenoxymethylpenicillin (Oracilline®) may be indicated, and genital or gastrointestinal forms are managed by the specialist [1]. The prophylactic dose in the French SmPC (indication of recurrent erysipelas) is 100,000 IU/kg/day up to 10 kg and 50,000 IU/kg/day between 10 and 40 kg, not exceeding 2,000,000 IU/day, and 2,000,000 IU/day in adults, in two doses; tablets are not used before the age of 6 [75]. Lymphatic pleural effusions are treated with repeated pleural drainage, a low-fat diet, chemical pleurodesis or surgery [1].

Orthopaedics. The spine is monitored clinically, especially at the onset of puberty and under growth hormone; a progressive curvature greater than 20° warrants paediatric orthopaedic referral, with a mainly night-time brace in the skeletally immature child, a daytime brace or serial casting (usually 2 × 45 days) if it progresses, and surgery generally at the end of growth if the angle exceeds 45°; before scoliosis surgery, Chiari malformation is systematically sought, as it increases the postoperative neurological risk [1]. In CFC with severe intellectual disability and without walking, the risk of scoliosis is greater, braces and moulded seating may be needed, and centring of the femoral heads is monitored with a pelvic radiograph every 2 years [1]. Clubfoot is treated with physiotherapy or the Ponseti method, with uncertain results, and sometimes surgery; pectus excavatum may be corrected from the age of 10, after pulmonary function tests and chest computed tomography; in villonodular synovitis, MRI and biopsy precede complete synovectomy, which often leaves stiffness; coagulation screening precedes any surgery [1]. In Costello syndrome, early splinting, physiotherapy, Achilles tendon lengthening and treatment of scoliosis (brace, surgery) [2].

Dentistry and maxillofacial care. Because of the risk of caries (reflux, long meals, difficult hygiene with intellectual disability), an oral hygiene programme is recommended from the eruption of the first teeth (at around 6 months), with fluoride toothpaste and visits 2–4 times a year, early orthodontic assessment (primary or early mixed dentition), functional therapies to stimulate the mandible, orthodontics and orthognathic surgery; before invasive procedures, endocarditis prophylaxis if there is heart disease and coagulation screening [1]. Swelling of the mandibular angles, or unexplained dental pain or mobility, require a panoramic radiograph and cone-beam computed tomography (possibly MRI) and biopsy; giant cell lesions, detected between the ages of 2 and 19, mainly in the mandible, are managed from surveillance (mainly in children and adolescents) to curettage or wide excision in aggressive lesions, with recurrence in 11–49%, and adjuvant therapies have been proposed (corticosteroids, calcitonin, imatinib, osteoprotegerin, interferon alfa-2, denosumab) [1].

Ophthalmology, hearing and kidney. Ophthalmological examinations follow the general population schedule (first week of life, 9 months, 2.5 years and 6 years), with immediate assessment in the event of strabismus or nystagmus; ptosis obstructing the visual axis is an indication for surgery, and incomplete eyelid closure requires lubricants; in CFC, optic atrophy may require low vision rehabilitation and adaptation of the living environment [1]. Hearing problems are screened for early (otitis media with effusion, with a tympanostomy tube if needed, and sensorineural hearing loss), and ear, nose and throat infections are actively treated; urinary tract malformations are sought at diagnosis [1]. In Costello syndrome, treatment of sleep apnoea and adenotonsillectomy are added [2].

7.9 Recommended surveillance

Sources: [4, 13, 15, 29, 53, 56].

7.10 Pregnancy in affected women

In NS, consider referral to an adult congenital heart disease programme and to haematology if there is a bleeding history or no coagulopathy screening [4]. In NSML, HCM or valve dysfunction increases the risk of heart failure, particularly in the second and third trimesters [29]. In CFC, pregnancy requires high-risk obstetric care because of polyhydramnios, cardiac problems and maternal hypertension [15]. The French PNDS adds that the couple should be informed of the 50% risk and of the possibility of ultrasound signs (increased translucency, heart disease, polyhydramnios), and a reference fetal echocardiogram may be offered; it recommends a preconception or early-pregnancy cardiology consultation in women with heart disease or HCM, review of medicines (antiepileptic, cardiological, thyroid, dermatological), avoidance of pregnancy on valproic acid, with any change of antiepileptic drug decided by the neurologist before contraception is stopped, and adequate thyroid replacement before conception with an increase in levothyroxine from the start of pregnancy; no pregnancy has been described in women with CFC [1]. Acitretin, which is teratogenic, requires the pregnancy prevention measures of its SmPC [75].

7.11 Pivotal trials and studies: interpretation

The studies in the table are not comparable and do not permit ranking interventions. Growth gains are expressed in different metrics (annualised velocity after one year, height SD, final height), and first-year growth velocity overestimates adult height gain; in REAL8, somapacitan superiority was obtained against a daily somatropin dose below the maximum US-labelled NS dose, and the study was open-label [90, 91]. The vosoritide trial and Norditropin® registration had no concurrent control group, and the vosoritide response (means for 30 patients with heterogeneous diagnoses) does not inform final height or slipped epiphysis risk, which prompted discontinuations [87, 94]. For MEK inhibition, Wolf's analysis is retrospective, with patients selected by severity and drug access, risks of indication and immortal-time bias, hazard ratios with broad intervals and adjusted results dependent on the model, and excludes PTPN11 patients — relative reduction in the composite endpoint must be read alongside absolute rates (17% vs. 87%) and does not establish efficacy in a controlled trial, precisely the objective of Baby MERIT [84, 86]. No negative trials of these interventions in NS have been published, but absence of publication does not equate to absence of negative results.

7.12 Comparative regulatory status and evidence hierarchy

Four levels of evidence are distinguished: peer-reviewed article (REAL8, vosoritide trial, Wolf's analysis), communication or trial registration without results (NCT06555237, Baby MERIT, NCT06668805), regulatory opinion (CHMP on Sogroya®, which is not an authorisation) and authorisation decision (FDA, European Commission). An authorisation does not guarantee marketing, reimbursement or access in each country; in the sources consulted we identified no information on the availability of these indications in Portugal (INFARMED) or Brazil (ANVISA/CONITEC), which does not prove their absence [80, 81, 93].

Evidence extrapolation and off-label use. The two concepts are distinct. The trametinib dose used in RASopathy HCM (0.02–0.04 mg/kg/day, according to the Costello syndrome GeneReviews) is extrapolated from case reports and retrospective analysis, and its use is off-label because no label includes HCM, regardless of age, usually with ethics committee oversight, informed consent and individual access [13, 74, 84]. Growth hormone in NS is within the indication for Norditropin® in the USA (and, from 27/02/2026, for Sogroya®), but the same treatment is off-label with another product or in another jurisdiction whose SmPC does not include it, even when clinical evidence is shared; extending the NS indication to NSML, Costello syndrome, CFC or NS-LAH is extrapolation, with the specific cautions described in 7.3 [13, 15, 29, 57, 87]. Use of any of these drugs during pregnancy lacks label support and should be discussed individually [78, 87].

7.13 Therapeutic education and emergency card

The French PNDS integrate therapeutic education into care: nasogastric tube or gastrostomy button technique, infection prevention and what to do if the button is pulled out; in HCM or arrhythmias, recognition of warning signs (loss of consciousness, prolonged palpitations), monitoring of heart rate and blood pressure under treatment and adapted physical activity; growth hormone injection pen technique; in epilepsy, placing the patient in safety and rescue therapy for prolonged or repeated seizures; in lymphoedema, skin care and a low-fat diet; and general hygiene and oral health care [1, 2]. For Costello syndrome, the PNDS mentions therapeutic education programmes for children aged 11–15 with a visible disability and for young people aged 15–25 with intellectual disability in transition to adulthood, usually organised in university hospitals and reference centres [2]. The 2021 PNDS includes an emergency card for NS, completed with the physician following the patient, which records contacts (family, general practitioner, follow-up centre, reference specialist, guardian), the presence of heart disease, cardiomyopathy, coagulation disorder, scoliosis or Chiari malformation, visual or hearing deficits, previous cardiac surgery, the level of comprehension and expression, the mode of communication and allergies [1].

7.14 Divergences between the French PNDS and the other guidance

On dosing topics, the French guidance and the other guidelines are the reference and the labels (FDA, SmPC) the comparison; in oncological surveillance, the 2024 AACR update is the most recent and specific guidance, and the French proposals, earlier or less intensive, are presented as a documented alternative.

8. Reproductive Options and Family Counselling

Noonan syndrome, dominant form. In 30–75% of families, one parent is affected (Oxford reports a family history in 50%), and many adults are diagnosed only after the birth of a more severely affected child [4, 7]. Parental assessment includes a targeted clinical examination, childhood photographs, echocardiography and electrocardiography, coagulation screening and testing for the proband's variant [4, 7]. If one parent carries the variant, the risk to siblings is 50%, with marked intrafamilial variability; if the variant is not detected in the parents, the recurrence risk is below 1%, slightly above the population risk because of germline mosaicism (described for PTPN11 c.922A>G) [4, 7]. When molecular testing is unavailable and the parents have no signs, an empirical risk of 5% applies (Sharland 1993) [7]. In simplex cases, the de novo variant was universally of paternal origin in one series, with advanced paternal age and a predominance of transmission to male offspring that remains unexplained [4, 37]. Each child of an affected individual has a 50% probability of inheriting the variant [4].

Autosomal recessive NS due to LZTR1. The parents are presumed to be heterozygous; parental testing confirms carrier status. If only one parent is a carrier, consider a de novo variant or uniparental isodisomy. Siblings have a 25% risk of being affected, a 50% risk of being heterozygous (asymptomatic or with mild features) and a 25% risk of not being carriers; the children of an affected individual are obligate heterozygotes, and the parents' siblings have a 50% risk of being carriers [4, 27].

NSML. Dominant inheritance; the proportion of de novo cases is unknown; if the variant is absent in the parents, the risk to siblings is estimated at approximately 1% because of germline mosaicism; at-risk relatives should undergo echocardiography to identify HCM early [29].

Costello syndrome. Almost always de novo, predominantly of paternal origin, with a paternal age effect [13, 36]. Vertical transmission has been described in only two families with an attenuated phenotype; recurrence in siblings has been reported and attributed to germline mosaicism, so the risk to siblings is slightly above the population risk; a parent with somatic and germline mosaicism may have only segmental skin changes [13, 35]. Individuals with the classic phenotype rarely have children [13]. According to Oxford, the recurrence risk for conditions with a paternal age effect is substantially below 1%, and additional testing directed by paternal age is not recommended in the absence of a family history [37].

CFC. Mostly de novo, but familial recurrence and vertical transmission (including transmission of MAP2K2 over four generations) have been described; the parents should be examined and tested; germline mosaicism is possible; children of an affected individual have a 50% risk [15, 38].

NS-LAH. Mostly de novo; maternal transmission of PPP1CB p.Met182Lys to three children demonstrates that the 50% risk applies when one parent carries the variant [40].

Counselling according to the French PNDS. The 2021 PNDS stresses that, in a sporadic case, dominant inheritance cannot be asserted without testing, because of the possibility of a recessive form due to LZTR1; in the recessive form, segregation of the two variants should be verified in the parents, inheritance is difficult to establish when one variant is inherited and the other de novo, the risk for siblings is 25% and the risk for the offspring of a patient is close to zero, unless the partner is a carrier (exceptional outside consanguinity) [1]. In CFC, the probability of an asymptomatic carrier is very low and testing relatives is not necessary when the clinical diagnosis is certain, but germline mosaicism maintains a residual risk [1]. The 2024 PNDS for Costello syndrome estimates the recurrence risk at 0.5–1%, recommends a consultation dedicated to counselling, with the parents and without the child, some time after disclosure of the diagnosis, and warns that attenuated signs in a parent may indicate somatic mosaicism, with a recurrence risk close to 50% and a possible tumour risk for that parent [2]. Disclosure of the diagnosis, in a protected setting, with time and preferably with both parents, includes explanation of the results, transmission, complications and the follow-up plan, with input from a psychologist during or soon after the consultation and provision of patient organisation contacts [1, 2].

Reproductive options. Once the familial variant has been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic diagnosis are possible [4, 7]. In a pregnancy with a 50% risk, high-resolution ultrasonography may show nuchal oedema and polyhydramnios, but these findings are non-specific [4, 7]. The ideal time for counselling is before pregnancy, and counselling should be offered to affected or at-risk young adults; storing DNA from probands without a molecular diagnosis is recommended [4]. Counselling should address variable expressivity: a mildly affected parent may have a child with severe HCM or JMML, and severity cannot be predicted from the variant, except for the correlations described in section 2 [4, 7]. In France, a request for prenatal diagnosis because of a family history requires a genetics clinic consultation and discussion in a multidisciplinary prenatal diagnosis centre, and preimplantation diagnosis is referred to one of the five authorised centres; after a child with a de novo variant (recurrence risk estimated at 1%), targeted prenatal diagnosis may be discussed to exclude recurrence, but preimplantation diagnosis is not justified [1].

Reference networks and patient organisations. In Europe, patients with RASopathies are managed within ERN ITHACA (rare malformation syndromes and neurodevelopmental disorders), in liaison with ERN GUARD-Heart (heart disease, including HCM), Endo-ERN (growth and endocrinology) and, for tumour predisposition and paediatric malignancies, ERN GENTURIS and ERN PaedCan [97]. Patient organisations include the RASopathies Network and the Noonan Syndrome Foundation (USA), the Noonan Syndrome Association (United Kingdom), CFC International and CostelloKids (United Kingdom), which provide information for families and support registries and research [98]. In France, care is organised within the AnDDI-Rares rare disease network (developmental anomalies with or without intellectual disability of rare cause), with coordinating reference centres for developmental anomalies and malformation syndromes in six regions (Île-de-France, South-West–Occitanie–Réunion, North-West, West, East and South-East) and competence centres, and with links to other networks (CARDIOGEN for heart disease, DéfiScience for intellectual disability and severe epilepsies, FIMARAD for genetic skin diseases, SENSGENE for ophthalmology, TêteCou for rare oral and dental diseases, FIRENDO for endocrinology, MaRIH for bone marrow aplasias and MHEMO for bleeding disorders); the coordinator of the 2021 PNDS was also the European coordinator of ERN ITHACA [1, 2]. The PNDS serves as the reference for the care protocol for exemption from co-payment as an off-list long-term condition [1]. The French patient organisations are the Association Noonan France and the Association française du syndrome de Costello et cardio-facio-cutané (also suggested to patients with NS and significant cognitive difficulties), as well as the Alliance Maladies Rares, the Maladies Rares Info Service, the Grandir association (growth), UNAPEI and the school resource Tous à l'École; the PNDS also refer to CFC International [1, 2].

9. Special Considerations: Population Diversity and Epidemiology

Prevalence. NS occurs in 1:1,000 to 1:2,500 people (approximately 1:2,000 in Smith's, ~1:2,500 in Oxford), and many mild forms remain undiagnosed [3, 4, 7]. Orphanet records a birth prevalence of 70/100,000 in the United States and a worldwide point prevalence of 1–5/10,000 [99]. The prevalence of NSML is unknown [29]. The birth prevalence of Costello syndrome has been estimated at 1:380,000 in the United Kingdom and 1:1,230,000 in Japan (national survey, probably underestimated because of ascertainment bias) [13, 36, 96]. The prevalence of CFC in Japan is 1:810,000, with approximately 300 published cases worldwide; the AACR update estimates approximately 1 in 800,000 newborns [15, 53, 96]. NS-LAH has a prevalence below 1/1,000,000 according to Orphanet [99]. The French PNDS estimates the incidence of NS at approximately 1 in 2,000 births, with a median age at diagnosis of 4 years, and that of CFC and related rare forms at less than 1 in 20,000 (approximately one-tenth of NS), an estimate much higher than the Japanese and AACR figures and without a population study identified in the document; for Costello syndrome, the 2024 PNDS cites more than 600 published cases and the absence of prevalence data [1, 2].

Population diversity. The NS phenotype has been characterised predominantly in populations of European ancestry. In a study of 125 patients from 20 countries, grouped into African, Asian, Latin American and other ancestries, NS was phenotypically similar across groups (only 2 of 21 clinical features differed); hypertelorism and low-set ears occurred in 80% or more, short stature in more than 70% and pulmonary stenosis in approximately half; facial analysis technology achieved sensitivity ≥94% and specificity ≥90% in Caucasian, African, Asian and Latin American patients [100]. GeneReviews refers to the NHGRI atlas with photographs of patients of diverse origins [4].

Founder effect. No founder variants of population relevance have been described in the RASopathies, which is consistent with the predominance of de novo variants subject to positive selection in the male germline [36, 37]. Recurrent variants (for example PTPN11 NM_002834.5:c.922A>G, HRAS NM_005343.4:c.34G>A, SHOC2 NM_007373.4:c.4A>G) result from recurrent mutation rather than shared ancestry [4, 13, 24].

Data gaps. The sources consulted did not identify population prevalence studies of NS, NSML, Costello syndrome or CFC in Portugal, Brazil and the rest of Latin America, Africa, the Middle East or South Asia; the available data come from the United States, the United Kingdom and Japan, and the absence of data in these sources does not prove that published studies do not exist [13, 96, 99]. Brazilian research is nevertheless represented in recent trials: the NS substudy of the REAL8 somapacitan trial had a first author from the Genetic Endocrinology Unit of the Hospital das Clínicas, Faculty of Medicine, University of São Paulo, and included participants from several continents [91]; in the US label, 51% of the patients with NS in this trial were White, 31% Asian and 5% Black [90]. The relative distribution of NS genes in non-European populations is also insufficiently documented [4].

Special populations. Advanced paternal age is a risk factor for de novo variants in PTPN11 and HRAS [4, 13, 37]. In NS, a sex-ratio bias favouring transmission to male offspring has been observed, and in Costello syndrome boys appear to be more severely affected cognitively and have more separation anxiety [4, 13, 35].

10. Illustrative Clinical Case

10.1 Neonatal hypertrophic cardiomyopathy in RIT1-related NS treated with MEK inhibition

The following case was published by Andelfinger and colleagues in the Journal of the American College of Cardiology (2019) [74]. Increased nuchal translucency was detected at 13 weeks of gestation; gestational diabetes and polyhydramnios developed at 24 weeks; fetal echocardiography was normal. After birth, the newborn girl required mechanical ventilation for 10 days and then continuous non-invasive ventilation. Examination showed hypertelorism and low-set ears. Genetic testing identified a heterozygous de novo variant in RIT1 (NM_006912.5:c.246T>G p.(Phe82Leu), transcript used by the authors). Echocardiography revealed progressive biventricular hypertrophy and subvalvular obstruction. Propranolol was started at up to 10 mg/kg/day, but chest radiographs showed progressive pulmonary congestion. Catheterisation at 2 months revealed post-capillary pulmonary hypertension, and balloon valvuloplasty of the associated pulmonary stenosis was unsuccessful. At 3 months, clinical deterioration required resuscitation, mechanical ventilation and drainage of bilateral chylothoraces.

After discussing cardiac transplantation, the team chose off-label pharmacological MEK inhibition, with ethics committee approval and informed consent. Trametinib was started at 13 weeks of age at a dose of 0.027 mg/kg/day. The chylous effusions ceased within 33 days; hypertrophy and pulmonary oedema regressed, allowing extubation at 18 weeks; magnetic resonance imaging confirmed improvement after 3.5 months, with normalisation of NT-proBNP, improvement in valvular and subvalvular obstruction and catch-up growth, with the response maintained during 17 months of treatment [74]. The author manuscript is available in PMC (https://pmc.ncbi.nlm.nih.gov/articles/PMC6916648/); the letter has no figures, and the clinical and echocardiographic course of the two patients is summarised in its Table 1. The authors justified the intervention by the poor prognosis of infants under 6 months with NS, HCM and congestive heart failure, citing 1-year survival of 34%, and trametinib was funded by the patients' health insurance [74]. The authors described the variant using transcript NM_006912.5; the normalised form on the MANE transcript is NM_006912.6(RIT1):c.246T>G p.(Phe82Leu), classified as pathogenic/likely pathogenic in ClinVar [66, 74]. A second infant in the same series (RIT1 c.104G>C, p.Ser35Thr), with dysplasia of all four valves and progressive HCM despite propranolol at up to 9 mg/kg/day, had a similar response at 0.02 mg/kg/day [74]. The management described was an individual off-label decision, with ethical approval, and is not a routine recommendation; the dose does not derive from a label, and its generalisation awaits prospective trials (see 7.11 and 7.12).

Discussion points. (1) Increased nuchal translucency with a normal karyotype and polyhydramnios are prenatal clues; (2) severe HCM before 6 months defines the group with the poorest prognosis, and RIT1 is associated with HCM in 70–75% [4, 47]; (3) identifying the gene changed the therapeutic decision; (4) evidence for MEK inhibition comes from case reports and a retrospective analysis, pending prospective trials [84, 86]; (5) family counselling, with a de novo variant, indicates a recurrence risk below 1% [4].

10.2 Application vignette: Costello syndrome and tumour surveillance

Based on the findings described in published series, consider an infant with severe polyhydramnios, high birth weight due to oedema, poor weight gain requiring gastrostomy, deep palmar creases, loose skin on the hands, ulnar deviation of the wrists and multifocal atrial tachycardia, with the HRAS variant NM_005343.4:c.34G>A p.(Gly12Ser) [13, 35]. The plan includes serial echocardiography and electrocardiography, monitoring for hypoglycaemia, assessment for growth hormone deficiency after cardiac assessment, brain and lumbar MRI at 1 year, abdominopelvic ultrasound every 3 months until age 14 (rhabdomyosarcoma) and every 6–12 months until age 10 (neuroblastoma), urinalysis with annual cytology from age 10, and parental education about warning signs; the cancer risk for p.(Gly12Ser) (9.2%) is lower than for c.35G>C p.(Gly12Ala) and c.34G>T p.(Gly12Cys) [13, 53, 54]. Two rhabdomyosarcomas of the umbilical ligament in patients with Costello syndrome were described by Sánchez-Montenegro and colleagues (2017), illustrating the predominant abdominopelvic location [35, 53].

11. Prognosis and Long-Term Follow-up

Noonan syndrome. Prognosis depends mainly on heart disease and, to a lesser extent, on haematological complications. Early-onset HCM with heart failure is the main cause of cardiac mortality in childhood [4, 47]; according to Smith's, JMML is the leading cause of death in patients with NS who develop it [3]. Most children attend mainstream school; 10–15% require special education [4, 7]. Female fertility is normal; in males it may be reduced by cryptorchidism and Sertoli cell dysfunction [3, 4, 7]. In a prospective British study of 112 patients (mean age 25.3 years) followed for a mean of 12 years, PTPN11 was identified in 35% of probands; ten patients died, three from heart failure associated with HCM; pulmonary stenosis affected 65% (58% of these without intervention) and HCM 19% (with remission in two and one transplant); there was no sudden death; mean final height was 167.4 cm in males and 152.7 cm in females; severe feeding problems in infancy predicted a poorer course (two-word phrases at 39 versus 26 months and special school attendance of 58% versus 12.5%), although overall academic performance was similar to that of the general population [49]. In adulthood, there remain needs for cardiac follow-up (assessment at least every 5 years), mental health surveillance (anxiety and depression reported by 49% of adults in one study) and surveillance for osteopenia, and the Italian consensus emphasises the need for structured transition [4, 62]. The French PNDS considers that the presentation evolves throughout life and recommends annual follow-up at a reference or competence centre during childhood, spaced out in adults to every 3–5 years (2–5 years in the visit table), and estimates the risk of adult cancer as unknown but apparently low [1]. Oxford summarises follow-up: cardiology if a defect is present, growth monitoring with endocrine referral, otorhinolaryngology (otitis media with effusion in 30%), orthoptic assessment at diagnosis (strabismus or refractive error in more than 50%), bleeding assessment and educational support [7].

NSML. HCM, which may be progressive, determines prognosis; deafness should be detected early; tumour risk is low and does not justify routine surveillance, but requires a low threshold for investigating suspicious signs [10, 29]. Patients should be monitored in adolescence for hypogonadism and possible hormone replacement [10].

Costello syndrome. The hazard of death is 3–4% until age 3, and the cumulative incidence of death without cancer at age 20 is 11% [54]. Patients aged 16 to 40 with moderate HCM or recent-onset arrhythmias present the greatest challenge, and their course is unknown; hypertension is common [13]. In a survey of 20 adults (≥16 years), one lived independently, three in residential accommodation and 16 with their family; 25% had seizures, 50% Chiari I, 45% osteoporosis or osteopenia and 75% kyphosis or scoliosis; 35% had no mobility limitations, whereas 15% depended on a wheelchair [13]. Quality of life between ages 16 and 34 is limited by restricted social relationships, lack of independence, male sex and major medical problems [13]. Adolescents may appear older because of kyphoscoliosis, sparse hair and aged-looking skin [13]. Adult malignancies, except for bladder carcinoma, show no identified increase, possibly because of early mortality, so annual examination and population screening are maintained [53]. The 2024 PNDS attributes mortality mainly to cardiac and tumour complications, reports osteoporosis in half of adults and identifies as unresolved questions the influence of growth hormone on tumour and cardiac risk and the stratification of arrhythmic risk in adults [2].

CFC. Follow-up is lifelong; refractory epilepsy, intellectual disability and feeding difficulties determine quality of life; hypotonia and feeding difficulties improve in late childhood, but palmoplantar hyperkeratosis and lymphoedema may worsen; HCM and arrhythmias may develop late, justifying periodic echocardiography and electrocardiography throughout life; some young adults participate in assisted living and supported employment programmes; long-term follow-up information is limited [15, 38].

NS-LAH. The phenotype tends to improve with age, particularly hyperactivity; final height with growth hormone remains reduced [4, 57]. In the PPP1CB-related form, most have developmental delay but not intellectual disability [40].

Surveillance according to the French PNDS. The table brings together the recommended tests and intervals; the divergences from the other guidance are in 7.14 and the comparative surveillance by entity in 7.9.

12. Summary and Final Considerations

RASopathies result from germline variants, mostly gain-of-function, in genes of the RAS-MAPK pathway, and share short stature, heart disease (pulmonary stenosis and HCM), facial dysmorphism, ectodermal and lymphatic changes, neurodevelopmental involvement and tumour predisposition [5, 6, 101]. Noonan syndrome is the most common (1:1,000–1:2,500) and genetically heterogeneous: PTPN11 accounts for approximately half of cases and is associated with pulmonary stenosis and JMML risk, whereas RAF1, RIT1, MRAS and biallelic LZTR1 are associated with HCM, and SOS1/SOS2 with more preserved stature and ectodermal or lymphatic involvement [4]. LZTR1 introduces recessive inheritance into the group [27]. NSML is distinguished by lentigines appearing from age 4–5, HCM in up to 70% and deafness, with PTPN11 variants causing loss of catalytic activity [29]. Costello syndrome, almost always due to a paternally derived de novo HRAS p.Gly12Ser variant, combines severe failure to thrive, a coarse face, papillomas, loose skin, HCM, multifocal atrial tachycardia and a tumour risk approaching 15%, with a specific surveillance programme [13, 53]. CFC (BRAF, MAP2K1, MAP2K2) has the most severe neurological involvement, with epilepsy in more than half and universal skin changes [15]. NS with loose anagen hair (SHOC2, PPP1CB) combines a hair defect, growth hormone deficiency and mitral dysplasia [4, 40].

Diagnosis relies on a RASopathy panel or exome/genome sequencing, and identifying the gene guides cardiac, haematological and oncological surveillance [4, 62]. Growth hormone has an approved indication for short stature in NS, with a gain of 0.6–1.8 SD and no demonstrated increase in malignancies, requiring caution in HCM, NSML and Costello syndrome [4, 53, 87]; since February 2026, the FDA has also approved the weekly somapacitan formulation in NS, which in the European Union has a favourable CHMP opinion, pending the Commission's decision [90, 93]. MEK inhibition with trametinib is the first mechanism-targeted therapy, with results in severe HCM and lymphatic disease awaiting confirmation in ongoing trials, and vosoritide is being studied for growth [84, 86, 94]. Neurofibromatosis type 1 and Legius syndrome, also RASopathies, enter the differential diagnosis. The 2021 (RASopathies) and 2024 (Costello syndrome) French PNDS add detailed surveillance schedules, the starting dose of 0.033 mg/kg/day of somatropin in NS and tumour surveillance for Costello syndrome that is less intensive than that of the AACR [1, 2].

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