Clinical consensus guidelines for the management of Noonan syndrome in Japan

Abstract.

Noonan syndrome (NS) is a multisystem RASopathy marked by characteristic facies, congenital heart disease, short stature, and variable neurodevelopmental and systemic complications. Although molecular and clinical knowledge has advanced, evidence-based clinical guidance in Japan has been limited. A multidisciplinary committee in pediatric endocrinology, clinical genetics, and pediatric cardiology developed consensus guidelines on diagnosis, comorbidity assessment, treatment, and transitional care. Clinical questions were defined, and the literature published through March 2024 was systematically reviewed. Evidence was graded in partial accordance with the Minds Clinical Practice Guideline Development Manual 2020 and the GRADE framework, with expert consensus supplementing areas of limited evidence. External review included patient groups and academic societies, and the guideline was approved in 2025. The guideline recommends expanding diagnostic panels to include LZTR1, SOS2, MRAS, RRAS, and RRAS2 in addition to established genes. It advises comprehensive childhood assessment for tumor predisposition, coagulation abnormalities, hearing and ophthalmologic problems, neurodevelopmental features, and endocrine and cardiovascular complications, with strong emphasis on cardiac evaluation. Growth hormone therapy is recommended for short stature with careful monitoring for malignancy risk. MEK inhibitors may help selected patients with refractory hypertrophic cardiomyopathy or lymphatic abnormalities. Lifelong multidisciplinary surveillance and structured transition to adult care are strongly emphasized.

Highlights

● The guidelines provide the first evidence-informed Japanese consensus framework for multidisciplinary Noonan syndrome care.

● The guidelines recommend expanded genetic testing and systematic multisystem assessment, with particular emphasis on cardiovascular evaluation.

● The guidelines support growth hormone therapy with careful monitoring and emphasize lifelong follow-up, including transition to adult care.

List of Recommendations

Diagnosis

CQ1. Which genes should be included for diagnostic purposes?Recommendation: We recommend that diagnostic gene panels for NS include LZTR1, SOS2, MRAS, RRAS, and RRAS2 in addition to PTPN11, SOS1, RAF1, RIT1, NRAS, KRAS, and CBL. For NS-like disorder with loose anagen hair (NS/LAH), PPP1CB should be included alongside SHOC2. The addition of YWHAZ, MAPK1, SPRED2, and ERF to NS panels warrants future consideration (Strength of recommendation: Strong, Level of evidence: B).

Q2: What clinical features should be assessed when diagnosing in adulthood?Recommendation: Although the characteristic facial features, one of the diagnostic criteria, become less noticeable in adulthood than in infancy, they often persist, including low-set, posteriorly rotated ears with thick helices, down-slanting palpebral fissures, epicanthal folds, and ptosis. In the absence of GH therapy, many individuals exhibit short stature. Cardiac complications typical of childhood, such as pulmonary valve stenosis, remain relevant in adults. Additionally, aortic aneurysm and coronary artery dilation can be observed in adulthood. Impairments in the perception and expression of social and emotional cues, and alexithymia are also noted as psychopathological characteristics in adulthood (Level of evidence: B).

Comorbidities

CQ3: What endocrine comorbidity assessments are recommended in childhood?Recommendation 1: Because short stature and delayed puberty are common, we recommend evaluating for these conditions (Strength of recommendation: Strong, Level of evidence: B).Recommendation 2: Because thyroid disease may occur, we suggest considering evaluation (Strength of recommendation: Weak, Level of evidence: C).

CQ4: What cardiovascular comorbidity assessments are recommended in childhood?Recommendation: Cardiovascular complications occur in roughly 80% of individuals with NS. Pulmonary valve stenosis and atrial septal defect are common, and hypertrophic cardiomyopathy is less common but occasionally observed. In addition, although less common, a variety of other congenital heart defects may be present. Evaluation with chest radiography, a 12-lead electrocardiogram, and transthoracic echocardiography are recommended (Strength of recommendation: Strong, Level of evidence: B).

CQ5: What comorbidity assessments are recommended in childhood (excluding endocrine and cardiovascular complications)?Recommendation: Because of the relatively high frequencies of tumor predisposition, coagulopathies, hearing loss, ophthalmologic abnormalities, and neurodevelopmental features, a comprehensive assessment for these comorbidities is recommended (Strength of recommendation: Strong, Level of evidence: C).

Treatment

CQ6: Is GH therapy effective for short stature?Recommendation: GH therapy is effective for short stature (Strength of Recommendation: Strong, Level of Evidence: A).

CQ7: Does GH therapy increase the risk of tumor development?Recommendation: No studies have clearly demonstrated that GH therapy increases the risk of tumors. However, given the elevated baseline risk of malignancy in NS, we suggest that GH therapy should be administered with careful attention (Strength of Recommendation: Weak, Level of Evidence: C).

CQ8: Can GH therapy worsen hypertrophic cardiomyopathy?Recommendation: Previous case-control studies and randomized trials have demonstrated that GH therapy does not increase left ventricular wall thickness or worsen HCM; however, regular follow-up with transthoracic echocardiography is recommended (Strength of Recommendation: Weak, Level of Evidence: C).

CQ9: Are pathway inhibitors (MEK inhibitors, mTOR inhibitors) effective?Recommendation 1: Based on a multicenter, international retrospective study reported in 2024, individuals with the MEK inhibitor showed reduced risks of cardiac surgery (outflow tract resection), heart transplantation, and death. MEK inhibitors may be a therapeutic option for treatment-refractory hypertrophic cardiomyopathy and lymphatic dysplasia. However, there are few reports from Japan, and careful consideration is required (Strength of Recommendation: Weak, Level of Evidence: B).Recommendation 2: Although mTOR inhibitors are approved in Japan for the treatment of symptoms associated with central conducting lymphatic anomaly (CCLA), which can occur as part of NS, there are limited reports specifically describing their use in individuals with NS, and their efficacy in this population remains undetermined (Strength of Recommendation: None, Level of Evidence: D).

Transitional care

Q10: In transition to adult care, which adult complications (excluding endocrine and cardiac) warrant attention?Recommendation: In adulthood, in addition to endocrine and cardiovascular issues, patients may develop lymphatic abnormalities, ophthalmologic and otolaryngologic disorders, gastrointestinal disease, psychiatric conditions, scoliosis, and bleeding/coagulation disorders. Some also develop epilepsy, leukemia, or other malignancies. Mortality is higher than in the general population, and sudden death has been reported (Level of Evidence: B).

Introduction

Noonan syndrome (NS; OMIM #163950) was first described in 1963 by Jacqueline Noonan and colleagues (1) as a disorder characterized by distinctive facial features, congenital heart disease, and short stature (2). In Japan, prevalence has been estimated at approximately 1 in 10,000 live births based on a project funded by the Ministry of Health, Labour and Welfare, Japan; however, its precise prevalence still remains to be elucidated. Inheritance is typically autosomal dominant, although autosomal recessive inheritance has been described in NS due to pathogenic variants in LZTR1 and SPRED2 (3, 4).

Diagnosis is generally based on clinical criteria proposed by Van der Burgt et al. (5), with genetic testing increasingly important for diagnostic confirmation and subtype definition. NS is now recognized as a RASopathy caused by pathogenic variants in genes encoding components of the RAS/MAPK signaling pathway (6, 7). Since the identification of PTPN11 in 2001 (8), multiple causative genes have been reported, including SOS1 (9, 10), RAF1 (11, 12), KRAS (13), NRAS (14), and RIT1 (15). Nevertheless, approximately 20% of clinically diagnosed individuals have no detectable pathogenic variant in currently known genes (4), underscoring the need for careful clinical assessment in parallel with molecular testing. In addition, evidence continues to accumulate regarding the genetic basis of NS; however, the relevance of newly proposed candidate genes remains uncertain. Accordingly, further studies are needed to identify additional genes responsible for NS.

NS is a multisystem disorder with a broad clinical spectrum, including characteristic facial features, short stature, developmental and learning difficulties, and various organ-specific complications (16). Congenital heart disease is a major manifestation, affecting approximately 50–80% of individuals, most commonly pulmonary valve stenosis, hypertrophic cardiomyopathy, and atrial septal defect (16). Although there is currently no curative therapy targeting the underlying genetic variant of NS, evidence is accumulating regarding emerging therapeutic opportunities for hypertrophic cardiomyopathy. For example, MEK inhibitors may offer a disease-modifying therapeutic option. Therefore, management relies on early recognition and treatment of complications through coordinated, longitudinal multidisciplinary care, and prognosis may depend on the severity of cardiac involvement (17).

This consensus guideline provides an evidence-informed framework for the diagnosis and comprehensive clinical management of NS by integrating clinical evaluation with molecular testing, outlining recommended baseline assessments, and promoting coordinated multidisciplinary care across the lifespan, including transition from pediatric to adult care, to improve health outcomes and quality of life.

Methods

Guideline development process

The guideline development committee was established in 2023, comprising 8 members representing the Japanese Society for Pediatric Endocrinology, the Japan Society of Pediatric Genetics, the Japanese Society of Pediatric Cardiology and Cardiac Surgery. Committee members included specialists in pediatric endocrinology, clinical and basic genetics, and pediatric cardiology. Through discussions by the guideline development committee, the following 10 Clinical Questions (CQs) and Questions (Qs) were established regarding the diagnosis, comorbidities, treatment, and adult care. CQs were defined as clinical questions for which the strength of recommendation could be assigned, whereas other clinical questions were addressed as Qs. Relevant publications were collected using public databases, including PubMed (up to the end of March 2024). For each CQ and Q, the guideline development committee member(s) in charge performed an initial screening of titles and abstracts. When necessary, eligibility was assessed by full-text review, and relevant studies were included. Evidence for each CQ was not restricted by study design; all types of studies, from randomized controlled trials to case series, were considered. After assessing the quality of the evidence, the draft was refined and approved at plenary meetings of the guideline development committee. For each CQ and Q, the responsible committee member(s) drafted the recommendation statements and assigned the evidence level. The content was then carefully reviewed and approved at plenary meetings of the guideline development committee. In determining the strength of recommendations, the committee carefully considered the overall body of evidence, including the balance of benefits and harms. The strength of each recommendation was ultimately decided by the guideline development committee members. Evidence levels and recommendation strength were defined in accordance with the Minds Clinical Practice Guideline Development Manual 2020 of the Japan Council for Quality Health Care and the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system (18). When sufficient evidence could not be obtained for some CQs, recommendations were determined based on consensus arising from discussions among experts experienced in the clinical management of NS. In this guideline, recommendation strength is categorized as strong or weak: a strong recommendation indicates that the guideline recommends either performing or not performing an intervention, whereas a weak recommendation indicates that the guideline suggests either performing or not performing an intervention. The certainty of evidence is graded as A (high), meaning we are very confident in the estimate of effect; B (moderate), meaning we are moderately confident; C (low), meaning our confidence is limited; and D (very low), meaning we have very little confidence in the estimate of effect.

The draft guidelines underwent external review through public comments solicited from NS patient support groups and relevant medical societies. The final guidelines were approved by the participating societies between September and October 2025.

1. Diagnosis

CQ1. Which genes should be included for diagnostic purposes?

Recommendation: We recommend that diagnostic gene panels for NS include LZTR1, SOS2, MRAS, RRAS, and RRAS2 in addition to PTPN11, SOS1, RAF1, RIT1, NRAS, KRAS, and CBL. For NS-like disorder with loose anagen hair (NS/LAH), PPP1CB should be included alongside SHOC2. The addition of YWHAZ, MAPK1, SPRED2, and ERF to NS panels warrants future consideration.

Strength of recommendation: Strong

Level of evidence: B

Evidence

In Japan, genetic testing for NS received national health insurance coverage in 2020. The initial gene panel included PTPN11, SOS1, RAF1, RIT1, KRAS, NRAS, and BRAF, with SHOC2 and CBL also incorporated as genes causative of NS-like phenotypes.

Additional genes implicated in NS or NS-related conditions have been reported since 2014, including LZTR1, PPP1CB, SOS2, RRAS, RASA2, A2ML1, and RASA1. A ClinGen Expert Panel curation classified LZTR1 as strong for NS, SOS2 as moderate, and PPP1CB as causative for NS/LAH (19). Although many autosomal dominant LZTR1 variants remain variants of uncertain significance, pathogenic LZTR1 variants are relatively frequent among NS cases, supporting a strong classification. SOS2 is a SOS1 homolog, and reported variants often affect protein domains analogous to those altered in SOS1. PPP1CB has been identified in individuals with NS/LAH and yields a phenotype that overlaps with that observed in individuals harboring SHOC2 variants.

MRAS, RRAS, and RRAS2 have been reported as causative genes for NS (20,21,22), but case numbers remain small; accordingly, their current evidence strength is limited (19). More recently, additional candidate genes, including YWHAZ, MAPK1, SPRED2, and ERF, have been described in individuals with NS phenotypes (23,24,25,26,27,28,29), though reported cases are still limited and require further accumulation. A2ML1 was initially proposed to be associated with NS in 2015 (26). However, subsequent studies failed to reproduce this association, and its clinical relevance to NS was withdrawn in 2021 (30). Likewise, ClinGen has classified RASA1 as disputed for NS, as RASA1 is established as the cause of capillary malformation–arteriovenous malformation 1 (MIM 608354) (19). Our working group concurs that A2ML1 and RASA1 currently lack diagnostic utility for NS.

BRAF was identified in 2006 by Niihori et al. and by Rauen’s group as a major cause of cardio-facio-cutaneous (CFC) syndrome (31, 32), and rare BRAF variants have since been reported in individuals with NS phenotype. ClinGen classifies BRAF as definitive for CFC syndrome, but moderate for NS. In contrast, GeneReviews for CFC syndrome notes that, although BRAF variants can be found in individuals with NS-like features, pathogenic BRAF variants should be classified as CFC syndrome (33). Accordingly, we removed BRAF from the list of prototypical NS genes from Diagnostic Criteria, and included a footnote that BRAF is causative for CFC syndrome, and a minority of individuals with pathogenic BRAF variants may present with a Noonan-like phenotype.

Given the autosomal dominant inheritance, marked genetic heterogeneity, and the challenges associated with variant interpretation, particularly for variants of uncertain significance, appropriate pre- and post-test genetic counseling is recommended when genetic testing is performed.

Q2: What clinical features should be assessed when diagnosing in adulthood?

Recommendation: Although the characteristic facial features, one of the diagnostic criteria, become less noticeable in adulthood than in infancy, they often persist, including low-set, posteriorly rotated ears with thick helices, down-slanting palpebral fissures, epicanthal folds, and ptosis. In the absence of GH therapy, many individuals exhibit short stature. Cardiac complications typical of childhood, such as pulmonary valve stenosis, remain relevant in adults. Additionally, aortic aneurysm and coronary artery dilation can be observed in adulthood. Impairments in the perception and expression of social and emotional cues, and alexithymia are also noted as psychopathological characteristics in adulthood.

Level of evidence: B

Evidence

In NS, aside from cardiovascular disease, there are relatively few complications that are known to affect life expectancy. Although medical management in adulthood remains important, the literature describing comorbidities in adulthood is limited. One reason may reside in the fact that the core features of NS tend to attenuate with age and that many adults do not require special medical care (34). Another reason is that diagnosing adults who were not identified with NS in childhood can be relatively difficult because the pediatric physical features become less noticeable over time (35). Women generally retain fertility, whereas fertility in men is reduced in some individuals by factors such as cryptorchidism, though it may be preserved in others (34). Accordingly, when diagnosing an affected child, clinicians should also keep in mind the possibility of parental involvement. In addition to managing the child’s health, it is important to encourage health management for the parents as well. The type and severity of complications do not necessarily match between parent and child.

In young adults, certain facial characteristics reminiscent of childhood may be accentuated, while others become less noticeable. Ptosis can also be seen. The nasal root is narrow and the nasal bridge is high and the nasolabial folds tend to become more prominent with increasing age. The characteristic chest-wall deformities, listed among the diagnostic criteria, persist into adulthood (35). Short stature is observed in about 70% of individuals. Birth weight and length are generally within the normal range, but a reduced growth velocity is often apparent within the first year of life. During childhood, height tends to fall below –2 SDS, and puberty is often delayed (36). Consequently, in untreated adults with NS, average height has been reported to remain below –2 SDS relative to the general population (37). In Japan, consistent with overseas studies, mean heights have been reported as 157.3 ± 7.4 cm in men (−2.3 ± 1.3 SDS) and 146.8 ± 6.9 cm in women (−2.1 ± 1.3 SDS) (38).

Characteristic congenital heart diseases in NS include pulmonary valve stenosis, hypertrophic cardiomyopathy, and atrial septal defect. Many patients are diagnosed and appropriately treated/managed in childhood. Although definitive evidence is still limited, studies by Pierpont and by Digilio strongly recommend careful follow-up for such patients (39). In individuals with pulmonary valve stenosis, attention should be paid to post-operative or post-catheterization regurgitation. Management of these patients should be the same as for non-syndromic individuals. Coronary artery aneurysm and coronary ectasia may also be encountered (40). Although relatively rare and of uncertain frequency, these are important considerations when assessing long-term prognosis.

Cornwall et al. reported that aortic root aneurysm (defined as a z-score ≥ 2) occurs in individuals with NS and can progress over time (41). These observations suggest that a subset of individuals with NS may show vascular changes in adulthood resembling those seen in connective tissue disorders, underscoring the importance of ongoing cardiac follow-up in adults with NS (42).

Meanwhile, as psychopathological features in adulthood, impairments in the recognition and expression of social and emotional cues as well as alexithymia have been described (43,44,45).

2. Comorbidities

CQ3: What endocrine comorbidity assessments are recommended in childhood?

Recommendation 1: Because short stature and delayed puberty are common, we recommend evaluating for these conditions.

Strength of recommendation: Strong

Level of evidence: B

Recommendation 2: Because thyroid disease may occur, we suggest considering evaluation.

Strength of recommendation: Weak

Level of evidence: C

Evidence

In NS, the prevalence of short stature is high (46). In a study evaluating height SDS among 116 Japanese patients with NS, those with pathogenic RIT1 variants had milder short stature (47, 48); patients with pathogenic SOS1 variants also showed milder short stature than those with pathogenic PTPN11 variants (47, 48). Reports from outside Japan have shown similar findings (49). GH therapy is effective for short stature and improves adult height (see CQ6). Accordingly, we recommend evaluating stature in individuals with NS.

A 2022 systematic review reported that pubertal onset occurs later in NS than in control populations (50). Likewise, a 2022 Brazilian study of 133 individuals with genetically confirmed NS found delayed pubertal onset in both sexes, and 49.1% of girls and 27.9% of boys met the criteria for delayed puberty (51). In addition, males with NS may be at risk for impaired testicular function due to cryptorchidism and genetic factors. In a cohort of 37 males with NS (16 of whom were pubertal; PTPN11n = 22, SOS1n = 16), testosterone levels were normal, indicating preserved Leydig cell function, whereas anti-Müllerian hormone and inhibin B (markers of Sertoli cell function) were decreased, consistent with Sertoli cell dysfunction. Four individuals with PTPN11 variants had severe azoospermia (52). As part of transitional care in NS, counseling on fertility should be provided to males.

Feeding difficulties with frequent vomiting and poor intake are common in infancy in NS. Although many improve by 18 mo, some require gastrostomy feeding. Several studies report mildly reduced BMI in NS. Shoji et al. evaluated BMI in 116 Japanese individuals with NS and reported a median BMI-SDS of –0.24 (48). Similar findings have been reported elsewhere (53). Evidence regarding the risks of disordered glucose and lipid metabolism in NS remains very limited. In one analysis of 93 individuals with NS, total cholesterol levels were reported to be low (54).

In an analysis of 151 patients with NS, six had hypothyroidism, and anti-microsomal antibodies were positive in 7 of 23 tested (55). However, another report found no difference in the prevalence of thyroid autoantibodies between NS and control groups (56). Because thyroid dysfunction cannot be completely excluded in patients with NS, periodic assessment of thyroid function, for example annually, may be considered as part of routine follow-up.

Bone mineral density may be reduced in NS. Delagrange et al. analyzed 35 children with NS and found decreased bone density in the long bones (57). Similarly, Baldassarre et al. evaluated bone density by ultrasound in 35 individuals with NS aged between 1 and 17.8 yr and found reductions in 25% (58). Given the high frequency of delayed puberty in NS, its impact should be considered when interpreting bone status. To date, an increased fracture risk in NS has not been reported.

CQ4: What cardiovascular comorbidity assessments are recommended in childhood?

Recommendation: Cardiovascular complications occur in roughly 80% of individuals with NS. Pulmonary valve stenosis and atrial septal defect are common, and hypertrophic cardiomyopathy is less common but occasionally observed. In addition, although less common, a variety of other congenital heart defects may be present. Evaluation with chest radiography, a 12-lead electrocardiogram, and transthoracic echocardiography are recommended.

Strength of recommendation: Strong

Level of evidence: B

Evidence

The most common cardiovascular complication in NS is pulmonary valve stenosis, with cohort studies reporting a prevalence of 51–68%. Another frequent lesion is atrial septal defect, reported at 10–41%. Other congenital heart diseases that have been reported include ventricular septal defect, tetralogy of Fallot, patent ductus arteriosus, coarctation of the aorta, and aortic valve stenosis (Table 1). Pulmonary valve stenosis and atrial septal defect are often seen together; when both are present, NS should be considered. Hypertrophic cardiomyopathy is also important, with many reports indicating a frequency of 16–27% (17, 59,60,61,62,63,64,65). Accordingly, we recommend evaluating for cardiovascular disease in NS. Initial assessment with chest radiography, a 12-lead electrocardiogram, and transthoracic echocardiography is recommended. Depending on those results, additional tests, such as cardiac catheterization or cardiac MRI, should be considered as needed. The choice of modality should be guided by the pathophysiological assessment obtained from echocardiography and related evaluations, as well as the relative invasiveness of each procedure. The evaluation and longitudinal management of cardiovascular complications should be undertaken in collaboration with cardiologists.

Table 1. Cardiovascular diseases associated with Noonan syndrome.

Characteristic 12-lead electrocardiogram findings in NS

Characteristic ECG features are seen in 58% of patients, including left axis deviation with a negative QRS axis in lead aVF, abnormal R/S ratios in the left precordial leads, abnormal Q waves, and a continuous rS pattern (“clockwise rotation”). This pattern is typically seen in the right precordial leads but may also appear in the left precordial leads. These findings can be present irrespective of underlying heart disease and are useful for diagnosing NS (66).

Arrhythmias in NS

Multifocal atrial tachycardia, which is well described in Costello syndrome, is considered rare in NS; however, several cases have been reported in NS harboring pathogenic variants in PTPN11, RAF1, and SOS1 (67). In NS with hypertrophic cardiomyopathy, ventricular tachycardia can be a risk factor for sudden cardiac death (68).

Representative test findings for cardiovascular diseases associated with NS

1. Pulmonary valve stenosis

• Physical findings: A systolic ejection murmur due to stenosis is heard at the upper left sternal border (pulmonary area).

• Chest radiography: Prominence of the second left cardiac contour (post-stenotic dilatation). Cardiomegaly is usually absent.

• 12-lead ECG: Right ventricular hypertrophy may be present in severe stenosis.

•Echocardiography: Typically, pulmonary valve stenosis shows thickened pulmonary valve leaflets. Continuous-wave Doppler measurement of transvalvular flow velocity is useful for grading severity. Pulmonary regurgitation should be assessed. When tricuspid regurgitation is present, measurement of the regurgitant jet velocity with continuous-wave Doppler allows estimation of right ventricular systolic pressure and aids in severity assessment of stenosis. Evaluation of right ventricular function, including hypertrophy and dilation, is also important.

• Cardiac catheterization: Cardiac catheterization is performed in cases of severe stenosis when surgical or catheter-based intervention is considered. Treatment indications are determined primarily by the pressure gradient across the pulmonary valve and right ventricular systolic pressure. It should be noted that anesthesia may underestimate pressure gradients compared with those in the awake or active state.

• Cardiac MRI: Like echocardiography, cardiac MRI can measure flow velocity across the pulmonary valve and quantify pulmonary regurgitation. It also allows volumetric quantification of the right ventricle and assessment of right ventricular systolic function.

2. Atrial septal defect

• Physical findings: With increased pulmonary blood flow from left-to-right shunting, a fixed split of S2 and a systolic ejection murmur from relative pulmonary stenosis may be heard at the upper left sternal border (pulmonary area). Small defects may produce no murmur. Large defects may cause relative tricuspid stenosis, producing an additional diastolic rumble at the lower left sternal border (tricuspid area).

• Chest radiography: In large defects, pulmonary vascular markings increase in proportion to shunt volume. Right atrial enlargement leads to prominence of the right cardiac contour; pulmonary artery enlargement leads to prominence of the left second contour.

• 12-lead ECG: Signs of right atrial enlargement and right ventricular overload (most commonly incomplete right bundle branch block) may be present. Isolated negative T waves have diagnostic value.

• Echocardiography: The subcostal sagittal view can be used to measure the defect diameter in pediatric patients. In larger patients, transthoracic imaging may be insufficient for accurate sizing, and transesophageal echocardiography can be helpful. Increasing shunt volume leads to enlargement of right-sided chambers and the pulmonary artery.

• Cardiac catheterization: Performed when surgical or transcatheter closure is considered. A pulmonary-to-systemic flow ratio (Qp:Qs) ≥ 1.5–2.0 is generally considered an indication for closure. It is also important to assess for coexisting pulmonary hypertension. Suitability for transcatheter closure depends on body size and accurate transesophageal echocardiographic assessment of defect size and location.

• Cardiac MRI: Can also measure Qp/Qs and allows volumetric and ejection-fraction assessment of both ventricles.

3. Hypertrophic cardiomyopathy

• Physical findings: With left ventricular outflow tract (LVOT) obstruction, a systolic ejection murmur can be heard at the mid-left sternal border. Third and fourth heart sounds may be present due to impaired ventricular diastolic function.

• Chest radiography: Cardiomegaly is often absent.• 12-lead ECG: 12-lead ECG may show left ventricular hypertrophy, q waves, and ST-T abnormalities. Monitor closely for ventricular arrhythmias.

• Echocardiography: Echocardiography evaluates left ventricular wall thickening. In NS, concentric hypertrophy as well as asymmetric septal hypertrophy are common. Continuous-wave Doppler assessment is useful for evaluating LVOT obstruction. Left ventricular volumes and ejection fraction, diastolic function, and atrial enlargement should also be assessed.

• Cardiac catheterization: Cardiac catheterization is considered in cases with impaired cardiac function or suspected severe LVOT obstruction. Measuring left ventricular apical pressure is necessary to assess LVOT obstruction. Cardiac output, LV end-diastolic pressure, and pulmonary artery pressures provide valuable information. Endomyocardial biopsy—including ultrastructural analysis—may aid definitive diagnosis excluding secondary cardiomyopathies.

• Cardiac MRI: Cardiac MRI allows assessment of left ventricular volumes and systolic function. Late gadolinium enhancement and T1-mapping can be used to evaluate myocardial fibrosis.

Genotype–phenotype correlations in cardiovascular disease

Historically, pathogenic PTPN11 variants were reported to be associated more often with pulmonary valve stenosis and atrial septal defect and less often with hypertrophic cardiomyopathy. However, a 2022 report found no significant differences between PTPN11 and other gene variants in the overall incidence of congenital heart disease or in pulmonary valve stenosis. There was a trend toward more intervention-requiring pulmonary valve stenosis in the PTPN11 group, though the difference was not statistically significant (61). By contrast, a 2024 study reported significantly higher rates of hypertrophic cardiomyopathy in RAF1 variants compared with PTPN11 and other variants, and significantly higher rates of pulmonary valve stenosis in PTPN11 variants compared with RAF1. No significant inter-variant differences were observed for atrial septal defect (60).

Risk of sudden cardiac death in NS with hypertrophic cardiomyopathy

Recent studies have examined risk of sudden cardiac death in NS-associated hypertrophic cardiomyopathy. In a 2023 North American cohort study of 188 individuals with RASopathy-related hypertrophic cardiomyopathy, including 152 with NS, the 5- and 10-yr post-diagnosis incidences of sudden death were 0.8% and 5.6%, respectively. In a comparison cohort of individuals with idiopathic hypertrophic cardiomyopathy (n = 567), the corresponding incidences were 2.8% and 4.2%, respectively. Although the difference in sudden cardiac death incidence between the RASopathy-related and idiopathic hypertrophic cardiomyopathy cohorts was not significant, the rate of implantable cardioverter-defibrillator implantation was significantly lower in the RASopathy-related hypertrophic cardiomyopathy cohort (69). In UK cohort studies from 2023 and 2024, 11 of 169 patients (6.5%) with RASopathy-related hypertrophic cardiomyopathy experienced sudden death or near-miss. Notably, a half of them were classified as low risk by pediatric hypertrophic cardiomyopathy risk scores. Reported risk factors for sudden cardiac death included histories of syncope, non-sustained ventricular tachycardia, congestive heart failure, and the presence of LVOT obstruction (68, 70).

Recently, the MEK inhibitor trametinib was reported to significantly improve freedom from major adverse cardiac events (cardiac death, transplantation, and septal myectomy) in patients with RASopathy-related hypertrophic cardiomyopathy (123). The development of new therapies for hypertrophic cardiomyopathy is anticipated.

Lifelong and transitional cardiac care in Noonan syndrome

Individuals with NS require lifelong cardiovascular follow-up. In individuals with hypertrophic cardiomyopathy, LVOT obstruction may worsen from adolescence into adulthood and warrants careful monitoring. In those with pulmonary valve stenosis, long-term follow-up of valvular function, including surveillance for late pulmonary regurgitation after intervention, is required. Depending on the specific pathology and severity, follow-up in adulthood every 3–6 mo to every few years is recommended.

CQ5: What comorbidity assessments are recommended in childhood (excluding endocrine and cardiovascular complications)?

Recommendation: Because of the relatively high frequencies of tumor predisposition, coagulopathies, hearing loss, ophthalmologic abnormalities, and neurodevelopmental features, a comprehensive assessment for these comorbidities is recommended.

Strength of recommendation: Strong

Level of evidence: C

Evidence

In NS, the frequencies of refractive errors (amblyopia, myopia, and astigmatism), visual-field defects, and abnormalities of ocular alignment and motility are high. Van Trier et al. analyzed ophthalmologic complications in 105 individuals with NS (mean age 12 yr; range 0–60 yr) and reported hyperopia in 37%, astigmatism in 33%, myopia in 24%, amblyopia in 27%, strabismus in 38%, and nystagmus in 15% (71). Because ophthalmologic complications are common in NS, regular ophthalmic evaluations are recommended, including at the time of diagnosis.

Hearing loss is also frequent in NS. Madej et al. analyzed otolaryngologic complications in 67 patients with RASopathies, including 60 individuals with NS, and found hearing loss in 15%, of which 9% had sensorineural hearing loss, and 10% had recurrent otitis media (72). Similarly, van Trier et al. reported sensorineural hearing loss in 9 of 44 patients, 7 of whom were diagnosed before 10 yr of age (73). Accordingly, hearing assessment is recommended in NS. Transient conductive hearing loss is also relatively common and may be attributable to concomitant otitis media; therefore, appropriate management of otitis media is important in preventing hearing impairment.

Coagulation abnormalities are observed in NS. In a 2018 systematic review of 428 patients (74), bleeding symptoms were documented in 43%, although bleeding-related data were not reported in 31%. Abnormal coagulation tests, including prolonged PT/APTT, thrombocytopenia, and platelet aggregation defects, were present in 90%, and 45% of these had a definitive hemostatic diagnosis. Among 195 individuals with a confirmed diagnosis, 154 (78%) had a single coagulation-factor deficiency or von Willebrand disease, and 42 (22%) had multiple factor deficiencies. Factor XI deficiency was most common (n=81), followed by factor XII (n = 34) and factor VIII (n = 28). Platelet abnormalities, including thrombocytopenia and aggregation defects, were identified in 46 individuals. Briggs et al. analyzed 101 individuals with NS. Among 70 individuals undergoing 164 surgical procedures, 9 experienced bleeding complications, and none had preoperative coagulation testing. Bleeding risk was estimated to be 6.2% (75). Because appropriate testing can minimize bleeding complications, we recommend coagulation screening, such as platelet count, PT, and APTT, when NS is diagnosed, with repeat testing prior to surgery. Aspirin should be used with caution.

Kratz et al. evaluated 632 individuals with NS and reported a standardized incidence ratio for childhood tumors (benign and malignant) of 8.1 (95% CI, 3.5–16.0) (76). Tumors occurred in 8 patients: juvenile myelomonocytic leukemia (JMML) in 3 (onset < 1 yr), acute lymphoblastic leukemia in 2 (onset at 4 and 8 yr), pilocytic astrocytoma in 1 (onset at 7 yr), a dysembryoplastic neuroepithelial tumor (benign) in 1 (onset at 6 yr), and neuroblastoma in 1 (onset at 3 yr). Separately, Jongmans et al. analyzed cancer risk in 297 patients with NS carrying pathogenic PTPN11 variants and found a 3.5-fold (95% CI, 2.0–5.9) increased risk of tumors by age 55 compared with the general population (77). In that study (including literature cases), 29 individuals with NS and pathogenic PTPN11 variants developed malignancies: pediatric-onset cases included neuroblastoma (n = 4; onset at 5 mo, 6 mo, 1 yr, 4 yr), JMML (n = 1; 1 yr), acute lymphoblastic leukemia (n = 2; 2 and 8 yr), acute myeloid leukemia (n = 1; 5 yr), hepatoblastoma (n = 1; 1 mo), dysembryoplastic neuroepithelial tumor (benign; n = 1; 10 yr), oligodendroglioma (n = 1; 17 yr), glioneuronal tumor (n = 1; 6 yr), and pilocytic astrocytoma (n = 1; 8 yr). Thus, malignancy risk is elevated in NS. In addition, variants in LZTR1 have been linked to schwannomatosis irrespective of the presence of NS (78).

Genotype–phenotype correlations with tumor predisposition have also been described. For example, PTPN11 codon 61 variants and the p.T73I variant, as well as KRAS p.T58I, are associated with an increased risk of JMML-like myeloproliferative disease; clinical examinations and peripheral blood testing every 3–6 mo until age 5 are recommended (79). Beyond these scenarios, evidence remains insufficient to support specific tumor surveillance protocols. Nevertheless, because an increased tumor risk in NS cannot be excluded, periodic clinical evaluations—including laboratory testing and assessment for hepatosplenomegaly—are advisable.

Recently, craniosynostosis has been reported in NS (80). A 2025 study from Spain of 121 patients with RASopathies (68 with pathogenic PTPN11 variants) identified craniosynostosis in 2 individuals, both with PTPN11 variants (81). Associations with ERF variants have also been suggested (82,83). Craniosynostosis may affect development; clinicians should monitor for skull deformity and microcephaly.

Malocclusion is present in 50%–67% of patients with NS (84). Regular dental visits are recommended, with orthodontic treatment as indicated.

In a 2016 systematic review, Pierpont reported mean (SD) IQs in NS ranging from 84.0 (21.4) to 92.9 (14.6), with 6%–23% having IQ < 70 (85). Similarly, in 2018 Perrino et al. assessed IQ in 27 patients with NS (ages 6–18 yr) and found a mean IQ of 94 (range 56–130); 22% met diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD) (44). Although many individuals with NS have IQs within the normal range, inter-individual variability is large, and neurodevelopmental traits are common. Developmental assessment is therefore recommended, with psychological and social support tailored to each patient’s developmental stage and profile.

3. Treatment

CQ6: Is GH therapy effective for short stature?

Recommendation: GH therapy is effective for short stature.

Strength of Recommendation: Strong

Level of Evidence: A

Evidence

As summarized by Romano et al., GH therapy for short stature in NS is effective (84). Subsequently, a large review of 28 reports by Stagi et al. (86) and an even larger review of 43 reports by Sodero et al. (87) were published. Taken together, these reviews establish the short-term efficacy of GH. Notably, a Japanese multicenter, randomized, double-blind, comparative trial over four years using 0.033 mg/kg/d and 0.066 mg/kg/d demonstrated increases in height SDS versus Japanese healthy children of +0.85 and +1.84, respectively (36).

Long-term data reflecting final outcomes are limited, but Romano et al. reported that GH at 0.33 mg/kg/wk for 5.6 yr starting at a mean age of 11.6 yr increased near-adult height (defined as height at ≥ 14 yr in girls and ≥ 16 yr in boys by both chronological and bone age) by 10.9 ± 4.9 cm in boys and 9.2 ± 4.0 cm in girls compared with predicted adult height based on pre-treatment height SDS (88).

Although dosing regimens, treatment duration, and causal genes vary across studies, the effectiveness of pharmacological dose GH in treating short stature in NS appears clear. By contrast, gene-specific responses, such as differences by causative genotype, remain uncertain (87) and are topics for future study. Serious adverse events have been rare.

The Japanese Society for Pediatric Endocrinology recommends taking into account the potential risk of tumor predisposition. Specifically, if the serum IGF-I level exceeds the age- and sex-adjusted upper limit (+2 SD), serum IGF-I should be remeasured at the next blood draw, and if it remains above the upper limit on consecutive measurements, the GH dose should be reduced to an appropriate level.

CQ7: Does GH therapy increase the risk of tumor development?

Recommendation: No studies have clearly demonstrated that GH therapy increases the risk of tumors. However, given the elevated baseline risk of malignancy in NS, we suggest that GH therapy should be administered with careful attention.

Strength of Recommendation: Weak

Level of Evidence: C

Evidence

To date, no published studies have conclusively shown that GH therapy increases tumor risk. Epidemiologic studies estimate that patients with NS have a 3.5–8.1-fold higher risk of cancer than the general population. The most common malignancies are hematologic cancers, followed by neuroblastoma and primary brain tumors (76, 77). Certain PTPN11 variants are specifically associated with juvenile myelomonocytic leukemia (JMML) (89).

Among individuals with NS who received GH therapy, cancer has been reported in seven genetically confirmed cases and seven clinically diagnosed cases; however, GH dose, age at initiation, and follow-up details varied widely across these reports (88, 90,91,92,93,94,95,96,97,98) (Table 2). Therefore, further study is needed to clarify the association between GH therapy and tumor risk.

Table 2. Tumor cases in individuals with Noonan syndrome receiving growth hormone therapy.

In light of these observations, it is advisable to confirm the diagnosis genetically before initiating GH therapy and to interpret the results in the context of published cases. Families should be counseled regarding the potential risk of cancer, with particular attention to the increased risk of myeloproliferative disorders, including JMML. We suggest long-term follow-up within a comprehensive management plan.

CQ8: Can GH therapy worsen hypertrophic cardiomyopathy?

Recommendation: Previous case-control studies and randomized trials have demonstrated that GH therapy does not increase left ventricular wall thickness or worsen HCM; however, regular follow-up with transthoracic echocardiography is recommended.

Strength of Recommendation: Weak

Level of Evidence: C

Evidence

GH therapy is approved for the treatment of short stature in NS in Japan. Given concerns that GH might promote cardiomyocyte hypertrophy, many reports have examined this issue. Observational studies assessing myocardial hypertrophy by echocardiography found no significant increase in left ventricular wall thickness at 1 and 3 yr after initiating GH compared with baseline (99, 100). In a case-control study that included myocardial hypertrophy as an outcome, no significant differences were observed between GH-treated and untreated groups in interventricular septal thickness or left ventricular posterior wall thickness at 1 yr, although the sample sizes were small. The other studies demonstrated that no significant increase in ventricular wall thickness was detected through 4 yr of treatment in the GH-treated group (101, 102). These reports included patients with pre-existing myocardial wall thickening before GH initiation; however, even in those cases, no significant post-treatment increase was observed.

Likewise, randomized controlled trials and large cohort studies that focused on height as the primary outcome did not show worsening of myocardial hypertrophy or increased cardiovascular adverse events in GH-treated groups (36, 92, 103,104,105). Nevertheless, there are individual case reports in which ventricular wall thickness increased after the initiation of GH therapy, although it remained within the normal range (100). A case report showed that a death occurred during GH therapy in a patient with obstructive hypertrophic cardiomyopathy, although the cause of death was unclear in relation to hypertrophic cardiomyopathy (106). Accordingly, during GH therapy for NS, we recommend periodic echocardiographic follow-up approximately every six months (107).

CQ9: Are pathway inhibitors (MEK inhibitors, mTOR inhibitors) effective?

Recommendation 1: Based on a multicenter, international retrospective study reported in 2024, individuals with the MEK inhibitor showed reduced risks of cardiac surgery (outflow tract resection), heart transplantation, and death. MEK inhibitors may be a therapeutic option for treatment-refractory hypertrophic cardiomyopathy and lymphatic dysplasia. However, there are few reports from Japan, and careful consideration is required.

Strength of Recommendation: Weak

Level of Evidence: B

Recommendation 2: Although mTOR inhibitors are approved in Japan for the treatment of symptoms associated with central conducting lymphatic anomaly (CCLA), which can occur as part of NS, there are limited reports specifically describing their use in individuals with NS, and their efficacy in this population remains undetermined.

Strength of Recommendation: None

Level of Evidence: D

Evidence

MEK inhibitors

Because RASopathies, including NS, result from activation of the RAS/MAPK pathway, MEK inhibition has shown efficacy in cell culture and mouse models (108,109,110,111). In 2019, Andelfinger et al. reported improvement of hypertrophic cardiomyopathy with the MEK inhibitor trametinib in two individuals with NS harboring RIT1 variants. Subsequently, case reports have described benefits of trametinib in otherwise treatment-refractory hypertrophic cardiomyopathy (112,113,114,115), particularly in lymphatic dysplasia (116,117,118,119,120), and in conditions accompanied by multifocal atrial tachycardia (121, 122). Pascarella and Mussa noted that while trametinib had some efficacy for hypertrophic cardiomyopathy, it did not improve pulmonary artery stenosis. Reported adverse effects included dermatitis/eczema (115, 117, 119) and enterocolitis (115, 117, 122).

In 2025, results of a retrospective study from the United States, Canada, and Europe were reported (123). In an analysis of outcomes in individuals with RASopathy-related hypertrophic cardiomyopathy, PTPN11-positive cases were excluded, and the study compared patients treated with a MEK inhibitor (trametinib; n = 30) with those who were not treated (n = 31). The trametinib-treated group showed lower risks of cardiac surgery (LVOT myectomy), heart transplantation, and death. Aside from dermatitis and enterocolitis, no serious adverse events were observed. This multicenter study provides real-world evidence supporting the use of MEK inhibitors in RASopathies.

Selumetinib, a MEK inhibitor, is approved in Japan for the treatment of plexiform neurofibromas associated with neurofibromatosis type 1. In NS, there is a case report describing its use in a patient with coagulopathy who developed pulmonary and gastrointestinal bleeding (124).mTOR inhibitors

In Japan, mTOR inhibitors are reimbursed for hemangiomas and vascular malformations. Because lymphatic dysplasia in NS can manifest as CCLA or, in adulthood, as lymphedema, mTOR inhibition may be a reasonable therapeutic option for refractory lymphatic disease. There have been few reports specifically describing the use of sirolimus for lymphangiectasia associated with NS in Japan. However, recently, a paper was published describing a NS patient with chylothorax and recurrent respiratory infections. Administration of sirolimus, an mTOR inhibitor, showed a significant reduction in perineal chyle discharge (125). However, there are virtually no reports specifically describing the use of sirolimus for lymphangiectasia associated with NS. Separately, NS with multiple lentigines (NSML) caused by PTPN11 variants has been shown to involve activation of the AKT-mTOR signaling pathway. There is a case report of an NSML patient with progressive hypertrophic cardiomyopathy who was treated with an mTOR inhibitor (126).

4. Transitional care

Q10: In transition to adult care, which adult complications (excluding endocrine and cardiac) warrant attention?

Recommendation: In adulthood, in addition to endocrine and cardiovascular issues, patients may develop lymphatic abnormalities, ophthalmologic and otolaryngologic disorders, gastrointestinal disease, psychiatric conditions, scoliosis, and bleeding/coagulation disorders. Some also develop epilepsy, leukemia, or other malignancies. Mortality is higher than in the general population, and sudden death has been reported.

Level of Evidence: B

Evidence

Mortality in NS appears to be higher than in the general population. In a prospective UK study of 112 adults, five deaths occurred, with no sudden deaths (59). In contrast, a German study of 103 individuals identified ten deaths, including three sudden deaths, yielding a standardized mortality ratio of 3.00 (95% CI, 1.44–5.52) (127). Cardiac disease, such as hypertrophic cardiomyopathy, has been reported to be associated with mortality (17, 128, 129).

In a series of 115 patients, lifetime lymphatic abnormalities were seen in 37% and were associated with SOS2 variants (130). In another study, lymphedema was present in 49% (17/35) of individuals (131).

Among malignancies, hematologic malignancies are the most common. In a cohort of 297 individuals with PTPN11 variants (mean age of 18 yr), 12 developed malignancies. The cumulative cancer risk by age 55 was 23%, a 3.5-fold increase over the general population (77).

Among 105 patients with NS (including 50 with PTPN11 variants), seven had permanent visual impairment and two had keratoconus (71).

Hearing impairment was reported in 4 of 112 adults (1) and in 34 of 97 adults (73); progressive high-frequency sensorineural hearing loss was observed in 50% of ears among 20 individuals (132).

Epilepsy prevalence was 10% in a cohort of 112 adults (59), with similar findings elsewhere (133). In a cohort of 35 adults, depression and anxiety were each present in 49% (131). In another series of 42 adults, autism was present in 10% and ADHD in 20% (133). There are reports showing an increase in IQ from childhood to adulthood (134), a nonverbal IQ around 99 (133), a selective reduction in information-processing speed compared with controls (45), and higher rates of alexithymia and introversion than in controls (135).

In a 35-case series, scoliosis occurred in 54%, gastroesophageal reflux in 60%, constipation in 51%, and keloid formation after injury or surgery in 34% (131). Easy bruising/bleeding was reported in 63%–79% (59, 131).

Given these adult comorbidities, structured transition to adult care is necessary. Because multidisciplinary management is often required, identifying a coordinating specialty service remains an important challenge.

Conclusion

This guideline provides a structured, evidence-informed approach to the diagnosis and management of NS across the lifespan. It emphasizes expanded genetic testing, systematic evaluation of multisystem comorbidities, and the central role of cardiovascular monitoring. GH therapy is effective in improving adult height and should be conducted with appropriate safety surveillance. Emerging targeted therapies such as MEK inhibitors show promise in selected cases. Given the broad spectrum of adult complications, coordinated transition to adult care is essential. Continued research is needed to refine genotype–phenotype correlations and optimize therapeutic strategies.

Disclosure: This article is a faithful English translation of the “Clinical Consensus Guidelines for the Management of Noonan Syndrome (2025 Edition),” originally published in Japanese, without substantive modification of the original content. This article has been jointly published in Clinical Pediatric Endocrinology by the Japanese Society for Pediatric Endocrinology and in the Journal of Pediatric Cardiology and Cardiac Surgery by the Japanese Society of Pediatric Cardiology and Cardiac Surgery. Dr. Masanobu Kawai is a member of the Editorial Board of Clinical Pediatric Endocrinology, and Dr. Hidekazu Ishida is a member of the Editorial Board of the Journal of Pediatric Cardiology and Cardiac Surgery.

Conflict of interests

In accordance with the Conflict of Interest (COI) Policy of the Japanese Society for Pediatric Endocrinology, all members of the guideline development committee submitted COI declarations covering the previous 3 yr (reporting period: April 1, 2020, to December 31, 2024; company names are listed as of December 2024). Dr. Masanobu Kawai received lecture fees from Novo Nordisk Pharma, Pfizer Inc., and JCR Pharmaceuticals and research funding from Novo Nordisk Pharma. Dr. Tsutomu Ogata received lecture fees from Novo Nordisk Pharma and JCR Pharmaceuticals. Dr. Hiroyuki Yamagishi received lecture fees from AstraZeneca, Sanofi, Janssen Pharma, and Shindan to Chiryo-sha; manuscript fees from Sanofi; research funding from Janssen Pharma, Astellas Pharma, Bristol-Myers Squibb, and Mitsubishi Tanabe Pharma. Dr. Yoko Aoki received research funding from the Kazusa DNA Research Institute. Drs. Kenji Kurosawa, Koji Muroya, Hidekazu Ishida, and Makiko Tachibana declared no relevant conflicts of interest. All disclosed relationships were reviewed by the Conflict of Interest Committee of the Japanese Society for Pediatric Endocrinology to ensure that they did not compromise the scientific integrity or independence of the recommendations presented herein.

Funding Statement

The present study was supported by MHLW Research on rare and intractable diseases Program (Grant Number 23FC1040) to M.T., K.M., Y.A., K.K., T.O., and M.K., and the Japan Agency for Medical Research and Development (Grant Number: JP23ek0109618) to Y.A., K.K., and T.O.