Version May 2024
INTRODUCTION — Noonan syndrome (NS) is a common autosomal-dominant condition that is associated with short stature and congenital heart disease (CHD), most often pulmonic stenosis. It is clinically and genetically heterogeneous. Although initial descriptions focused on characteristic facial features as part of the clinical picture, the availability of genetic testing has demonstrated a highly variable clinical presentation in which behavioral and emotional features may be more prominent. Hypertrophic cardiomyopathy (HCM) is present in approximately 20 percent of patients, although the proportion of patients with this varies greatly according to the gene mutated.
This topic reviews the epidemiology, genetics, pathophysiology, clinical manifestations, diagnosis, and management of NS. Other causes of short stature and of CHD are reviewed in detail separately. (See "Diagnostic approach to children and adolescents with short stature" and "Causes of short stature" and "Identifying newborns with critical congenital heart disease" and "Common causes of cardiac murmurs in infants and children".)
EPIDEMIOLOGY — The prevalence of NS is widely quoted as 1 in 1000 to 1 in 2500 [1]. However, the true prevalence remains unknown. The features of NS change with age [2], and it is not uncommon for a parent to be diagnosed only after the birth of a more severely affected child. NS affects males and females equally but may be more recognizable in boys since they can present with cryptorchidism. NS occurs across all ethnic groups [3]. NS is associated with advanced paternal age, similar to several other conditions with dominant inheritance [4]. (See 'Ras-MAPK pathway' below.)
GENETICS — NS is nearly always an autosomal-dominant condition, and two-thirds of patients are the first affected person in their family due to a de novo pathogenic variant [4]. Approximately 50 percent of patients have a pathogenic variant in protein tyrosine phosphatase, nonreceptor type 11 (PTPN11), with clustering of variants in specific codons. The PTPN11 gene encodes the protein Src homology region 2 domain-containing phosphatase 2 (SHP2), a dual-specificity phosphatase [4]. The genetic basis in the remainder of patients is usually a pathogenic variant in one of many other genes encoding a protein of the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway (figure 1). Variants in some of these genes are associated with particular clinical characteristics (table 1). Pathogenic variants in leucine zipper-like transcription regulator 1 (LZTR1) may underpin approximately 10 percent of NS, and these may show either autosomal-dominant or autosomal-recessive inheritance, with consequent implications for recurrence risk in future pregnancies in the family [5].
Approximately 10 percent of patients tested do not have an identifiable pathogenic variant in any of the known genes, suggesting that additional genes are involved [6]. A number of candidate genes for NS have been identified using high-throughput technologies such as exome sequencing and are awaiting further evaluation before their role in NS can be confirmed [6].
PATHOPHYSIOLOGY
Ras-MAPK pathway — The clinical phenotype of NS results from germline pathogenic variants in genes encoding proteins that interact within the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway (figure 1). Ras-MAPK pathway signaling is crucial to many cellular functions, including proliferation and differentiation. Activating pathogenic variants in Ras genes were the first identified human oncogenes [7]. Hence, the intricacies of Ras-MAPK pathway signaling were studied extensively in cancer pathogenesis prior to the identification of germline pathogenic variants in these same genes. The effect of these variants, irrespective of the causative gene, is to perturb signal transduction through the Ras-MAPK pathway and is a type of RASopathy [8].
The association of de novo occurrence of NS with older paternal age is due to the enrichment of mutated alleles in the sperm of males as they age, consistent with a clonal advantage in the spermatogonia that harbor such variants over those that do not [9], a process that is accentuated over increasing numbers of cell divisions. This mechanism may help to account for the relatively high prevalence of NS compared with other de novo genetic conditions.
Altered signal transduction — Functionally characterized pathogenic variants causing NS most often confer a "gain of function" (GOF) to the resultant protein [8]. As examples, pathogenic variants in the genes for KRAS proto-oncogene, GTPase (KRAS) and NRAS proto-oncogene, GTPase (NRAS) can render these proteins constitutively active. PTPN11 pathogenic variants also most commonly result in SHP2 proteins that have increased signal transduction through the Ras-MAPK cascade. However, there are limited readouts of pathway activity available, and NS-associated mutated proteins probably have a more complex effect across the Ras-MAPK signal transduction network than can be demonstrated in functional assays.
In NS with multiple lentigines (NSML, previously LEOPARD syndrome; small, darkly pigmented macules that often appear from puberty onwards) (picture 1), a different spectrum of pathogenic variants in PTPN11 is observed than is seen in NS. NSML-associated pathogenic variants may result in decreased signaling through RAF, MAPK/ERK kinase (MEK), and extracellular signal-regulated kinase (ERK) proteins and increased activity of the protein kinase AKT/mammalian (mechanistic) target of rapamycin (mTOR) pathway [8]. The NSML phenotype has also been reported in patients with pathogenic variants in other Ras-MAPK pathway genes, namely B-Raf proto-oncogene, serine/threonine kinase (BRAF) and Raf-1 proto-oncogene, serine/threonine kinase (RAF1), reflecting that cardiomyopathy, deafness, and lentigines are common manifestations of variants in many of the pathway genes. (See "Congenital and inherited hyperpigmentation disorders", section on 'LEOPARD syndrome'.)
Neurofibromin and sprouty-related EVH1 domain containing 1 (SPRED1) are both negative regulators of the Ras-MAPK pathway. In keeping with this, loss-of-function (LOF) pathogenic variants in neurofibromin 1 (NF1) and SPRED1 cause neurofibromatosis type 1 and Legius syndrome, respectively, Ras-MAPK pathway disorders with some features similar to NS [10]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Pathogenesis' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Legius syndrome'.)
CLINICAL MANIFESTATIONS — NS is clinically heterogeneous and can present at any age. Typical presenting features at each stage of life are outlined below. The most consistent clinical features are widely spaced eyes and low-set ears (>80 percent), short stature (>70 percent), and pulmonic stenosis (approximately 50 percent) [3].
Prenatal — Fetuses with NS may present with manifestations of disordered lymphatic development, which include increased nuchal translucency (most common), distended jugular lymphatic sacs/cystic hygroma, ascites, and generalized hydrops. Additional presenting features include kidney anomalies such as hydronephrosis, hypertrophic cardiomyopathy (HCM), and congenital heart disease (CHD), although this is less commonly identified prenatally because the defects are frequently valvular or septal and hence not readily identifiable in utero. Pulmonary stenosis and HCM may be progressive [11].
Supporting features include polyhydramnios, mild limb shortening, relative macrocephaly, and fetal macrosomia. These features are not unique to NS and are also observed in other conditions involving the Ras-mitogen-activated protein kinase (MAPK) pathway such as Costello and cardio-facio-cutaneous (CFC) syndrome (figure 1).
Birth and infancy — Many infants with NS appear completely unremarkable at birth. Birth weight and head circumference are usually within the normal range but may be relatively large (relative macrosomia and/or macrocephaly). Pulmonic stenosis or other CHD may be detected on routine examination of the newborn. Cyanotic CHD is rare. Feeding difficulties of some degree are common, but the etiology of these appears complex. In a small number of children, ongoing nasogastric feeding or gastrostomy is required. In males, cryptorchidism may be present. Talipes equinovarus (clubfoot) occurs in 5 percent of patients with NS. (See "Identifying newborns with critical congenital heart disease" and "Undescended testes (cryptorchidism) in children: Clinical features and evaluation".)
Childhood — Characteristic facial and other physical features of NS emerge during early childhood. Children with NS may present with short stature (the 50th centile for NS follows the 3rd centile for the general population, with normal growth velocity), a murmur indicating CHD, or delayed speech or motor milestones. Easy bruising or bleeding is common and is most frequently associated with variants in PTPN11. Platelet function disorders or deficiencies of clotting factors have been implicated in some patients, but no consistent pattern of hematologic defects has been observed across tested cohorts. Dry skin and keratosis pilaris are common. Strabismus or deafness (sensorineural, conductive, or mixed loss) may be present and can be progressive. Lymphedema may present in childhood and is most likely due to disordered lymphatic development. Craniosynostosis is a rare but recognized association of NS [12]. Giant cell tumors (nonmalignant lesions) of the jaw are another rare but highly suggestive feature that may present in childhood [13]. (See "Diagnostic approach to children and adolescents with short stature" and "Common causes of cardiac murmurs in infants and children" and "Evaluation and management of strabismus in children" and "Hearing loss in children: Screening and evaluation" and "Pathophysiology and etiology of edema in children" and "Overview of craniosynostosis" and "Giant cell tumor of bone".)
When the facial features of NS are present, they are usually most recognizable from the end of the first year of life and throughout childhood. The most helpful facial features are a high forehead, hypertelorism, downslanting palpebral fissures with high arched eyebrows, epicanthic folds, a full upper lip with a depressed nasal bridge, and low-set ears. Strikingly blue irides, ptosis, and a degree of neck webbing may be observed [2]. Over time, lengthening of the jaw occurs, so the face may have a triangular shape.
NS is associated with a range of intellectual function, from normal to significantly impaired, with most patients having mild developmental delay [13].
Adulthood — There is an increased risk of male infertility, even in those who have not had cryptorchidism. HCM or lymphedema may present for the first time in adulthood, as may symptoms of Chiari malformation. Facial features in adult life often show signs of premature aging, with deep nasolabial folds being a common feature. Despite frequent developmental difficulties, the majority of individuals with NS will function within the normal range as adults [13]. (See "Causes of male infertility" and "Approach to the male with infertility" and "Chiari malformations".)
DIAGNOSIS — The diagnosis of NS often can be made on clinical features alone, but molecular confirmation is usually attempted, particularly in view of the emerging genotype-phenotype correlations. Some patients may receive a diagnosis from molecular genetic investigations such as whole-genome sequencing performed for indications such as congenital heart disease (CHD), short stature, or intellectual disability.
Clinical assessment — The diagnosis is suspected in patients of any age with a constellation of features from those described above (see 'Clinical manifestations' above). Particular consideration should be given to presence of prenatal features, feeding difficulties, relative macrocephaly, and short stature. Review of early childhood photographs (where the facial features may be more characteristic) may be helpful in the older individual. Aside from molecular genetic testing, there are no laboratory studies that indicated the diagnosis.
Formal diagnostic criteria are listed in the table (table 2) [14]. These are helpful in patients with features associated with a classic presentation but may not be helpful in patients with pathogenic variants in some NS-associated genes such as Cbl proto-oncogene (CBL) or RAF1 (table 1).
Genetic testing — Molecular confirmation of the clinical diagnosis of NS is possible in the large majority of patients. Many diagnostic laboratories now offer a "Noonan syndrome" or "RASopathy" panel test, which includes many or all of the genes known to be mutated in NS. As with any extended-spectrum test, there is a chance of identifying variants of uncertain significance. The testing should be delivered in a setting where genetic counseling is available. Cascade testing of first-degree relatives (who may be minimally affected) is available once the causative variant in the proband has been identified. Increasing numbers of patients are diagnosed via broad-scope genetic tests such as whole-exome or whole-genome sequencing. (See "Genetic testing" and "Secondary findings from genetic testing".)
Prenatal testing — Several studies have supported NS variant testing in pregnancy in the presence of nuchal thickening along with cystic hygroma, polyhydramnios, hydrops, renal anomalies, distended jugular lymphatic sacs, hydrothorax, or cardiac anomalies [11,15,16]. Variant detection rates of 17 percent are reported, depending upon gestation, pattern of abnormalities, and the number of genes tested [11].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for individual presentations consistent with NS is broad. Chromosomal abnormalities detectable by microarray are a common cause of congenital heart disease (CHD), short stature, and developmental delay. Apparently isolated short stature is frequently familial. A number of topics address the causes and evaluation of CHD, short stature, and developmental delay. (See "Common causes of cardiac murmurs in infants and children" and "Cardiac causes of cyanosis in the newborn" and "Causes of short stature" and "Diagnostic approach to children and adolescents with short stature" and "Intellectual disability in children: Evaluation for a cause" and "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray" and "Congenital cytogenetic abnormalities" and "Chromosomal translocations, deletions, and inversions" and "Sex chromosome abnormalities".)
Differentiation between NS and other disorders of the Ras-mitogen-activated protein kinase (MAPK) pathway (figure 1), particularly cardio-facio-cutaneous (CFC) syndrome, may be difficult. Molecular characterization can assist in this, but the overlap in clinical features with pathogenic variants in different genes can make attribution of a precise diagnostic label challenging. In addition, different variants in the same gene can result in different clinical phenotypes, with one patient having NS and another CFC.
COMPLICATIONS — The number and frequency of associated complications reported for NS indicate that greater health surveillance is warranted. A number of guidelines or care pathways for NS have been published [17,18]. Although the detail of these varies with health systems, the key and common recommendations are similar and summarized in the table (table 3). The management of the complications seen in patients with NS, when they occur, is the same as for the general population and is discussed in greater detail separately. (See appropriate disease-specific topic reviews.)
Cardiac — More than 80 percent of patients with NS have cardiac involvement [19], most often pulmonary valve stenosis (pulmonic stenosis). Atrial septal defects are also frequent, and 20 percent of patients overall have hypertrophic cardiomyopathy (HCM). More than one cardiac defect is present in most patients [20]. The electrocardiogram (ECG) is usually abnormal, with both right and left axis deviation common.
Atrial tachycardia is rare in NS, although it has occurred in patients with RAF1 pathogenic variants. Coronary artery atresia, ectasia, and aneurysms are all reported [21-24]. Aortic root dilatation was observed in 5 percent of patients in one series, although it did not require intervention [25]. A retrospective study of 37 NS patients, 16 with a known variant, mostly PTPN11, demonstrated dilatation of the aortic root and annulus but not the sinotubular junction and ascending aorta [25]. This appeared to slowly increase over time. The aortic root was aneurysmal in 21 percent overall, but the natural history and the optimal management of this risk are unknown.
Patients with NS and HCM have a high incidence of concomitant congenital heart disease (CHD), a high rate of presentation in the first year of life (57 percent), and a 15 percent mortality if diagnosed in infancy. Despite this, however, there was a spontaneous regression of HCM in 17 percent of patients who presented early in life. The incidence of HCM is higher in NS due to RAF1 or Ras-like without CAAX 1 (RIT1) variants. In addition, pediatric-onset dilated cardiomyopathy [26] and pulmonary arterial hypertension [27] have both been described in NS due to RAF1 variants.
Patients with pathogenic variants in RAF1 or RIT1 can present with severe neonatal cardiomyopathy [27,28], and, in this clinical situation, urgent RASopathy gene testing is advised. The potential therapeutic benefit of this testing is illustrated by individual reports of clinical responses to a rapamycin analog, everolimus, in an infant with severe HCM and the Q510E RAF1 variant [29] and trametinib, a MEK inhibitor, in two infants with RIT1 S35T and F82L, respectively.
Although management is similar to that in the general population, patients with NS and pulmonic stenosis in one large retrospective study had a higher reintervention rate after percutaneous balloon pulmonary valvuloplasty than non-NS patients due to the dysplastic nature of the valve [20].
Endocrine — NS-specific growth charts are available [30], but their utility is disputed due to the differential degrees of short stature observed across the various genes mutated in NS. Average final height for males with NS is 169.2 cm (range 153 to 188.7) and for females 154.4 (range 146.1 to 167.8), without growth hormone treatment, in comparison to mean heights in the general European-origin population of 177 cm for males and 164 cm for females [31]. Growth retardation is more common in patients with NS-associated PTPN11 pathogenic variants than in NS patients with SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1) variants [32]. The pubertal growth spurt is frequently delayed or absent, and bone age is also delayed. Thus, there is still growth potential extending well into the third decade of life. As such, children below the 50th centile for height on an NS-specific growth chart or with decelerating growth rate should be referred to endocrinology for evaluation.
Growth hormone (GH) deficiency has been observed in patients with NS, particularly in those with SHOC2, leucine rich repeat scaffold protein (SHOC2) pathogenic variants. Despite concerns regarding the risk of exacerbation of HCM or tumor formation, GH therapy appears safe in NS [31] and is of clear benefit in those who are GH deficient. However, GH resistance is more common than deficiency, and the benefits of GH administration in these patients may be more marginal.
Thyroid status should also be checked in patients with NS since autoimmune thyroiditis, which can manifest as short stature/failure to thrive, is relatively common. Screening of thyroid function (and thyroid autoantibodies) is recommended every three years or sooner if there is any clinical concern.
Neurodevelopment and behavior — Patients with NS can have a number of different neurodevelopmental problems including developmental delay, executive function deficits, mild intellectual disability, autism spectrum disorder, and attention deficit hyperactivity disorder. Structural brain anomalies, seizures, moyamoya angiopathy, and hypertrophic neuropathy are also reported. Routine neurodevelopmental surveillance is recommended for children with NS. Whilst routine magnetic resonance imaging (MRI) is not universally recommended, there should be a low threshold for performing this in patients with significant neurodevelopmental delay, seizures, gain in centile of head circumference, or other concern. There are not data to suggest that neurodevelopmental abnormalities identified in NS should be managed differently from similar features occurring in the general population.
Gross motor milestones and expressive (more so than receptive) language skills are delayed in some patients with NS [2,33]. Increased mean ages of several developmental milestones were observed in one study of 151 patients with NS, including sitting at 11 months, walking at 21 months, and use of simple, two-word sentences at 31 months [2] compared with normal milestones of 6 to 7 months for sitting, 15 months for walking well alone, and use of two-word phrases by 24 months.
However, early milestones are normal in many children with NS, and any developmental differences that are present are relatively subtle and may not manifest until school entry or later childhood. There is a correlation between significant feeding difficulty and later, more significant developmental delay [33]. Motor skills remain impaired across childhood, with an impact on fine motor skills and coordination. A significant impairment in motor strength, performance, and endurance has been demonstrated [34] and widely reported anecdotally, along with significant muscle pain. These problems remain unexplained.
Intelligence quotient (IQ) tends to be mildly lowered in children with NS, with most individuals functioning in the average range, albeit often with a pattern that is inconsistent across domains [33]. In childhood, visual processing abilities and visual-motor integration are often impaired. Language and articulation are frequently impaired in school-age children and may be worsened by hearing loss. Impairments in pragmatic language (social language skills) are common but do not show a consistent pattern [35].
For both adults and children, difficulties with everyday tasks that rely on executive functioning are reported, particularly those requiring working memory or self-monitoring. Social skills competence is also decreased [33]. Although the need for special schooling in children with NS is uncommon, detailed neuropsychological testing has demonstrated a considerable educational and behavioral morbidity. In children with molecularly proven NS, there are high rates of autistic spectrum disorder and attention deficit hyperactivity disorder [33,36,37].
Overall, adults with NS tend to have milder cognitive deficits than children and function in a way comparable with other adults with similar educational attainment [38]. Although some general conclusions can be drawn on the influence of genotype on intellectual phenotype, for all genes, a broad range of intellectual abilities has been observed for all NS-associated genes.
The incidence of structural brain abnormalities is unclear [33]. Chiari malformation and hydrocephalus have been reported [33]. Seizures occur in 13 percent of patients [30] and may have multiple subtypes. Moyamoya angiopathy has been described in a number of children with NS [39,40], including as the presenting feature in two individuals with pathogenic variants in CBL identified on exome sequencing [41]. Subtle signs of a RASopathy were found in these patients retrospectively. There are also reports of hypertrophic neuropathy, similar to that seen in patients with neurofibromatosis type 1, in patients with pathogenic variants in NS-associated genes [42].
Hematologic — A variety of hematologic manifestations are associated with NS, including myeloproliferative disorders such as juvenile myelomonocytic leukemia (JMML) (see 'Malignancy' below). Hepatosplenomegaly, which may resolve spontaneously, is occasionally seen in patients with NS without other evidence of myeloproliferative disease. A subset of patients with NS have autoimmune disease. Systemic lupus erythematosus has been diagnosed in NS patients, particularly those with SHOC2 variants, and a variety of other autoimmune diseases may also be overrepresented in this patient group [43]. Autoimmune thyroiditis is more common than in the general population.
Easy bruising is common, most characteristically in those with PTPN11 variants [13]. An increased bleeding tendency has also been observed. The bleeding diathesis was moderate in 39 percent of patients and severe in 18 percent in one small series [44]. Partial factor VII deficiency was found in some of these patients, along with deficiency of other vitamin K dependent factors, abnormalities of coagulation, and defects in platelet function, aggregation, and secretion. Coagulation and platelet function tests are recommended in patients with a suspected bleeding diathesis or prior to surgery. While a complete blood count (CBC) every three months has been suggested for patients with a high risk of JMML, the exact risk is hard to determine, even with variants described in association with JMML, and the risk of symptomatic interval presentation remains. It may be preferable to educate caregivers and primary clinicians regarding the risk of JMML and presenting features and suggest a low threshold for checking CBC in the event of any concern.
Lymphatic — Lymphedema may present at any age in NS. Some of the physical manifestations such as neck webbing and ptosis may result from edema in utero. A specific lymphedema phenotype, consisting of childhood or adult onset of bilateral lower limb edema, genital edema, and chylous reflux with lymphorrhea, has been identified [45]. Systemic involvement, such as chylothoraces or intestinal lymphangiectasia, is frequent and may be progressive. Chylous reflux is an underlying mechanism.
Management of lymphedema is standard, with physical measures and dietary modification for systemic manifestations. Vulvar lymphangiectasia can be managed surgically [45].
Kidney — A variety of kidney anomalies have been described in association with NS. Kidney pelviectasis is commonly observed in fetuses on pregnancy scans performed at 20 weeks and may resolve spontaneously. Kidney ectopia and structural anomalies are also commonly seen [2]. Thus, kidney ultrasound after diagnosis is indicated postnatally.
Skin — Dry skin (xerosis) is more common in NS than the general population and can be managed with standard advice regarding emollients and avoidance of exacerbating factors. Nevi and lentigines can be a progressive feature of NS with increasing age, but these appear to be of low malignant potential and can be managed as are similar lesions occurring in the general population.
Ophthalmic — Refractive errors occur in most NS patients, with strabismus, hypermetropia, and astigmatism all reported [13]. In addition to the common extraocular manifestations of NS, such as hypertelorism, ptosis, downslanting palpebral fissures, and epicanthic folds, anterior segment abnormalities and optic nerve hypoplasia have been reported [46,47]. Routine optometric screening and provision of appropriate glasses for refraction as per standard ophthalmic care for children and adults are recommended.
Audiologic — Deafness is more common in NS than the general population. It may be sensorineural, conductive, or mixed and of any severity, including severe-profound sensorineural hearing loss [48]. Successful cochlear implantation has been reported [49]. Far more common are recurrent otitis media and eustachian tube dysfunction leading to conductive hearing loss.
Malignancy — Malignancy risk in NS appears increased compared with the general population. A relative risk of 8.1 (95% CI 3.5-16) was observed across childhood in one population-based study [50]. An increased relative risk of malignancy in adulthood has not been confirmed. Much of the increase in risk in childhood is attributable to the high frequency of JMML. Increased risks for brain tumors, acute lymphoblastic leukemias, and neuroblastomas have also been described [50,51], as well as individual instances of other unusual malignancies [50]. In keeping with the prevalence of PTPN11 variants, most NS-associated malignancies have been recorded in patients with pathogenic variants in this gene, but embryonal rhabdomyosarcoma has been recorded in several patients with SOS1-associated NS [52] and neuroblastoma in multiple patients with SHOC2 variants [53]. KRAS variants are a rare cause of NS/RASopathy diagnosis but may be associated with a high risk of certain malignancies, with a case of astrocytoma and a case of JMML identified in the German population study [50]. Given the overall low incidence of malignancy and the wide range of different tumors for which risk may be modestly elevated, no routine screening investigations are recommended.
In patients with NS, a myeloproliferative disorder resembling JMML may follow a more indolent course [54]. This disorder may be congenital or develop in infants or young children, is polyclonal, and usually resolves without treatment. The estimated incidence is 10 percent. This indolent pattern is frequently seen in patients with an underlying CBL variant, particularly Y371H. However, aggressive disease, resembling sporadic JMML, may arise as a progression from an initially indolent state [54,55]. Pathogenic variants in codon 61 or T73I of PTPN11 or KRAS T58I are associated with a higher risk of progression. Surveillance, consisting of a physical examination including for splenomegaly and CBC with differential white cell count every three to six months until age five years, is suggested for patients with these variants or a CBL variant [55].
The rather nonspecific phenotype that is associated with CBL variants in particular means that children with a hematologic malignancy should be assessed for an underlying RASopathy, with particular attention paid to development, birth weight, facial features, head circumference, and skin [56]. In addition, gene testing for RASopathies is warranted in any child presenting with JMML or a JMML-like disorder given the more favorable prognosis in the presence of a CBL variant.
Although JMML risk appears higher for certain pathogenic variants, a low threshold for investigating possible malignancy-related symptoms such as pallor, onset of spontaneous bruising, or malaise is recommended in all patients with NS. However, routine surveillance in patients without malignancy-related symptoms is not suggested.
Orthopedic — A variety of orthopedic complications have been described in association with NS, such as talipes equinovarus (clubfoot, seen in 5 percent) and sequelae of small joint hypermobility. A pectus deformity, particularly pectus excavatum, is commonly present to some degree but is rarely severe enough to warrant intervention. Surgical management is usually reserved for those with respiratory compromise. Similarly, scoliosis is commonly seen to a mild degree, but only a proportion will require intervention [17].
Dental and oral — Dental and oral anomalies such as malocclusion and abnormalities of tooth number or morphology are common in NS [57]. These are all managed as for persons in the general population, and routine dental follow-up protocols are appropriate. Nonmalignant giant cell lesions of the jaw are a rare but known association in NS and require expert evaluation and management [13].
Surgical and anesthetic considerations — The cardiac and vascular abnormalities described in NS, together with the risk of hemodynamically significant HCM and CHD, and the bleeding tendency are important considerations in the setting of anesthesia and surgery. Airway issues may also arise for patients with craniofacial (eg, micrognathia or craniosynostosis) or cervical (eg, scoliosis) anomalies [58]. Preoperative assessment of clotting function is advised in patients with NS prior to surgical procedures. (See 'Cardiac' above and 'Hematologic' above and 'Orthopedic' above and 'Dental and oral' above.)
PROGNOSIS — The severity of NS varies widely, from presentations that are lethal prenatally to mildly affected persons with a normal lifespan and minimal morbidity. Despite frequent developmental difficulties, the majority of persons with NS are able to attend mainstream school, function within the normal range as adults, and perform a variety of roles in the community.
In the absence of a large longitudinal study, reliable information about long-term morbidity and mortality is lacking. Mortality was relatively low in one multicenter retrospective study of cardiac disease [19]. The highest risk of cardiac death was in young adults with hypertrophic cardiomyopathy (HCM) diagnosed under the age of two years, with biventricular obstruction a further indicator of poor prognosis.
SUMMARY AND RECOMMENDATIONS
●Clinical features – Noonan syndrome (NS) is a clinically and genetically heterogenous autosomal-dominant disorder. The classical features include short stature and congenital heart disease (CHD). However, the clinical features of NS can affect all body systems, and a subtle constellation of clinical signs and symptoms may be observed. These include difficulties with feeding in early life; vision, hearing, and growth problems; specific learning difficulties; and easy bruising and bleeding. (See 'Genetics' above and 'Clinical manifestations' above.)
●Diagnosis – The diagnosis of NS often can be made on clinical features alone (table 2). However, achieving a correct diagnosis is increasingly important, given the emerging therapeutic implications and the need for increased health surveillance across the lifespan for people with NS. Thus, molecular testing is usually attempted to confirm the clinical diagnosis and is indicated in many different clinical contexts (table 1). (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis for individual presentations consistent with NS is broad and includes other disorders of the Ras-mitogen-activated protein kinase (MAPK) pathway (figure 1) and other chromosomal abnormalities. (See 'Differential diagnosis' above.)
●Management – Management of the complications that can occur in patients with NS is the same as for such complications occurring in the general population (see appropriate disease-specific topic reviews). However, greater health surveillance is warranted given the number and frequency of complications reported for NS (table 3). (See 'Complications' above.)
●Prognosis – The severity of NS varies widely, from presentations that are lethal prenatally to mildly affected persons with a normal lifespan and minimal morbidity. Despite frequent developmental difficulties, the majority of persons with NS are able to attend mainstream school and function within the normal range as adults. (See 'Prognosis' above.)
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