Noonan syndrome (NS) is an autosomal-dominant genetic disorder characterized by a distinctive phenotypic triad: craniofacial dysmorphic features resulting in a distinctive facial phenotype, congenital heart disease and short stature.1 First described by Dr Jacqueline Noonan more than 50 years ago, it is a relatively frequent disorder with an estimated incidence of 1 in 1000 to 2500 live births. Since 2001, it is known that mutations in genes that encode proteins involved in the intracellular RAS-MAPK (Mitogen Activated Protein Kinases) signalling pathway are responsible for NS and other genetic disorders with similar phenotypes, such as Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines (NS-ML, formerly known as LEOPARD syndrome) or la neurofibromatosis type 1. Due to the overlap in phenotypic characteristics and the underlying molecular mechanisms of these diseases, they have been grouped under the label of “neurocardiofaciocutaneous syndromes” or, more generally, “RASopathies”.

Our aim was to synthesise the current evidence on this disease and propose guidelines for the follow-up of these patients from infancy to adulthood.

Noonan syndrome is characterised by multisystemic involvement, a broad phenotypic heterogeneity and a variable clinical presentation.

It is characterised by a distinctive facies that changes with age, with more striking features in children that become less prominent in adulthood.2 The characteristics features are a triangular face shape (broadened forehead with narrowing down toward the chin), low-set posteriorly rotated ears with a thick helix (90%), downslanting palpebral fissures (95%), hypertelorism, ptosis, strongly arched diamond shaped brows, usually blue or blue-green irises, nose with a flattened bridge and bulbous tip, a long and deep philtrum, wide peaks in upper lip (Cupid’s bow appearance), short neck, and low posterior hairline shaped like a W (55%) (Fig. 1). Infants may exhibit webbing of the neck.

Figure 1.

Drawing illustrating the typical facial features of Noonan syndrome.

(0.07MB).

Cardiac involvement is one of the main clinical features of NS. The prevalence of cardiovascular abnormalities is estimated at 70%–80% of cases,1,3 although prenatal diagnosis is rare. A wide spectrum of abnormalities has been described, the most frequent being pulmonary stenosis, commonly associated with valve dysplasia (50%–60%), hypertrophic cardiomyopathy (20%)4, usually detected early in life,5 atrial septal defects (6%–10%) and ventricular septal defects, pulmonary artery branch stenosis, anomalies in the mitral valve or coronary arteries, coarctation of the aorta and, less frequently, tetralogy of Fallot and patent ductus arteriosus.

The literature also describes electrocardiographic abnormalities in these patients (50%).6 Frequently, these involve wide QRS intervals with a predominantly negative pattern in the left precordial leads and left axis deviation with giant Q waves, even in the absence of structural cardiac abnormalities. Arrythmias are infrequent.7

Prenatal growth is not usually affected, although there is a higher prevalence of small for gestational age compared to the general population.8

Children with NS exhibit a pattern of postnatal growth retardation characterised by a prepubertal growth in the 3rd percentile, delayed onset of puberty with attenuated growth spurts and an adult height approximately 2 standard deviations (SD) below the mean. Delayed puberty is common, with a mean age at onset of 13.4 years (10.8–16.4 years) in boys and 13 years (10.9–15 years) in girls. There is a mean delay in bone age of 2 years. Specific growth charts for children with NS have been developed,9 but none of them have been developed in the Spanish population.

Some authors have found hormone profiles suggestive of growth hormone deficiency in patients with NS, with decreased levels of insulin‐like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP-3) and responses to stimulation with growth hormone in the upper limit.10 Other studies suggest that hyperactivation of RAS-MAPK could affect chondrocyte differentiation during bone growth through an IGF1-independent mechanism.11

In the neonatal period, infants with NS exhibit difficulty feeding with weak sucking, prolonged duration of feedings and sporadic episodes of nausea and vomiting, in some cases requiring nasogastric tube feeding (25%), and gastroesophageal reflux. These symptoms usually improve or resolve completely by age 15 months.12,13

Several studies have described a tendency toward a low body weight not only in the first years of life, but through the lifespan. An animal model with the genetic variant p.Thr468Met (characteristic of NS-ML) with a metabolic phenotype characterised by defective adipogenesis, enhanced energy expenditure and mitochondrial activity, enhanced insulin sensitivity and resistance to the effects of an obesogenic diet.14 The implications of these findings are unclear, although future research will likely uncover further information on these disturbances in energy homeostasis.

Cryptorchidism has been described in 60%–80% of male patients with NS.12 Several studies have reported elevated levels of luteinising hormone (LH) and follicle-stimulating hormone (FSH) and decreased levels of inhibin B and anti-Müllerian hormone (AMH) in patients with NS compared to the general population, with a high prevalence of a hormone pattern suggestive of Sertoli cell dysfunction both in patients with cryptorchidism and patient without it.15 This hypothesis is further supported by the critical role played by Src-homology 2 domain-containing tyrosine phosphatase 2 (SHP2) in maintaining Sertoli cell function. The literature also describes a higher frequency of infertility in male patients with NS.

In contrast, it appears that women with NS have normal fertility (which would explain why maternal transmission predominates in familial cases).

Renal abnormalities are present in 10% of cases (duplex collecting system, solitary kidney, pyeloureteral stenosis and renal pelvis dilation).16

Most studies have found a higher incidence of autoimmune thyroiditis compared to the general population,13 although with levels similar to or slightly above subclinical hypothyroidism.17 Other features described in the literature include coeliac disease, systemic lupus erythematosus, vitiligo and anterior uveitis.

Chest deformities (with pectus excavatum inferiorly and pectus carinatum superiorly) occur in 70%–95% of cases, possibly accompanied by wide-spaced nipples, cubitus valgus, genu valgum,18 scoliosis (10%–15%) or other less frequent deformities of the spine, such as kyphosis, spina bifida or malformations of vertebrae or ribs. There is redundant skin in the neck and a prominent trapezius. Joint hypermobility is also common.13

There is evidence that the overall bone mineral density in children with NS is lower compared to controls matched for age, sex, height and ethnicity. However, the incidence of childhood fractures does not appear to be higher compared to the general population. The incidence of fractures in adults with NS is unknown, and therefore the clinical relevance of these findings is unclear and needs to be established through performance of longitudinal studies. Histomorphometric analysis of bone tissue from NS patients and mouse models of NS may further elucidate the relationship between the RAS-MAPK pathway and skeletal homeostasis.19

A tendency to develop bruises and bleeding is frequent, especially in childhood, although severe haemorrhage is rare (3%). Some of the haemostatic abnormalities in NS described in the literature are bleeding diathesis, factors VIII, XI and XII deficiency, low platelet count and platelet function defects, in isolation or combined.20 In many cases, there is no association between the results of coagulation tests and bleeding diathesis.

As is the case of all RASopathies, NS carries an increased risk of blood cancers and solid tumours that is actually estimated to be 8.1 times greater (95% confidence interval [CI], 3.5–16) compared to the general population.21 The most frequent malignancies are gliomas (dysembryoplastic neuroepithelial tumours), acute lymphoblastic leukaemia, neuroblastoma and rhabdomyosarcoma. Substitutions in codon 61 and substitution 218C > T (p.Thr73Ile) in the PTPN11 gene, the p.Thr58Ile variant of the KRAS gene and mutations in the CBL gene are associated with a higher incidence of juvenile myelomonocytic leukaemia (JMML), a severe myeloproliferative disorder.22 Cases of JMML tend to have an early onset and a benign course, and there are reports of spontaneous resolution in the literature. However, a recent study documented a mortality greater than expected in NS attributable to severe JMML in the neonatal period,23 which suggests that JMML may go undetected in this age group due to the fatal outcome of these cases.

Cognitive functioning is within the range of normality in up to 80% of cases, 24 with an intelligence quotient ranging from 70 to 120.2,25 There have been reports of deficiencies in the ability to identify and verbally express emotions (alexithymia). Other psychiatric disorders described in these patients include mood disorders, difficulties with communication and interpersonal interaction and attention-deficit hyperactivity disorder.13 Language impairments are more frequent in children with NS compared to the general population and, when present, are associated with an increased risk of reading and spelling difficulties.24

Frequently described features include a high-arched palate (55%–100%), dental malocclusion (50%–67%), temporo-mandibular joint problems (72%) and micrognathia. There have been reports of class II malocclusion and an increased incidence of open bite and posterior crossbite compared to the general population. There may also be multiple unerupted permanent teeth, submerged deciduous teeth and supernumerary teeth.26 Multiple giant cell lesions are infrequent, but highly suggestive of NS.

Lymphoedema occurs in fewer than 20% of cases, but when present causes significant morbidity. Peripheral lymphoedema may be present as early as birth (palms and soles) and resolve in the early years of life.27 Other, less frequent lymphatic abnormalities may include hydrops fetalis, pulmonary, intestinal or testicular lymphangiectasia, chylothorax or chylous ascites, hypoplastic inguinal and iliac lymphatic vessels, absent or atretic thoracic duct or localised lymphoedema in the scrotum or vulva.16,28

Patients with NS may present with pigmented nevi (25%), café au lait spots (10%) and lentigines. Keratosis pilaris is common (in the upper arms), and in cases in which it affects the face, the eyebrows may be absent.29 The skin is hyperelastic, the hair thick and curly and the nails dystrophic. Foetal pads on fingers and toes are common (67%).13

Ocular abnormalities are frequent (95%): strabismus (40%–65%), refractive errors (60%), amblyopia (33%) or nystagmus (10%). Anterior segments may occur (60%), including cataracts. Other possible ocular abnormalities are optic nerve head or disc drusen (20%), optic nerve hypoplasia and coloboma.13,30 Hearing loss secondary to otitis media is a frequent complication (15%–40%). Sensorineural hearing loss is less frequent.31 There have been descriptions of vestibular anomalies and structural anomalies of the inner ear in some cases.

Long-term data are scarce. There is evidence that feeding difficulties in infancy could be an early predictor of future language delay. One study found that one third of adults with NS had attended a school for children with learning disabilities and 20% a conventional school while receiving academic support. Forty-three percent of participants in the study had achieved an educational certification (lower level secondary general education certificate or higher). The reported data on health-related quality of life has shown no difference relative to the general population.32

Adults with NS require long-term cardiological follow-up. An absence of symptoms, a normal cardiac output and pulmonary arterial blood pressure and a right ventricular pressure of less than 100 mmHg are associated with a good prognosis.33 The mortality associated to hypertrophic cardiomyopathy is the same in patients with NS and patients without NS. The mortality was 9% at a mean age of 60 years.15

To date, mutations in more than 20 genes have been described in association with NS, the RASopathy with the greatest known locus heterogeneity. Yet, the RASopathies are monogenic disorders and only rare cases have been reported where patients had mutations in more than 1 gene. Table 1 presents the genes currently known to be involved in NS. Given the growing number of identified genes and how many laboratories have the capability for massive gene sequencing, efforts must be made to confirm the role of identified genes and each of the variants identified for each gene. The RASopathy Expert Panel of the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health of the United States, has recently published a guideline for the interpretation of 19 genes involved in RASopathies34 that also provides a classification of the strength of the clinical and experimental evidence available on the different variants and the correlated phenotypes.

There are multiple descriptions of genotype-phenotype correlations in NS in the literature, although there are no exclusive phenotypic features of any given genotype, probably due to genetic and epigenetic factors that influence penetrance and expressivity. Table 2 presents a brief description some of the most widely accepted genotype-phenotype correlations.

While the notion of a strong correlation between a given gene and a specific phenotype is appealing from a theoretical perspective, clinical experience suggests that reality is far more complex. For this reason, the classification of RASopathies based on clinical features currently continues to be favoured over a classification based on the involved genes.

Despite advances in molecular testing, NS is diagnosed essentially based on clinical features, and an underlying genetic mutation is not identified in 20%–30% of patients. The variability in its phenotypic expression, the overlap with other diseases and the changes in phenotype that take place with age pose a significant challenge in its diagnosis, especially in the first year of life. The diagnostic criteria that are now universally accepted were first developed by van der Burgt in 1994 and revised in 2007 (Table 3).29

The differential diagnosis must include other RASopathies as well as other syndromes unrelated to the RAS-MAPK pathway, such as Aarskog syndrome, Turner syndrome, Baraitser-Winter syndrome and actinopathies. While other RASopathies must be considered in the differential diagnosis, they are much less prevalent than NS with the exception of neurofibromatosis type 1.

It is important that the different specialists potentially involved in the management of these patients be knowledgeable of the clinical features and potential complications associated with NS. Having a physician in charge of coordinating the care delivered by different specialists is helpful. This role could be assigned to the clinical geneticist or otherwise any other physician (primary care paediatrician, endocrinologist or cardiologist) that is particularly involved in the management of the patient, and the aim is to ensure that the multiple aspects that require care and follow-up are being covered. Table 49,28,29 offers a summary of the recommendations for management of patients with NS by age group.

In patients with a positive genetic test, we recommend that clinicians periodically obtain updated information on the clinical manifestations associated with the specific variant, especially in case of rare mutations, consulting with an expert clinical geneticist as needed.

Lastly, in patients with RASopathies other than NS or patients with NS associated with uncommon mutations, consider follow-up in multidisciplinary units with experience in these diseases.

One of the options for symptomatic treatment of NS is recombinant human growth hormone (rhGH). Its use for this indication was approved by the United States Food and Drug Administration in 2007, and more recently by the European Medicines Agency (https://mri.cts-mrp.eu/Human/Product/Details/14639), and the Spanish Agency for Medicines and Medical Devices (Agencia Española de Medicamentos y Productos Sanitarios, AEMPS) (https://cima.aemps.es/cima/dochtml/ft/62977/FT_62977.html). However, we ought to highlight that no randomised clinical trials with follow-up through achievement of final height have been published to date.

T studies in the literature are difficult to compare due to the heterogeneity of the methodologies used, patient ages, dosage and duration of treatment. Overall, they have reported a significant increase in final height z-score of 1.4 ± 0.8 (corresponding to 9.5 ± 5.4 cm),35–38 although some studies reported significantly more modest increases (Table 5). Most studies have found better outcomes the longer the duration of treatment in the prepubertal period. Consistently with the hypothesis that growth impairment in NS is due to growth hormone resistance, some studies have reported poor responses in patients with a mutation in the PTPN11 gene,35 although other studies have not corroborated this result.37 While growth hormone deficiency has been described in some patients with NS, this does not seem to be the main reason for growth impairment in these patients, with the exception of those with a SHOC2 mutation, who frequently have this deficiency. When it comes to dosage, recent studies have found an improved short-term response at higher doses,37 although there are no data on long-term safety and efficacy. In short, the following are reasonable recommendations based on the current medical literature:

• none-

  Independently of the conditions established for the indication for treatment once it is approved, the decision to use rhGH in patients with NS should be made on a case-by-case basis. Factors to be taken into account include the height, age (early initiation is preferred to maximise prepubertal linear growth), the presence of comorbidities (hypertrophic cardiomyopathy is not a contraindication but would require rigorous cardiological follow-up; scoliosis would require close monitoring as it could worsen during treatment; nutrition should be assessed and energy intake deficits resolved before initiation of treatment, and in case of clinical features compatible with growth hormone deficiency, evaluation of the somatotropic axis should be considered) and the genotype (in patients with variants associated with a high risk of cancer, the use of rhGH should be considered with utmost caution and, if initiated, requires close monitoring).

• none-

  The recommended initial dose is 33 μg/kg/day (to be increased to up to 66 μg/kg/day in case of poor response), and especial attention should be paid to IGF1 levels, carbohydrate metabolism and other possible adverse events. If the patient exhibits a poor response despite 1–2 years of treatment at high doses, consider discontinuation of treatment, as the peak response should occur in the early years of treatment. Patients with a clinical diagnosis with negative genetic test results should be considered eligible for treatment, although in these cases assessment by a clinical geneticist with experience in the RASopathies is recommended, as is the maintenance of a watchful and critical attitude throughout treatment.

Strategies aimed at decreasing activity in the RAS-MAPK pathway have attracted considerable attention, with of preclinical trials showing favourable results. Off-label use of trametinib in 2 patients with severe hypertrophic cardiomyopathy in the transplant waiting list succeeded in resolving the myocardial involvement nearly in full.39 Inhibition of the PI3/AKT/mTOR cascade with rapamycin has been proven to improve cardiac involvement in animal models of NS-ML, and the drug was effective in a critically ill patient.40

It has also been hypothesised that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (known as statins) could be useful by inhibiting RAS farnesylation and its localization to the plasma membrane. An animal model of the use of statins in NS found increases in growth by improving chondrocyte differentiation,11 and a phase 3 clinical trial is currently underway to evaluate the efficacy of statins in improving growth in NS (ClinicalTrials.gov identifier NCT02713945).

Noonan syndrome is a disease with substantial heterogeneity in its clinical manifestation and underlying genetics, requiring a multidisciplinary approach to management and regular follow-up. This article presents guidelines for the follow-up of patients with NS based on the current literature. The recent authorization by the AEMPS of the use of rhGH for treatment of short stature in patients with NS adds a symptomatic treatment tool that did not use to be available in Spain.

In recent decades, advances in gene sequencing techniques have allowed the identification of the genetic cause of NS in most patients and allowed the development of many preclinical studies focused on the identification of potential therapeutic targets in these patients. Hopefully, these studies will allow the development in upcoming years of gene-targeted therapies to treat NS and other RASopathies.

The authors have no conflicts of interest to declare.