Noonan syndrome is an autosomal dominant genetic condition characterized by distinctive facial features, short stature, cardiac defects, coagulopathy, skeletal abnormalities, and normal to mild cognitive impairment. In most affected individuals, it is a result of mutations in one or more of the following genes: PTPN11, SOS1, KRAS, BRAF, NRAS, RAF1, MEK1.
Presentation
Individuals with Noonan syndrome have abnormal facial features, congenital heart disease, short stature, and chest deformity [1]. Skeletal, genitourinary, neurologic, lymphatic, and eye findings may also be present. Abnormal facial features include a deep groove in the area between the mouth and nose (philtrum), widely spaced eyes that are strikingly blue or blue-green in color, low-set ears, and short, and webbed neck [2]. Coagulation disorders are present in half of people with Noonan syndrome; affected individuals may report excessive bruising, nosebleeds, or excessive bleeding upon an injury or surgery. Less often, women with Noonan syndrome will present with menorrhagia (excessive bleeding) during menstruation [3]. Cryptorchidism (undescended testes) and infertility in males have been associated with Noonan syndrome. Affected individuals may have cognitive impairment. Cognitive impairment may include low to average intelligence, slower processing speed, deficits in language skills, impaired memory and attention deficits [4].
Entire Body System
- Pulmonary Valve Stenosis
The most common cardiac conditions are pulmonary valve stenosis and hypertrophic cardiomyopathy. [symptoma.com]
STENOSIS), and some degree of INTELLECTUAL DISABILITY. [profiles.umassmed.edu]
Definición: A multifaceted disorder characterized by short stature, webbed neck, ptosis, skeletal malformations, hypertelorism, hormonal imbalance, CRYPTORCHIDISM, multiple cardiac abnormalities (most commonly including PULMONARY VALVE STENOSIS ), and [hon.ch]
Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most prevalent cardiovascular abnormalities. We report on a 14-year-old girl with NS due to SOS1 mutation with pulmonary stenosis and idiopathic coronary ectasia. [ncbi.nlm.nih.gov]
- Developmental Delay
More key diagnostic factors Other diagnostic factors abnormalities identified antenatally chest deformity developmental delay/learning difficulty skeletal anomalies muscle weakness historyof renal malformation Other diagnostic factors Risk factors family [bestpractice.bmj.com]
This degree of developmental delay was atypical for an individual with Noonan syndrome, raising concerns for a chromosomal abnormality. Array-CGH showed an interstitial duplication of 10 Mb including the PTPN11 gene. [ncbi.nlm.nih.gov]
Noonan syndrome is a disorder that involves unusual facial characteristics, short stature, heart defects present at birth, bleeding problems, developmental delays, and malformations of the bones of the rib cage. [genome.gov]
It is characterized by congenital heart disease, short stature, a broad and webbed neck, sternal deformity, variable degree of developmental delay, cryptorchidism, increased bleeding tendency, and characteristic facial features that evolve with age. [aafp.org]
- Atrial Septal Defect
Noonan syndrome in patients with such mutations is more often associated with pulmonary stenosis or atrial septal defect, bleeding diathesis and juvenile myelomonocytic leukemia. [news-medical.net]
We report a child with Noonan syndrome status post pulmonary stenosis and atrial septal defect repair, who developed bilateral coronary artery aneurysms. [ncbi.nlm.nih.gov]
The principal features include congenital heart defect (typically pulmonary valve stenosis; also atrial septal defect and hypertrophic cardiomyopathy), short stature, learning problems, pectus excavatum, impaired blood clotting, and a characteristic configuration [dbpedia.org]
septal defect, ventricular septal defect, and patent ductus arteriosus.3,4 The incidence is estimated to be from 1 in 1000 to 1 in 2500.5,6 The diagnosis is made clinically, but there can be a spectrum of expression of the phenotype from mild to severe [jamanetwork.com]
- Lymphedema
Older individuals can also develop lymphedema, usually in the ankles and lower legs. [medicinenet.com]
Talipes equinovarus, radioulnar synostosis, cervical spine fusion, and joint contractures are less common findings. [13] Skin findings These include the following: Lymphedema (See the images below) Lymphedema of the feet in an infant is shown. [emedicine.medscape.com]
Noonan syndrome is less likely to have mental retardation and more likely to have lymphedema and cryptorchidism. LEOPARD syndrome: Also referred to as Noonan Syndrome with Multiple Lentigines (NSML). [pedclerk.bsd.uchicago.edu]
Noonan syndrome (NS) is characterized by short stature and elevated risk of lymphedema. The mechanism underlying lymphedema may be mediated by vascular endothelial growth factors (VEGFs). [ncbi.nlm.nih.gov]
- Multiple Congenital Anomalies
Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. [ncbi.nlm.nih.gov]
congenital anomalies and intellectual disability. [invitae.com]
Inheritance LEOPARD syndrome is an autosomal dominant multiple congenital anomaly syndrome, with high penetrance and markedly variable expression. [atlasgeneticsoncology.org]
Cardiovascular
- Heart Disease
The challenges faced during anesthetic management of patients with NS could be due to congenital heart diseases, hemostatic disorders, and airway anomalies. [ncbi.nlm.nih.gov]
Noonan syndrome PTPN11 SOS1 BRAF KRAS NRAS RAF1 SHOC2 Ras/MAPK signal transduction congenital heart disease short stature Accepted July 23, 2010. [pediatrics.aappublications.org]
Congenital heart disease occurs in 50% of individuals and the most common heart defects are pulmonary valve stenosis and hypertrophic cardiomyopathy. Additional heart diseases may more rarely be diagnosed. [angelinoonan.it]
Researchers find new drug compound that treats laboratory mice with congenital heart disease Congenital heart disease is the most common form of birth defect, affecting one out of every 125 babies, according to the National Institutes of Health. [news-medical.net]
A new syndrome with associated congenital heart disease. American Journal of Diseases of Children, Chicago, 1968, 116: 373-380. J. M. Opitz, P. D. Pallister: Brief historical note: the concept of gonadal dysgenesis. [whonamedit.com]
- Heart Murmur
murmur in the first few hours of life. [revespcardiol.org]
Echocardiography was performed due to heart murmur and patent ductus arteriosus and mild coarctation of aorta were found; during short follow-up the ductus closed spontaneously and the coarctation remained unchanged. [doi.org]
Many patients with this condition may not experience any symptoms at all, the only sign being a heart murmur on auscultation. [aboutkidshealth.ca]
For example, in mild asymptomatic cases of pulmonary stenosis, the condition may initially be suspected through the detection of an abnormal heart murmur during such stethoscopic evaluation. [rarediseases.org]
Fetus
- Hydrops Fetalis
Prenatal findings of polyhydramnios, hydrops fetalis and cystic hygroma in combination with an increased nuchal translucency have been found most frequently in NS [ 8 - 10 ]. [raredisorders.imedpub.com]
We describe an infant prenatally diagnosed with hydrops fetalis ultimately found to have Noonan syndrome (NS). [ncbi.nlm.nih.gov]
Antenatal presentation of an increased nuchal translucency, hydrothoraces or hydrops fetalis are common in these disorders and represent abnormalities in lymphatic development. [nature.com]
[…] resonance imaging of the brain) Ocular Dysmorphic findings, vision problems Detailed eye examination in infancy and/or at diagnosis — Eye reevaluation as indicated if abnormal or every two years thereafter Pregnancy Congenital heart defects, effusion, hydrops [aafp.org]
Eyes
- Antimongoloid Slant
These include a short, wide neck; ears set low and towards the rear, hypertelorism with antimongoloid slanting eyes, epicanthus, ptosis, retromicrognathia and a wide philtrum. [revespcardiol.org]
Both children had typical leonin facies (prominent eyes, anteverted nares, antimongoloid slant, depressed nasal bridge and posteriorly placed prominent ears), low hair line, short and webbed neck, shield chest, small widely placed nipples, cubitus valgus [indianpediatrics.net]
Apparent ocular hypertelorism and antimongoloid slant of the palpebral fissures, a deep philtrum, and mild retrognathia may also be present. [touchendocrinology.com]
We noted a facial dysmorphism associating a triangular facies with hypertelorism [Figure 1A], wide forhead, proeminent eyes with antimongoloid slant, long philtrum, large low-set and posteriorly rotated ears with a thickened helix [Figure 1B]. [amhsr.org]
- Blepharoptosis
Eyelid abnormalities such as ocular hypertelorism and blepharoptosis are the most commonly observed eye complications. We report a case of Noonan syndrome associated with mature cataract that required operation. [ncbi.nlm.nih.gov]
Lopez et al. reported a case of unilateral eyelid angiofibroma with complete blepharoptosis as the presenting sign of TSC [78]. [hindawi.com]
Ears
- Low-Set Posteriorly Rotated Ears
Patient 7 (male) presented with dysmorphic facies typical of CFC with low-set posteriorly rotated ears, and hypertelorism. [nature.com]
Definition A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic [uniprot.org]
The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, and low-set, posteriorly rotated ears. Cardiac involvement is present in up to 90% of patients. [flybase.org]
The typical facies is characterized by hypotelorism, down-slanting palpebral fissures (95%) with thick hooded eyelids, low set posteriorly rotated ears with a thick helix (90%), a deeply grooved philtrum with high arched palate of the upper lip vermilion [indianpediatrics.net]
Skin
- Pterygium Colli
colli), thoracic abnormalities, congenital heart defects and short stature, associated with a very frequent ocurrence of juvenile myelomonocytic leukemia. [orpha.net]
Background: Noonan syndrome is often described as a “Male Turner syndrome” presenting with pterygium colli, short stature, pectus excavatum, webbed neck, down-slanting palpebral fissures and eyelid ptosis, and congenital heart disease (most commonly, [mhaus.org]
Symptoms are variable and range from facial dysmorphia (broad forehead, hypertelorism, low ears and outward-sloping eyelid axis), proportionate short stature, pterygium colli, breast deformations, cryptorchidism, intellectual disability, a slight tendency [medical-genetics.de]
Breast
- Widely Spaced Nipples
[…] intermamillary distance Wide-spaced nipples Widely spaced nipples Widely-spaced nipples [ more ] 0006610 30%-79% of people have these symptoms Abnormal bleeding Bleeding tendency 0001892 Abnormal dermatoglyphics Abnormal fingerprints 0007477 Abnormal [rarediseases.info.nih.gov]
spaced eyes Depressed nasal bridge Down -slanting palpebral fissures Low set ears, posteriorly rotated High arched palate Misalignment of the teeth Micrognathia Short neck with webbing Low hairline on the neck Widely spaced nipples Pectus excavatum or [pedclerk.bsd.uchicago.edu]
Clinical phenotype (facial dysmorphism, soft hair, short neck, broad chest, widely spaced nipples, mild pectus carinatum, deep palmar creases, unilateral cryptorchidism), and moderate pulmonary valve stenosis with mild psychomotor delay were indicative [ncbi.nlm.nih.gov]
The chest is broad with widely spaced nipples and a specific chest shape which consists of pectus carinatum superiorly and pectus excavatum inferiorly. The hands show brachydactyly and persistence of fetal fingertip pads. [patient.info]
Thorax: Sternal deformities including pectus carinatum involving the superior sternum and pectus excavatum involving the inferior sternum.[5] Widely spaced nipples.[2] Cardiovascular: Classic finding is pulmonic stenosis often associated with dysplasia [eyewiki.aao.org]
Face, Head & Neck
- Hypertelorism
Patients classically have lentiginosis, ECG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. [pedclerk.bsd.uchicago.edu]
Facial features These include the following: Triangular-shaped face Hypertelorism Down-slanting palpebral fissures Ptosis Strabismus (48%) Amblyopia (33%) Refractive errors (61%) Low-set ears with thickened helices: In a study of 97 patients with Noonan [emedicine.medscape.com]
A genetically heterogeneous, multifaceted disorder characterized by short stature, webbed neck, ptosis, skeletal malformations, hypertelorism, hormonal imbalance, CRYPTORCHIDISM, multiple cardiac abnormalities (most commonly including PULMONARY VALVE [profiles.umassmed.edu]
Patients with Noonan syndrome also have a characteristic appearance: short neck, cervical skin fold, low set ears, hypertelorism. [asperbio.com]
Neonate and Infancy [ edit ] (age features are most striking) tall forehead hypertelorism with downslant palpebral fissures (95%) prominent eyes Nose has depressed root, wide base, bulbous tip Deeply grooved philtrum High wide peaks to vermillion border [en.wikibooks.org]
- Short Neck
Patients with Noonan syndrome also have a characteristic appearance: short neck, cervical skin fold, low set ears, hypertelorism. [asperbio.com]
Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. [uniprot.org]
Noonan syndrome is an autosomal, dominantly inherited disease; it is physically characterized by short stature, short neck, webbed neck, abnormal auricles, high arched palate, and cardiovascular malformation. [ncbi.nlm.nih.gov]
Neurologic
- Delayed Milestone
Delayed milestones (predicted by feeding difficulty). Average age to walk is 21 months. [pedclerk.bsd.uchicago.edu]
milestones Mean age sitting 10 mth, walking 21 mth, two-word sentence 31 mth 10-15 % require special ed IQ usually within normal range, but mild MR seen in 1/3 Verbal lower than nonverbal performance Usually good peer, social interactions and self-esteem [en.wikibooks.org]
Some children with Noonan syndrome can have delayed milestones or learning difficulties. However, when recognized early, they respond well to additional support. [aboutkidshealth.ca]
History revealed that the child had delayed milestones and had undergone cardiac surgery and a surgery in her anal region three years back. [jisppd.com]
- Average Intelligence
Cognitive impairment may include low to average intelligence, slower processing speed, deficits in language skills, impaired memory and attention deficits. [symptoma.com]
Urogenital
- Cryptorchidism
However, in our study, no difference in Sertoli cell markers was shown between cryptorchid and non-cryptorchid NS patients. [eje.bioscientifica.com]
Introduction Noonan syndrome is a relatively common autosomal dominant syndrome characterized by dysmorphic facial features, cardiac abnormalities, short stature, chest wall abnormalities, and cryptorchidism. [pedclerk.bsd.uchicago.edu]
Boys frequently present with cryptorchidism and manifest delayed puberty. Caused by activating mutations in multiple genes in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. The most commonly implicated gene is PTPN11. [bestpractice.bmj.com]
Other features All of the following: intellectual disability, cryptorchidism, and lymphatic vessel dysplasia One of the following: intellectual disability, cryptorchidism, or lymphatic vessel dysplasia Table 2. [aafp.org]
Noonan syndrome (NS) is a genetic condition presenting with typical facies, cardiac defects, short stature, variable developmental deficit, cryptorchidism, skeletal, and other abnormalities. [ncbi.nlm.nih.gov]
Workup
Workup for Noonan syndrome consists of a patient and family history, physical findings, confirmation of specific abnormalities associated with Noonan syndrome through radiological, laboratory, and genetic tests. A definitive diagnosis of individuals with the Noonan syndrome is achieved by genetic testing. Family history should be elicited for any immediate family members that have mild facial abnormalities and cardiac defects.
Physical findings commonly associated with Noonan syndrome include short stature, congenital heart defects (e.g., pulmonary valve stenosis, cardiac hypertrophy, atrial septal defect), broadened neck or webbed neck, either a protruding chest or pectus excavatum, low-set nipples, undescended testicles, abnormal facial characteristics (e.g., bright blue or green colored iris, wide-spaced eyes, low-set fleshy ears) [1]. Noonan syndrome should be considered in individuals with pulmonary valve stenosis, eye abnormalities (e.g., epicanthal folds, ptosis, ocular hypertelorism), and micrognathia [5]. Individuals with Noonan syndrome often may have either pectus excavatum or pectus carinatum. Scoliosis may also be present.
Occasionally the disorder will be diagnosed prenatally when there is an abnormal maternal serum triple screen, non-invasive prenatal testing, or prenatal ultrasound [6]. Ultrasound abnormalities associated with Noonan syndrome consist of polyhydramnios, cystic hygroma, anatomical cardiac abnormalities, and fetal musculoskeletal anomalies.
Most people with Noonan syndrome have congenital heart disease [7]. The most common cardiac conditions are pulmonary valve stenosis and hypertrophic cardiomyopathy. Tests that can be used to evaluate the heart include echocardiogram [8], cardiac catheterization (to examine the rate of cardiac blood flow and measure the pressure within the heart), and an electrocardiography to screen for electrical abnormalities or arrhythmias (e.g., left anterior hemiblock, left axis deviation).
Bleeding disorders have been associated with Noonan syndrome. Coagulation studies are used to screen for coagulation factor deficiencies and platelet dysfunction.
Genetic testing permits definitive diagnosis of Noonan syndrome [9]. Affected individuals will have normal chromosome studies. Mutations in the PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, or MEK1 genes are identified in two-thirds of people with Noonan syndrome [10] [7]. The clinician should keep in mind that not all patients with Noonan syndrome have a detectable alteration in one of these genes and therefore a failure to identify a mutation in one of the aforementioned genes does not exclude the diagnosis of Noonan syndrome.
Hypertrophy
- Ventricular Hypertrophy
[…] in LS differ from ventricular hypertrophy of other causes. [revespcardiol.org]
The phenotype includes a high frequency of high birth weight, relative macrocephaly, left ventricular hypertrophy, and ectodermal findings, such as curly hair, hyperpigmentation, and wrinkled palms and soles. [ncbi.nlm.nih.gov]
The child's medical reports indicated that the child had Noonan syndrome with severe pulmonary stenosis, moderate right ventricular hypertrophy and large ostium secundum atrial septal defect (ASD). [jisppd.com]
Signs of right ventricular hypertrophy were present in 13 patients and left ventricular hypertrophy in 5. [scielo.br]
Treatment
It has not been investigated whether they would benefit from a substitutive treatment and whether this treatment would influence the effect of GH treatment on final height. [frontiersin.org]
This case illustrates that diuretics treatment can be the first-line treatment of PLE regardless of the causative physiology, and can be effective in refractory PLE with Noonan syndrome. [ncbi.nlm.nih.gov]
Treatment focuses on the individual symptom, and may include surgery for undescended testes in boys, optimisation of cardiac function, and growth hormone treatment for short stature. The majority of patients lead normal lives. [bestpractice.bmj.com]
What is the treatment for Noonan syndrome? Some children with Noonan syndrome will benefit from treatment with growth hormone to help with their growth. [columbiadoctors.org]
Prognosis
Juvenile myelomonocytic leukemia (JMML) is a rare childhood neoplasm with poor prognosis except in the setting of Noonan syndrome, where prognosis is generally favorable. [ncbi.nlm.nih.gov]
Am J Med Genet A 2008; 146A: 620-628 Am J Cardiol 2007; 100:736-41 Noonan-LEOPARD Syndromes Genotype – Prognosis Correlations “PREDICTIVE MEDICINE” Gene-prognosis correlation 18. [slideshare.net]
However further studies are needed to determine overall long-term prognosis.[1] In terms of ocular prognosis, it appears that the severity of visual findings varies with an individual’s genetic variant. [eyewiki.aao.org]
Prognosis The prognosis is variable since the presentation ranges from mild/unrecognized manifestations in adulthood to severe disorder with life-threatening heart disease or malignancy in infancy. Severe cardiomyopathy may lead to early demise. [orpha.net]
Etiology
Noonan syndrome (NS) is an etiologically heterogeneous disorder caused by mutations in the RAS-MAPK signaling pathway. [ncbi.nlm.nih.gov]
Noonan syndrome is phenotypically and etiologically heterogeneous. Detecting specific mutations in a patient ensures the correct diagnosis and appropriate care. Reproduction options can also be considered when familial mutations are found. [cadth.ca]
Moreover, using phoshoproteomics we show hypo- and hypertyrosyl phosphorylation of Fer kinase and PZR (Protein zero related), respectively and study their roles as (potential) interacting proteins in the etiology of both NS and LS. [universiteitleiden.nl]
In that report I spoke in terms of a "new syndrome" in order to stress that this condition could affect not only males but also females, and that it was also clinically and etiologically different from the true Turner 6 syndrome. [doi.org]
Epidemiology
It is unknown whether the development or progression of tumors is augmented by GH therapy, however there is concern based on epidemiological, animal and in vitro studies. [ncbi.nlm.nih.gov]
Summary Epidemiology The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. [orpha.net]
Pathophysiology
While the underlying pathophysiologic mechanism of PIG is unclear, we suggest that the mitogen-activated protein kinase signal transduction pathway members (PTPN11, KRAS, SOS1, RAF1, SHOC2, NRAS) involved in cellular growth factor signaling, which are [ncbi.nlm.nih.gov]
The final chapter covers the critical area of treatment including prospects emerging from an improved understanding of the pathophysiology of these disorders. [bol.com]
Over the last decade, knowledge on clinical and genetic features and pathophysiologic backgrounds of Noonan syndrome has increased. [mdpi.com]
Although treatment algorithms are similar between LS patients with ventricular hypertrophy and patients with familial HCM, without an evidence-based diagnosis, despite their analogous character it is clear that the pathophysiology and dynamics of HCM [revespcardiol.org]
Prevention
For example, severe heart defects may need to be repaired with surgery, and growth hormone medication may be used to help prevent restricted growth. [nhs.uk]
Prevention Couples with genetic history can have genetic counseling before having children. 13. Conclusion 14. Reference Nightingale nursing times, volume 4, number 2, February 2009. [slideshare.net]
Early surgical revascularization should be pursued in order to prevent symptom progression. [ncbi.nlm.nih.gov]
Bruce Gelb, MD Professor of Pediatrics Mount Sinai School of Medicine New York NY Disclosures BG received royalties from GeneDx, Correlegan, Preventative Genetics, Baylor College of Medicine, and Harvard Medical School/Partners for genetic testing of [bestpractice.bmj.com]
Prevention Couples with a family history of Noonan syndrome may want to consider genetic counseling before having children. References Cooke DW, Divall SA, Radovick S. Normal and aberrant growth in children. [mountsinai.org]
References
- Romano AA, Allanson JE, Dahlgren J, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010;126:746-59.
- Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381:333-42.
- Rohrer T. Noonan syndrome: introduction and basic clinical features. Horm Res. 2009;72 Suppl 2:3-7.
- Roelofs RL, Janssen N, Wingbermühle E, Kessels RP, Egger JI. Intellectual development in Noonan syndrome: a longitudinal study. Brain Behav. 2016;6:e00479.
- Wilkinson JD, Lowe AM, Salbert BA, et al. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: A study from the Pediatric Cardiomyopathy Registry. Am Heart J. 2012;164:442-8.
- Baldassarre G, Mussa A, Dotta A, et al. Prenatal features of Noonan syndrome: prevalence and prognostic value. Prenat Diagn. 2011;31:949-54.
- Sznajer Y, Keren B, Baumann C, Pereira S, Alberti C, Elion J, Cavé H, Verloes A. The spectrum of cardiac anomalies in Noonan syndrome as a result of mutations in the PTPN11 gene. Pediatrics. 2007;119:e1325-31.
- Prendiville TW, Gauvreau K, Tworog-Dube E, Patkin L, Kucherlapati RS, Roberts AE, Lacro RV. Cardiovascular disease in Noonan syndrome. Arch Dis Child. 2014;99:629-34.
- Allanson JE, Roberts AE. Noonan Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from http://www.ncbi.nlm.nih.gov/books/NBK1124/
- Kouz K, Lissewski C, Spranger S, et al. Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation. Genet Med. 2016;18:1226-34.