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Noonan Syndrome
Introduction
Noonan syndrome is a genetically inherited disorder with heterogeneous phenotypic manifestations that can affect multiple organ systems. The severity of the presentation can vary from mild to severe and is characterized by a distinctive facial appearance, short stature, bleeding dyscrasias, cardiac issues, skeletal malformations, renal anomalies, lymphatic malformations, and other complications.[1]
The underlying genetic mechanism involves a disruption of the RAS-mitogen-activated protein kinase (MAPK) pathway—a cell-signaling pathway that transmits signals from the cell membrane to the nucleus and is one of the most studied pathways in molecular biology.[2] This condition is part of a family of genetically related disorders affecting this pathway, known as the RASopathies.[3] Although these conditions share similar genetic causes and organ system manifestations, each has its own distinct set of morbidities and prognoses.
Noonan syndrome is typically present at birth but is often diagnosed later in childhood when characteristic physical signs and symptoms become more apparent. In some cases, this condition may be diagnosed in infancy, especially if patients are born with congenital heart, lung, or hearing issues detected during postnatal screening examinations.[4][5]
Etiology
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Etiology
Noonan syndrome is a pleomorphic, autosomal dominant inherited disorder. Consequently, parents with Noonan syndrome have a 50% chance of passing the mutation on to their children. The condition has been associated with advanced paternal age, a phenomenon known as the paternal age effect, which is also observed in other RASopathies.[6]
Noonan syndrome can also occur from a de novo or sporadic mutation. The mutation in the RAS-MAPK pathway classifies Noonan syndrome as a RASopathy, with at least 8 distinct causative genetic mutations identified.[3][7]
Epidemiology
Noonan syndrome occurs in approximately 1 in 1000 to 2500 individuals. As the inheritance pattern is autosomal dominant, it affects both females and males equally. Males may present with cryptorchidism, which can lead to an earlier diagnosis. Noonan syndrome is observed across all ethnic groups at similar rates.[3][7]
Pathophysiology
RASopathies are a group of genetic syndromes caused by germline mutations in the RAS-MAPK pathway. These syndromes include cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type-1, Legius syndrome, and LEOPARD syndrome.[8] The RAS-MAPK pathway is crucial for cell division, proliferation, differentiation, and migration, making it essential for normal development and growth.
In Noonan syndrome, the most common mutation occurs in the PTPN11 gene.[9] A smaller portion of mutations occurs in SOS1, RAF1, and RIT1 genes. Mutations in the PTPN11 gene can be inherited in an autosomal dominant pattern or occur de novo through sporadic mutations. The genetic mutations are considered gain-of-function mutations, resulting in the inappropriate prolongation of RAS-MAPK signaling. This prolonged signaling pathway contributes to the pleomorphic characteristics observed in Noonan syndrome.[3][7]
Short stature in Noonan syndrome is believed to result from several potential mechanisms, including mild growth hormone resistance, growth hormone deficiency, or neurosecretory dysfunction. Low levels of insulin-like growth factor 1 compared to healthy, short children indicate partial growth hormone insensitivity, probably at a post-receptor level. The impaired RAS-MAPK pathway function in a subset of children may explain this. Additionally, other factors such as feeding problems or a cardiac defect may also contribute to short stature.[10][11]
History and Physical
Noonan syndrome presents with heterogeneous phenotypical manifestations that evolve with age. As an autosomal dominant inherited disorder, it is essential to inquire about any family history of Noonan syndrome. Additionally, a family history of congenital heart disease, bleeding disorders, lymphatic malformations, or congenital hearing loss should raise suspicion. A physical examination of the parents may reveal characteristic features of Noonan syndrome, even if a formal diagnosis has not yet been confirmed.[12] The most consistent physical findings include widely spaced eyes, low-set ears, short stature, and pulmonic stenosis. Diagnostic criteria have been established to aid in the diagnosis of Noonan syndrome.
Table. Diagnostic Criteria for Noonan Syndrome
| Features | A = Major | B = Minor |
| Facial | Typical facial dysmorphology (facial features vary with age) | Suggestive facial dysmorphology |
| Cardiac | Pulmonary valve stenosis, hypertrophic cardiomyopathy, and electrocardiographic results typical of Noonan syndrome | Other defects |
| Height | <3rd percentile | <10th percentile |
| Chest wall | Pectus carinatum or pectus excavatum | Broad thorax |
| Family history | First-degree relative with definite Noonan syndrome | First-degree relative with suggestive Noonan syndrome |
| Other features |
All of the following:
|
Any one of the following:
|
NOTE: A diagnosis of Noonan syndrome can be made under the following criteria:
- The patient has typical facial dysmorphology and at least 1 feature from categories 2A through 6A.
- The patient has typical facial dysmorphology and 2 features from categories 2B through 6B.
- The patient has suggestive facial dysmorphology and at least 2 features from categories 2A through 6A.
- The patient has suggestive facial dysmorphology and 3 features from categories 2B through 6B.
Adapted from van der Burgt I, Berends E, Lommen E, van Beersum S, Hamel B, Mariman E. Clinical and molecular studies in a large Dutch family with Noonan syndrome. Am J Med Genet. 1994;53(2):190.
Prenatal Presentation
Noonan syndrome is not typically included in routine antenatal genetic testing; however, one of its more common prenatal features is increased nuchal translucency in utero.[13] Increased nuchal translucency can also be associated with other conditions, such as Down syndrome. Additional manifestations of Noonan syndrome may include polyhydramnios due to renal anomalies; congenital heart defects; mild limb shortening; lymphatic malformations, formerly known as cystic hygroma; and fetal macrosomia.[14]
As mentioned earlier, the vague symptoms observed during the prenatal period can indicate various other conditions. Therefore, a high index of suspicion for Noonan syndrome is necessary. Noonan syndrome should be considered in fetuses with increased nuchal translucency, polyhydramnios, and cardiac abnormalities, especially when the karyotype is normal. In such cases, formal testing through chorionic villus sampling should be offered.[15]
Postnatal and Childhood Development
Many individuals with Noonan syndrome do not show clinical manifestations at birth. Although some individuals may present with macrosomia or macrocephaly, most individuals are born with normal weight and height. However, growth slows during childhood, and up to 60% of affected individuals have short stature by puberty.[16] Growth delay leading to short stature is one of the major diagnostic criteria and a common reason to seek medical consultation. Affected individuals typically present with borderline short stature, characterized by growth velocity parallel to the lowest centile on the growth chart.[10] Infants may experience feeding difficulties, leading to failure to thrive and delayed speech or motor milestones.[17] Congenital hearing loss or deafness may also be present.[18][19] Additionally, children with Noonan syndrome may have cognitive challenges, including attention and memory deficits, executive functioning impairments, and language development difficulties, independent of hearing status.[20][21]
Puberty: Puberty in individuals with Noonan syndrome is delayed and prolonged, with a limited pubertal spurt. As a result, final adult height is often reached in the late second decade or early third decade of life.[10] Adults with Noonan syndrome are typically described as having low-normal intelligence, often accompanied by reduced cognitive processing speed. Males may have cryptorchidism and face an increased risk of infertility, even in the absence of this diagnosis.[22] Most females are not at risk for infertility.[23] The most common congenital heart defects include pulmonic stenosis and hypertrophic cardiomyopathy, which may be detected during a routine physical examination depending on severity.[24][25] Pectus excavatum may present at birth or develop as the child ages and enters puberty.[26] Young individuals with Noonan syndrome, especially those with a mutation in the PTPN11 gene, are at an increased risk for juvenile myelomonocytic leukemia and other lymphoproliferative disorders.[27]
Adulthood: Distinct facial characteristics associated with Noonan syndrome develop in early childhood and evolve with age. These features include hypertelorism, low-set ears, blue irises, ptosis, mild neck webbing, a high forehead, down-slanting palpebral fissures, and epicanthic folds.[12] In adulthood, facial features often exhibit signs of premature aging, and a lengthened jaw can give the face a triangular shape.[28] Facial dysmorphia can be mild, and many reports indicate that Noonan syndrome is first diagnosed when a patient gives birth to a more severely affected child.[1]
Lymphatic dysplasia is a common condition that can lead to early-onset generalized lymphedema in the extremities and abdomen.[29] Patients may experience easy bruising or bleeding due to coagulopathy, which affects 50% to 89% of those with Noonan syndrome, with factor XI deficiency being the most common cause.[30] Young individuals with Noonan syndrome are at an increased risk of juvenile myelomonocytic leukemia and other myeloproliferative disorders, and an increased risk of malignancy, especially hematological malignancy, persists into adulthood.[31] Skeletal abnormalities such as pectus carinatum or excavatum are also commonly observed.[32][33][1]
Evaluation
Noonan syndrome is typically suspected based on physical examination, family history, and established clinical diagnostic criteria. Molecular genetic testing can be conducted to confirm the diagnosis. Once Noonan syndrome is diagnosed, various organ systems should be evaluated thoroughly.
Along with a comprehensive physical and neurological examination, the following evaluations should be considered:
Treatment / Management
Noonan syndrome is a genetically inherited condition with no cure. The treatment of this condition aims to improve symptoms and provide supportive care, with a multidisciplinary approach being standard practice. Multiple organ systems must be addressed. Hearing tests and ophthalmic exams are recommended throughout childhood. In males with cryptorchidism, orchiopexy should be performed around age 1, if the testes have not descended, to reduce the risk of developing testicular cancer in adulthood.[34](A1)
Echocardiogram and electrocardiography should be performed in patients with congenital heart defects. Even in patients without a diagnosis of cardiac defects, a cardiac evaluation is recommended every 5 years.
Short stature should be evaluated for potential growth hormone therapy. Recombinant human growth hormone has been approved by the Food and Drug Administration (FDA) since 2007 for treating short stature in individuals with Noonan syndrome. This treatment was recently approved by the European Medicines Agency in 2020. A recently published multicenter nationwide study with adult height data showed a mean gain of 1.4 SD in height, with safety documented for patients with hypertrophic cardiomyopathy.[35] Other adult height studies have shown an increase of 0.8 to 1.7 SD.[10] The negative impact of PTPN11 mutation on growth hormone response has been hypothesized in these children. However, a recent study specifically addressing this issue did not find any difference in the growth response among children with or without PTPN11 involvement.[36](B3)
The safety of human growth hormone therapy in individuals with Noonan syndrome has been a concern, as Noonan syndrome itself is a tumor predisposition condition, and human growth hormone, being a growth factor, may potentially increase this risk. Although there are a few case reports in the literature, the majority of studies have not shown an increase in the incidence of tumors in patients with Noonan syndrome treated with recombinant human growth hormone. However, in the absence of long-term studies specifically designed to address this outcome, surveillance should be continued.[10]
Appropriate supportive measures should be implemented to manage lymphedema.[1][37]
Differential Diagnosis
The differential diagnoses for Noonan syndrome are broad. Several other chromosomal abnormalities can present with a similar combination of symptoms, including congenital heart defects, short stature, and developmental delay.
Turner Syndrome
Noonan syndrome is often referred to as pseudo-Turner syndrome due to similarities with Turner syndrome.[38] Both syndromes are characterized by a webbed neck and short stature. However, Turner syndrome (45,X0) affects only females, as it involves an abnormality of the X chromosome. In contrast, Noonan syndrome affects both males and females, and the karyotype remains normal.[39]
Noonan syndrome is considered a RASopathy, as the genetic mutations affect the RAS-MAPK pathway. Other RASopathies share similar features to those observed in Noonan syndrome. These conditions include: [40]
- Cardiofaciocutaneous syndrome
- Costello syndrome
- Neurofibromatosis type-1
- Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome)
Prognosis
The prognosis for individuals with Noonan syndrome depends on the severity of their phenotype. The severity of any associated heart defects is closely linked to the patient's mortality and morbidity. However, many patients can expect an average lifespan with minimal morbidity.[1]
Complications
Complications associated with Noonan syndrome include developmental delays and cognitive deficits that can limit functionality, often necessitating aggressive support services. Physical complications may arise from severe cardiac abnormalities, such as valvular stenosis and hypertrophic cardiomyopathy, which require ongoing medical care. Additionally, some patients experience bleeding disorders, requiring frequent medical attention to manage bleeding diatheses.[41][42]
Consultations
Genetic counseling should be offered to patients and their families to provide support and guidance regarding the inheritance and management of Noonan syndrome.
Deterrence and Patient Education
Parents, and eventually patients, require supportive services to optimize development and provide a conducive environment for the affected individuals. Early referral to the specialized Noonan Syndrome Support Group is recommended, as it offers valuable resources and support for all patients.
Enhancing Healthcare Team Outcomes
The diagnosis and management of Noonan syndrome require an interprofessional healthcare team, including a geneticist, pediatrician, primary care provider, ENT surgeon, audiologist, ophthalmologist, and cardiologist. As Noonan syndrome is a genetically inherited disease with no cure, management focuses on symptomatic improvement and supportive care. Interprofessional care is essential, as multiple organ systems need attention.
Regular hearing tests and ophthalmic examinations should be conducted throughout childhood. In males with cryptorchidism, orchiopexy is recommended around age 1 if the testes have not descended. This procedure is performed to help reduce the risk of testicular cancer in adulthood. For congenital heart defects, echocardiography and electrocardiography are recommended. A cardiac evaluation should be performed every 5 years, even for patients without a cardiac diagnosis. Short stature can be assessed for potential growth hormone treatment, and appropriate supportive measures can be implemented to manage lymphedema.[43][44][45][37]
References
Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet (London, England). 2013 Jan 26:381(9863):333-42. doi: 10.1016/S0140-6736(12)61023-X. Epub 2013 Jan 10 [PubMed PMID: 23312968]
Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2006 Jan:1(1):7-9 [PubMed PMID: 17409820]
Rauen KA. The RASopathies. Annual review of genomics and human genetics. 2013:14():355-69. doi: 10.1146/annurev-genom-091212-153523. Epub 2013 Jul 15 [PubMed PMID: 23875798]
Level 3 (low-level) evidenceRomano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010 Oct:126(4):746-59. doi: 10.1542/peds.2009-3207. Epub 2010 Sep 27 [PubMed PMID: 20876176]
Dendrinou GE, Zagarelos P, Sofronas A, Katsenos S. Primary pulmonary lymphangiectasia in Noonan syndrome: apropos of an extremely rare manifestation and a brief literature review. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace. 2020 Dec 10:90(4):. doi: 10.4081/monaldi.2020.1576. Epub 2020 Dec 10 [PubMed PMID: 33305557]
Tartaglia M, Cordeddu V, Chang H, Shaw A, Kalidas K, Crosby A, Patton MA, Sorcini M, van der Burgt I, Jeffery S, Gelb BD. Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. American journal of human genetics. 2004 Sep:75(3):492-7 [PubMed PMID: 15248152]
Myers A, Bernstein JA, Brennan ML, Curry C, Esplin ED, Fisher J, Homeyer M, Manning MA, Muller EA, Niemi AK, Seaver LH, Hintz SR, Hudgins L. Perinatal features of the RASopathies: Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome. American journal of medical genetics. Part A. 2014 Nov:164A(11):2814-21. doi: 10.1002/ajmg.a.36737. Epub 2014 Sep 22 [PubMed PMID: 25250515]
Level 3 (low-level) evidenceGelb BD, Yohe ME, Wolf C, Andelfinger G. New prospectives on treatment opportunities in RASopathies. American journal of medical genetics. Part C, Seminars in medical genetics. 2022 Dec:190(4):541-560. doi: 10.1002/ajmg.c.32024. Epub 2022 Dec 19 [PubMed PMID: 36533679]
Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, Boute O, Gaillard D, Lacombe D, Layet V, Marlin S, Mortier G, Toutain A, Beylot C, Baumann C, Verloes A, Cavé H, French Collaborative Noonan Study Group. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. Journal of medical genetics. 2004 Nov:41(11):e117 [PubMed PMID: 15520399]
Rodríguez F, Gaete X, Cassorla F. Etiology and Treatment of Growth Delay in Noonan Syndrome. Frontiers in endocrinology. 2021:12():691240. doi: 10.3389/fendo.2021.691240. Epub 2021 Jun 4 [PubMed PMID: 34149626]
Bertelloni S, Baroncelli GI, Dati E, Ghione S, Baldinotti F, Toschi B, Simi P. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens, Greece). 2013 Jan-Mar:12(1):86-92 [PubMed PMID: 23624134]
Zenker M, Edouard T, Blair JC, Cappa M. Noonan syndrome: improving recognition and diagnosis. Archives of disease in childhood. 2022 Dec:107(12):1073-1078. doi: 10.1136/archdischild-2021-322858. Epub 2022 Mar 4 [PubMed PMID: 35246453]
Tangshewinsirikul C, Wattanasirichaigoon D, Tim-Aroon T, Promsonthi P, Katanyuwong P, Diawtipsukon S, Chansriniyom N, Tongsong T. Prenatal Sonographic Features of Noonan Syndrome: Case Series and Literature Review. Journal of clinical medicine. 2024 Sep 26:13(19):. doi: 10.3390/jcm13195735. Epub 2024 Sep 26 [PubMed PMID: 39407794]
Level 2 (mid-level) evidenceJian W, Yuan H, Liu Y, Sun J, Chen F, Li Y, Chen M. Prenatal diagnosis of Noonan syndrome in a set of monozygotic twins- a case report. BMC pregnancy and childbirth. 2023 Jan 6:23(1):10. doi: 10.1186/s12884-022-05323-5. Epub 2023 Jan 6 [PubMed PMID: 36609239]
Level 3 (low-level) evidenceBakker M, Pajkrt E, Mathijssen IB, Bilardo CM. Targeted ultrasound examination and DNA testing for Noonan syndrome, in fetuses with increased nuchal translucency and normal karyotype. Prenatal diagnosis. 2011 Sep:31(9):833-40. doi: 10.1002/pd.2782. Epub 2011 Jun 27 [PubMed PMID: 21706501]
Croonen EA, Draaisma JMT, van der Burgt I, Roeleveld N, Noordam C. First-year growth in children with Noonan syndrome: Associated with feeding problems? American journal of medical genetics. Part A. 2018 Apr:176(4):951-958. doi: 10.1002/ajmg.a.38649. Epub [PubMed PMID: 29575624]
Rippert AL, Reef R, Mani A, Stefanatos AK, Ahrens-Nicklas RC. Longitudinal outcomes in Noonan syndrome. Genetics in medicine : official journal of the American College of Medical Genetics. 2025 Apr:27(4):101355. doi: 10.1016/j.gim.2025.101355. Epub 2025 Jan 11 [PubMed PMID: 39807623]
Gao X, Huang SS, Qiu SW, Su Y, Wang WQ, Xu HY, Xu JC, Kang DY, Dai P, Yuan YY. Congenital sensorineural hearing loss as the initial presentation of PTPN11-associated Noonan syndrome with multiple lentigines or Noonan syndrome: clinical features and underlying mechanisms. Journal of medical genetics. 2021 Jul:58(7):465-474. doi: 10.1136/jmedgenet-2020-106892. Epub 2020 Jul 31 [PubMed PMID: 32737134]
Level 2 (mid-level) evidenceCremers CW, van der Burgt CJ. Hearing loss in Noonan syndrome. International journal of pediatric otorhinolaryngology. 1992 Jan:23(1):81-4 [PubMed PMID: 1592554]
Roelofs RL, Janssen N, Wingbermühle E, Kessels RP, Egger JI. Intellectual development in Noonan syndrome: a longitudinal study. Brain and behavior. 2016 Jul:6(7):e00479. doi: 10.1002/brb3.479. Epub 2016 May 3 [PubMed PMID: 27247851]
Wingbermühle E, Roelofs RL, van der Burgt I, Souren PM, Verhoeven WM, Kessels RP, Egger JI. Cognitive functioning of adults with Noonan syndrome: a case-control study. Genes, brain, and behavior. 2012 Oct:11(7):785-93. doi: 10.1111/j.1601-183X.2012.00821.x. Epub 2012 Aug 10 [PubMed PMID: 22783933]
Level 2 (mid-level) evidenceOrsolini F, Pignata L, Baldinotti F, Romano S, Tonacchera M, Canale D. Gonadal dysfunction in a man with Noonan syndrome from the LZTR1 variant: case report and review of literature. Frontiers in endocrinology. 2024:15():1354699. doi: 10.3389/fendo.2024.1354699. Epub 2024 Apr 16 [PubMed PMID: 38689733]
Level 3 (low-level) evidenceEdouard T, Cartault A. Gonadal function in Noonan syndrome. Annales d'endocrinologie. 2022 Jun:83(3):203-206. doi: 10.1016/j.ando.2022.04.008. Epub 2022 Apr 27 [PubMed PMID: 35489412]
Linglart L, Gelb BD. Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment. American journal of medical genetics. Part C, Seminars in medical genetics. 2020 Mar:184(1):73-80. doi: 10.1002/ajmg.c.31765. Epub 2020 Feb 5 [PubMed PMID: 32022400]
Kriz C, Flores S, Villarreal EG, Bronicki RA, Loomba RS. Impact of Noonan Syndrome on admissions for pediatric cardiac surgery. Minerva pediatrics. 2022 Aug:74(4):461-467. doi: 10.23736/S2724-5276.19.05461-6. Epub 2019 Jun 28 [PubMed PMID: 31264394]
Cobben JM, Oostra RJ, van Dijk FS. Pectus excavatum and carinatum. European journal of medical genetics. 2014 Aug:57(8):414-7. doi: 10.1016/j.ejmg.2014.04.017. Epub 2014 May 10 [PubMed PMID: 24821303]
Arrabito M, Li Volsi N, La Rosa M, Samperi P, Pulvirenti G, Cannata E, Russo G, Di Cataldo A, Lo Nigro L. Transient Myeloproliferative Disorder (TMD), Acute Lymphoblastic Leukemia (ALL), and Juvenile Myelomonocytic Leukemia (JMML) in a Child with Noonan Syndrome: Sequential Occurrence, Single Center Experience, and Review of the Literature. Genes. 2024 Sep 10:15(9):. doi: 10.3390/genes15091191. Epub 2024 Sep 10 [PubMed PMID: 39336782]
Dahlgren J, Noordam C. Growth, Endocrine Features, and Growth Hormone Treatment in Noonan Syndrome. Journal of clinical medicine. 2022 Apr 5:11(7):. doi: 10.3390/jcm11072034. Epub 2022 Apr 5 [PubMed PMID: 35407641]
Swarts JW, Kleimeier LER, Leenders EKSM, Rinne T, Klein WM, Draaisma JMT. Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study. American journal of medical genetics. Part A. 2022 Nov:188(11):3242-3261. doi: 10.1002/ajmg.a.62955. Epub 2022 Aug 18 [PubMed PMID: 35979676]
Level 2 (mid-level) evidenceBriggs BJ, Dickerman JD. Bleeding disorders in Noonan syndrome. Pediatric blood & cancer. 2012 Feb:58(2):167-72. doi: 10.1002/pbc.23358. Epub 2011 Oct 19 [PubMed PMID: 22012616]
Ney G, Gross A, Livinski A, Kratz CP, Stewart DR. Cancer incidence and surveillance strategies in individuals with RASopathies. American journal of medical genetics. Part C, Seminars in medical genetics. 2022 Dec:190(4):530-540. doi: 10.1002/ajmg.c.32018. Epub 2022 Dec 19 [PubMed PMID: 36533693]
van der Burgt I. Noonan syndrome. Orphanet journal of rare diseases. 2007 Jan 14:2():4 [PubMed PMID: 17222357]
Bhambhani V, Muenke M. Noonan syndrome. American family physician. 2014 Jan 1:89(1):37-43 [PubMed PMID: 24444506]
Chan E,Wayne C,Nasr A, Ideal timing of orchiopexy: a systematic review. Pediatric surgery international. 2014 Jan; [PubMed PMID: 24232174]
Level 1 (high-level) evidenceŞıklar Z, Berberoğlu M, Kızılcan Çetin S, Yıldız M, Turan S, Darcan Ş, Çetinkaya S, Hatipoğlu N, Yıldırım R, Demir K, Vermezoğlu Ö, Yavaş Abalı Z, Özalp Kızılay D, Görkem Erdoğan N, Şiraz ÜG, Orbak Z, Özgen İT, Bideci A, Selver Eklioğlu B, Karakılıç Özturan E, Tarçın G, Bereket A, Darendeliler F. Evaluation of Growth Characteristics and Final Height of Cases Diagnosed with Noonan Syndrome on Growth Hormone Treatment. Journal of clinical research in pediatric endocrinology. 2025 Mar 19:17(1):76-86. doi: 10.4274/jcrpe.galenos.2024.2024-7-3. Epub 2024 Oct 8 [PubMed PMID: 39377546]
Level 3 (low-level) evidenceJorge AAL, Edouard T, Maghnie M, Pietropoli A, Kelepouris N, Romano A, Zenker M, Horikawa R. Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status. Endocrine connections. 2022 Apr 15:11(4):. pii: e210615. doi: 10.1530/EC-21-0615. Epub 2022 Apr 15 [PubMed PMID: 35245205]
Moniez S, Pienkowski C, Lepage B, Hamdi S, Daudin M, Oliver I, Jouret B, Cartault A, Diene G, Verloes A, Cavé H, Salles JP, Tauber M, Yart A, Edouard T. Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency. European journal of endocrinology. 2018 Dec 1:179(6):409-418. doi: 10.1530/EJE-18-0582. Epub [PubMed PMID: 30325180]
Chacko E, Graber E, Regelmann MO, Wallach E, Costin G, Rapaport R. Update on Turner and Noonan syndromes. Endocrinology and metabolism clinics of North America. 2012 Dec:41(4):713-34. doi: 10.1016/j.ecl.2012.08.007. Epub 2012 Sep 28 [PubMed PMID: 23099266]
Carcavilla A, Suárez-Ortega L, Rodríguez Sánchez A, Gonzalez-Casado I, Ramón-Krauel M, Labarta JI, Quinteiro Gonzalez S, Riaño Galán I, Ezquieta Zubicaray B, López-Siguero JP. [Noonan syndrome: genetic and clinical update and treatment options]. Anales de pediatria. 2020 Jul:93(1):61.e1-61.e14. doi: 10.1016/j.anpedi.2020.04.008. Epub 2020 May 31 [PubMed PMID: 32493603]
Hebron KE, Hernandez ER, Yohe ME. The RASopathies: from pathogenetics to therapeutics. Disease models & mechanisms. 2022 Feb 1:15(2):. doi: 10.1242/dmm.049107. Epub 2022 Feb 18 [PubMed PMID: 35178568]
Briggs B, Savla D, Ramchandar N, Dimmock D, Le D, Thornburg CD. The Evaluation of Hematologic Screening and Perioperative Management in Patients with Noonan Syndrome: A Retrospective Chart Review. The Journal of pediatrics. 2020 May:220():154-158.e6. doi: 10.1016/j.jpeds.2020.01.048. Epub 2020 Feb 25 [PubMed PMID: 32111381]
Level 2 (mid-level) evidenceYamamoto M, Takashio S, Nakashima N, Hanatani S, Arima Y, Sakamoto K, Yamamoto E, Kaikita K, Aoki Y, Tsujita K. Double-chambered right ventricle complicated by hypertrophic obstructive cardiomyopathy diagnosed as Noonan syndrome. ESC heart failure. 2020 Apr:7(2):721-726. doi: 10.1002/ehf2.12650. Epub 2020 Feb 20 [PubMed PMID: 32078254]
Koh AL, Tan ES, Brett MS, Lai AHM, Jamuar SS, Ng I, Tan EC. The spectrum of genetic variants and phenotypic features of Southeast Asian patients with Noonan syndrome. Molecular genetics & genomic medicine. 2019 Apr:7(4):e00581. doi: 10.1002/mgg3.581. Epub 2019 Feb 19 [PubMed PMID: 30784236]
Gurovich Y, Hanani Y, Bar O, Nadav G, Fleischer N, Gelbman D, Basel-Salmon L, Krawitz PM, Kamphausen SB, Zenker M, Bird LM, Gripp KW. Identifying facial phenotypes of genetic disorders using deep learning. Nature medicine. 2019 Jan:25(1):60-64. doi: 10.1038/s41591-018-0279-0. Epub 2019 Jan 7 [PubMed PMID: 30617323]
Hemmati P, Dearani JA, Daly RC, King KS, Ammash NM, Cetta F, Schaff HV. Early Outcomes of Cardiac Surgery in Patients with Noonan Syndrome. Seminars in thoracic and cardiovascular surgery. 2019 Autumn:31(3):507-513. doi: 10.1053/j.semtcvs.2018.12.004. Epub 2018 Dec 18 [PubMed PMID: 30576779]